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Annual Review of Immunology
Annu. Rev. Immunol. 2008.26:1-28. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:1-28. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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Contents
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Doing What I Like
Annu. Rev. Immunol. 2008.26:1-28. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
K. Frank Austen Department of Medicine, Harvard Medical School, Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Boston, Massachusetts 02115; email:
[email protected] Annu. Rev. Immunol. 2008. 26:1–28
Key Words
First published online as a Review in Advance on September 17, 2007
slow reacting substance of anaphylaxis, mast cell, alternative complement pathway, cysteinyl leukotrienes, mast cell progenitors
The Annual Review of Immunology is online at immunol.annualreviews.org This article’s doi: 10.1146/annurev.immunol.26.021607.090339 c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0001$20.00
Abstract I have spent my entire professional life at Harvard Medical School, beginning as a medical student. I have enjoyed each day of a diverse career in four medical subspecialties while following the same triad of preclinical areas of investigation—cysteinyl leukotrienes, mast cells, and complement—with occasional translational opportunities. I did not envision a career with a predominant preclinical component. Such a path simply evolved because I chose instinctively at multiple junctures to follow what proved to be propitious opportunities. My commentary notes some of the highlights for each area of interest and the mentors, collaborators, and trainees whose counsel has been immensely important at particular intervals or over an extended period.
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EARLY CAREER DETERMINANTS
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In 1946, after I graduated from high school, I was hospitalized with paralytic poliomyelitis. Although I was spared respiratory involvement, I experienced a loss and gradual recovery of strength in my extremities. I vividly recall the lumbar puncture on admission, the hospital-based management of the muscular discomfort with “hot packs,” and exercising with my mother’s cooking weights after discharge. The hospitalization prevented my entry into Amherst College with my class but did lead to one spring and three summer semesters at Akron University. I concentrated on the physical sciences at Akron University and finished Amherst College on schedule. It was this illness that prompted me to envision a career in medicine. Thus, I set serious academic goals for my Amherst years, whereas during high school, my studies had been secondary to sports. I majored in both chemistry and biology, as biochemistry did not have department status. My honors thesis, entitled “The Structure and Synthesis of Certain Uracil Analogs,” was directed to development of dietary inhibitors of Tetrahymena geleii. My remembrances of my student years at Harvard Medical School (HMS) are highlighted by three very different events. One was a contact from the Admissions Committee via a professor of gross anatomy to ask whether the selection of my brother, W. Gerald Austen, a senior at MIT majoring in mechanical engineering, for the next entering class would negatively affect my academic performance. Gerry and I shared a dormitory room for the next three years and pooled our advance yearly tuition to purchase a car in the fall, which we sold in a timely manner in the spring. Our competitive natures maximized our individual performances. The second event was a rather complex episode in which I and some old friends from Amherst College acquired a sheep from the Biophysics Department late one evening, which we then
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slipped into the dormitory and introduced during intermission at the annual first-year dance. At 3:00 am, a security officer knocked on my door with an offer to forget what had occurred if I would quietly collect and return the sheep to its campus location. The third and most important remembrance relates to my exposure to Cliff Barger of the Physiology Department. He involved students in meaningful laboratory experimentation that required both technical skill and the ability to understand and analyze the observations being recorded. The experiments led students to an understanding of certain principles of renal physiology. Many years later, when I was preparing a presidential address to the American Association of Immunologists, I borrowed what I had learned from Dr. Barger about homeostasis. The talk, entitled “Homeostasis of Effector Systems Which Can Also Be Recruited for Immunologic Reactions,” noted the remarkable array of negative regulators for the inflammatory functions of the complement pathway as well as those for activated cell types in IgE-mediated reactions (1). In 1954, after completing medical school, I became one of 12 interns in internal medicine at the Massachusetts General Hospital (MGH). In contrast to my colleagues, I had never heard of the NIH, and thus, I was the only one to enter into the Berry Plan to meet my two years of obligated military service. At the end of my internship year, there was a major outbreak of poliomyelitis in the Boston area, and the two hospitals that conventionally accepted affected patients reached saturation. At that point, the MGH decided to fill a major medical need by accepting these patients. As there was no one at the MGH with particular expertise in the management of patients with poliomyelitis, Dr. Walter Bauer, Chief of Medicine, asked two of the newly minted assistant residents, Jan Koch-Weser and me, to take responsibility for managing what he assumed would be a small polio service. In a relatively short time, the MGH had hundreds of admissions, and we became
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responsible for those patients cared for in iron lungs. No one else was permitted to write orders for these patients. Patients and their families were somewhat encouraged by the fact that I had had polio, whereas I was most distressed by the substantial mortality rate of individuals approximately my own age. While using positive pressure to force the flow of air into the lungs of a patient with poliomyelitis in the interval when the linens were being changed in the iron lung, I noted an improvement in his skin color and blood pressure, suggesting better oxygenation. By comparing an arterial oxygen determination made with the patient inside the machine, which applied negative pressure to suck air in versus that during a positive pressure period, I noted that the patient had marked hypoxia while in the iron lung. This condition had not been recognized owing to the limited facial exposure and congestion from the collar around the patient’s neck when in the iron lung. By removing patients from the iron lung and breathing them with a positive pressure method, we prevented any further deaths from vascular collapse. As a result, I published a paper in the New England Journal of Medicine (NEJM ) (2) while a house officer and learned that dogma based on existing knowledge could be incorrect. The dogma was that these patients died of midbrain damage from the virus, whereas the real cause was inadequate lung function. The latter was correctly termed a ventilation-perfusion pulmonary mismatch many years later by Jeffrey Drazen when he presented me with the Kober Medal from the American Association of Physicians (3). A second NEJM paper with two microbiologists focused on the intercurrent respiratory infections in bulbospinal poliomyelitis (4). While on the neurology service later in the year, I recognized that individuals with pulmonary insufficiency and CO2 necrosis had not only a disorder of consciousness but also a tremor, termed asterixis, and papilledema. This insight arose from my reading about hypoxia while on the polio service and led to another publication in the NEJM (5).
Dr. Bauer had arranged for me to be assigned to direct a Rheumatology Service at Walter Reed Army Hospital during my obligated military service. However, during basic training, my credentials were reviewed, and the decision at Fort Sam Houston based on my three NEJM publications was that I should proceed to the Walter Reed Army Institute of Research. I was immensely fortunate to be assigned to Elmer L. Becker, MD, PhD, who had discovered that the first component of guinea pig complement was an enzyme with esterase activity. He introduced me to the discipline of immunology and to the view that immunologic reactions initiate biochemical events. At the same time, I was required to meet my second set of orders to the hospitalbased Rheumatology Service and studied the effects on patients of aspirin at a dose that uncoupled oxidative phosphorylation and raised the metabolic rate (6, 7). On returning to the MGH as a medical resident in l958, I received my first NIH grant, which provided me with technical support to shift the studies begun with Dr. Becker to human serum (8). Dr. Becker provided the recommendation essential for acceptance into the immunology laboratory directed by John Humphrey at the National Institute for Medical Research in Mill Hill, England, and the NIH provided a fellowship. I decided to join that laboratory because I hoped to develop a program to learn how immunologic reactions initiated biochemical events that, in turn, had biologic implications. It occurred to me that the immunologic release of histamine from mast cells (MCs) might afford the in vitro model that I sought. John Humphrey was isolating rat MCs from the peritoneal cavity with density gradients, and his colleague, Walter Brocklehurst, was studying the antigeninduced release of histamine and slow reacting substance of anaphylaxis (SRS-A) from sensitized guinea pig lung. That histamine release was a biochemical process rather than an exchange with external cations seemed likely based on the reported calcium and temperature dependence of this reaction. An www.annualreviews.org • Doing What I Like
MC: mast cell SRS-A: slow reacting substance of anaphylaxis
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unanticipated bonus was my introduction to SRS-A, a material that constricted guinea pig airways in an isolated heart-lung preparation and was not inhibited by antihistamines. I knew that antihistamines were efficacious for treating allergic rhinitis but not bronchial asthma, and I had the instinctive feeling that SRS-A might be a mediator of airways constriction in bronchial asthma. Brocklehurst had developed the first bioassay to measure both histamine and SRS-A in the diffusate of antigen-challenged guinea pig lung fragments. Histamine, which elicited distinct rapid contractions of guinea pig ileal smooth muscle in an organ bath, was measured first. Then the ileal muscle was rendered unresponsive to histamine with an antihistamine, and the samples were reassessed for their content of SRS-A, which elicited a slow, progressive contraction. These studies led to three publications with Dr. Brocklehurst in the Journal of Experimental Medicine (9–11). The work with John Humphrey on isolated rat MCs resulted in a collaboration with another visitor, Herbert Rapp (12), who felt that I should have yet another fellowship to learn formal immunochemistry in the laboratory of Manfred Mayer at Johns Hopkins. In July 1961, I returned to the MGH to serve one year as Dr. Bauer’s chief medical resident. During that year, the physician responsible for the subspecialty of infectious diseases had a sabbatical, and Dr. Bauer assigned me the additional task of answering the consults in infectious diseases. He observed that I had had experience in managing microbial infections in patients with bulbospinal polio and understood the host through immunology. He added that Louis Weinstein, a distinguished infectious diseases clinician elsewhere in Boston, would make weekly rounds with me to facilitate my education and to advise on difficult cases. After completing the chief residency, I had a period with Manfred Mayer and Herb Rapp in the Microbiology Department at Johns Hopkins during which we demonstrated the enzymatic activity of the first complement component (C1) on one of its natu-
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C: complement (used only with numbers to indicate components)
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ral substrates, the second component (C2), by immunochemical techniques (13). This work was particularly rewarding since during my time with Elmer Becker, the Mayer group had openly doubted the acetyltyrosine esterase activity Becker had reported for C1. My departure from Hopkins after only six months was somewhat precipitous. Walter Bauer had entered into pulmonary failure from emphysema, and he asked me to share the responsibility for his care with his personal physician. To the extent that Dr. Bauer could talk when we unplugged the tracheotomy, he focused on issues of academic medicine, my career development, and my family. He left me his desk, which I treasure in my home. After three years as a faculty member of the Infectious Disease group, I was asked by Robert Ebert, Chairman of Medicine, to become chief of the Pulmonary Unit. The rationale was that I was Board-certified in allergy and immunology, had experience in infectious diseases, had some knowledge of pulmonary function from my polio duties, and had a laboratory interest pertinent to bronchial asthma. The Pulmonary Unit was housed in new facilities and appreciably increased our laboratory space. The space contained a new cyclotron, a machine I did not understand and never used, for a physician-scientist who never appeared. My new responsibilities to pulmonary medicine energized my interest in one human disease, bronchial asthma, and reinforced my goal to study SRS-A.
BECOMING A DEPARTMENT In 1966, when Robert Ebert was appointed dean of HMS, he suggested that my immunology program would benefit if I moved closer to the HMS campus as physician-inchief of the Robert B. Brigham Hospital (RBBH), a small institution entirely committed to the subspecialty of rheumatology. By now, I had been clinically active in infectious diseases and in pulmonary diseases at the MGH and in rheumatology during my service at the Walter Reed Army Hospital,
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although my only subspecialty certification was in allergy and immunology. I requested support to recruit two colleagues with different research backgrounds in immunology so that we could offer a coherent and broadly based training program. John R. David and I had been house officers together at the MGH and had encountered each other again when we were postdoctoral fellows in England, albeit at different institutions. His expertise was in cell-mediated immunity, whereas mine was in antibody-mediated events. Peter Schur, who had also trained with Elmer Becker during his military service and then with Henry Kunkel, conducted clinical research, whereas John David and I were working with in vitro systems. The goal for the three of us in 1966 was to form a cohesive, yet technically diverse program through which to facilitate our individual research and improve our postdoctoral mentoring. The RBBH allocated all its research space to our program and had a patient base that allowed us to engage in clinical teaching as well as research. As John David, Peter Schur, and I not only shared common training experiences but also had the same goals for the department, its administrative structure was flat. In the early 1970s, I was invited to take a chairmanship and historical chair of medicine at a school that at one time would have been my life’s goal. To my own astonishment, I made a decision that profoundly changed my career path. I found that my commitment to my personal research and my enjoyment of our developing department were so great that I preferred to remain at the RBBH. I would not again seriously consider becoming a chairman or accepting another major administrative task elsewhere. My decision to remain at the RBBH was driven by the knowledge that becoming a proper chairman would end my opportunity to unravel the aspects of the inflammatory response that seemed so intriguing and yet approachable. In 1974, our Rheumatology and Immunology program at the RBBH was granted departmental appointing status at HMS for ap-
proximately 20 years. This decision meant that promotions and appointments could be discussed directly with the HMS dean and further assured the development of our enterprise. Although we had significant clinical and teaching responsibilities, they were elective. Thus, we had an optimal amount of time for research. However, as we were not a line department within the structure of HMS, we also had no budget from the school and were almost entirely responsible for our own funding. Thus, the department was dynamic and was supported almost entirely by the peer review process. We enjoyed a continued influx of outstanding trainees, who progressed to faculty rank and then were recruited away at higher rank to fine schools and teaching hospitals. We began to attract individuals with PhDs who were interested in the integrated biology of the inflammatory response. Over time, the MD faculty was enriched with fulltime clinical scholars and the laboratory faculty with PhD-trained investigators who often had received their postdoctoral training in the department. This combination of faculty improved our shared and ever-evolving technology and added to the quality of the training program. While at the MGH, I had begun to collaborate with Albert L. Sheffer in the study of patients with hereditary angioedema (HAE) due to a lack of a functional inhibitor of the first component of complement (ClINH). After my appointment to the RBBH, we continued to study the roles of the complement system in HAE and the MC in patients with physical allergies. Indeed, the triad of complement, MC, and SRS-A research favored translational research in allergy and asthma over other medical applications. Thus, we added a training program in allergy and immunology and, in 1971, were funded as one of the seven initial Asthma and Allergic Diseases Centers conceived by the NIAID. At the same time, with the history and focus of the RBBH on the medical and surgical care of patients with arthritic diseases, we had a training grant in rheumatology www.annualreviews.org • Doing What I Like
HAE: hereditary angioedema
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and a Clinical Research Center supported by the NIAMD. HMS appointed me the first incumbent of the Theodore Bevier Bayles Professorship in 1972; and in 1974, I was elected to the National Academy of Sciences and the American Academy of Arts and Sciences. In the background during the 1970s was the merger of the RBBH with the Peter B. Brigham Hospital (PBBH) and the Boston Hospital for Women (BHW). I chaired a committee composed of two physicians and one administrator from each of the hospitals to work out the new bylaws. There was also much to do in the community to acquire a Certificate of Need so that construction could proceed for what is now known as the Brigham and Women’s Hospital (BWH). Although our department benefited greatly from being the focus of the RBBH, we sought the merger because of concern that a subspecialty hospital built on the need for in-patient care would not thrive with the changing paradigms and increasing complexity of medical and surgical care. As our three laboratories continued to expand, we began to appreciate that the benefits from the cohesion of our setting were perhaps mitigated by its off-site location. Again, Dean Ebert played a key role in my life. He suggested that the RBBH and the BHW gift HMS the matching funds needed to build the Seeley G. Mudd Building on the HMS campus. The cost of our space would be discounted, and we would have state-of-theart new laboratories on the quadrangle adjacent to the new medical center encompassing the merged hospitals. Hence, in 1977, after 11 years at the RBBH, we moved to the campus of HMS. With the transfer of our clinical activities to the BWH, we retained our status as a separate appointing Department of Medicine at HMS, but for clarity we were designated as the Department of Rheumatology and Immunology within the BWH. In 1987, Dean Dan Tosteson funded the K. Frank Austen Professorship of Medicine with a gift from David A. Jones and the Humana Foundation. After a typical, somewhat
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long HMS search, Michael Brenner, MD, was appointed to the K. Frank Austen Professorship in 1991. In 1995, our department became a division of the Department of Medicine of HMS at the BWH with Dr. Brenner as chair. Over three decades, our program had grown from four full-time and seven parttime faculty members with five postdoctoral fellows to 55 full-time and 6 part-time faculty members with 45 fellows. Two years later, we moved from the Seeley G. Mudd Building to an expanded site in the Dana-Farber Cancer Institute. Michael Brenner added “Allergy” to the name of the division, and from 1995 onward I have focused on the formal development of that program with Al Sheffer. As I did previously for rheumatology, this effort has meant developing the needed laboratory-based and clinically oriented faculty directly from our training program. As the Bayles Chair was named for a distinguished RBBH rheumatologist, it was appropriate to transfer that chair to Dr. Brenner and for me to take a new chair directed to inflammation and respiratory diseases.
THE LABORATORY TRIAD: SRS-A/CYSTEINYL LEUKOTRIENES, MAST CELLS, AND COMPLEMENT As I was learning about SRS-A from Walter Brocklehurst and MCs from John Humphrey, Rodney Porter and others were unraveling the structure of antibody through protein chemistry. Perhaps because of my four years of training in internal medicine, I believed that interventions for the outcome or inflammatory side of immune injury would precede any development of therapies for the recognition side. As I also wished to maintain a clinical life, I felt that it would be best to work in areas relevant to a clinical question. Only later did I recognize the additional requirement that these questions needed to be addressed with state-of-the-art technology. Happily, because I entered these research areas at such an
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early point, I could add the needed technology in a workable time frame that also allowed for a clinical life. Indeed, the latter stimulated my bench research. The three inflammatory components—mast cells, cysteinyl leukotrienes, and complement—that retained my interest all intersect with one another, providing occasional insights into parts of an integrated host inflammatory response. Nonetheless, the Study Section that awarded me a 10-year merit-based grant included the message that I could not in the future aggregate three strong areas into a single RO1. Below are my observations on each area, from the early years to the present.
THE CYSTEINYL LEUKOTRIENES (SRS-A) We now know that SRS-A, an antihistamineresistant constrictor of smooth muscle that is released from antigen-challenged guinea pig and human lung, is a mediator of bronchial asthma. We also know that the substance originally termed SRS-A was in fact composed of three cysteinyl leukotrienes (cysLTs): the biosynthetic intracellular product, leukotriene C4 (LTC4 ), and its extracellular metabolites, LTD4 and LTE4 . A limited number of cell types including MCs, eosinophils, basophils, and monocyte/macrophages possess the full biosynthetic pathway for LTC4 . Arachidonic acid released from the outer nuclear membrane by cytosolic phospholipase A2 (cPLA2 /type IV PLA2 ) in the presence of 5-lipoxygenase (5-LO) activating protein (FLAP) is converted sequentially by 5LO into 5-hydroperoxy-eicosatetraenoic acid (5HPETE) and LTA4 . LTA4 is then conjugated to reduced glutathione (GSH) to form LTC4 by LTC4 synthase (LTC4 S), an integral outer nuclear membrane protein. After carrier-mediated export of LTC4 , the cleavage removal of glutamic acid and then glycine from the GSH moiety provides the metabolites, LTD4 and LTE4 . The functions of the cys-LTs, which extend well beyond their historical smooth muscle–constricting action on
airways and microvasculature to include a range of leukocyte responses, are mediated by two known receptors, the CysLT1 and CysLT2 receptors. The structural definition of SRS-A as a conjugate of a cysteine-containing peptide and a metabolite of arachidonic acid, termed LTC4 , by Robert (Bob) Murphy with Sven Hammarstrom and Bengt Samuelsson (14) in 1979 profoundly changed the direction of my work. Through collaboration with E.J. Corey of the Chemistry Department of Harvard University, we immediately had synthetic LTC4 and then its metabolites, LTD4 and LTE4 , for pharmacologic studies in animals and humans. The use of these products to standardize an analytic reverse phase–high performance liquid chromatography (RP-HPLC) system allowed the identification of LTC4 , LTD4 , and LTE4 in complex biologic mixtures; the characterization of their extracellular inactivation; the purification of native human LTC4 S from lung; and, most important, the construction of a novel assay for expression cloning of human LTC4 S. As we had previously addressed such areas as the cell sources and immunoglobulin (Ig) classes involved in SRS-A generation and the physicochemical characteristics (with Robert Murphy) and pharmacologic actions (with Jeffrey Drazen) of SRS-A, our studies with SRSA/cys-LTs can be divided into those before and those after the structure was known.
cys-LT: cysteinyl leukotriene LTC4 S: leukotriene C4 synthase CysLT1 and CysLT2 receptors: receptors for the cysteinyl leukotrienes PCA: passive cutaneous anaphylaxis
SRS-A My initial studies with Brocklehurst demonstrating various common biochemical requirements for the antigen-induced release of SRS-A and histamine from actively sensitized guinea pig lung (9–11) did not reveal the responsible Ig class or cellular source. With Kurt Bloch, we found that haptenspecific guinea pig IgG1, but not IgG2, sensitized guinea pig lung fragments for DNPBSA-elicited histamine and SRS-A release and also mediated a passive cutaneous anaphylaxis (PCA) reaction implicating the MC www.annualreviews.org • Doing What I Like
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(15). A second Ig class, rat IgE, was shown to passively sensitize the rat peritoneal cavity for DNP-BSA-elicited histamine and SRSA release, and that response was lost with MC depletion (16). Definitive studies linking MCs and IgE to SRS-A generation were conducted in monkey lung fragments, with Teruko and Kimishige Ishizaka, using isolated IgE myeloma or atopic serum for passive sensitization followed by challenge with anti-IgE (17). Rat IgGa, which also prepared the peritoneal cavity for antigen-induced SRS-A generation and was produced more easily than IgE, was used routinely to generate product for characterization (18). As agonists other than SRS-A contracted the guinea pig ileum in an antihistamine-resistant manner, we considered it critical to produce the material immunologically. Because solubility studies revealed SRS-A to have both polar and nonpolar characteristics, we recruited Bob Murphy from the Department of Chemistry at MIT to help with a structural analysis. Robert (Bob) Orange produced heroic amounts of SRS-A from hundreds of rats and conducted the chromatography, while Bob Murphy used gas chromatography, gas chromatographymass spectroscopy, and high-resolution mass spectroscopy to identify the contaminants remaining after each purification step and to assess the final product from their combination. Rat and human SRS-A behaved in an identical fashion, with the final product being an acidic, low-molecular-weight (400–1400 MW) moiety bioactive at a nanogram level or less (19). Although the moiety was not suitable for conventional mass spectrometric analyses, spark source mass spectroscopy demonstrated the sulfur atom to be more abundant in the bioactive samples, a finding confirmed by electron probe analysis (20). The inactivation of SRS-A by arylsulfatases but not by a range of other enzymes and the ability of SRS-A to inhibit the cleavage of synthetic substrates of the enzyme were puzzling since the electrophoretic mobility and isoelectric point of SRS-A did not suggest a sulfate residue. In
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retrospect, the triene structure of the cys-LTs was read as an aromatic ring in the inhibition studies of arylsulfatases by SRS-A, and a contaminant was responsible for the inactivation (21). Nonetheless, the partial purification and characterization of SRS-A as a sulfur-enriched substance and the finding of Charles Parker’s group that labeled arachidonic acid could be incorporated into SRS-A (22) provided background for the generation of double-labeled SRS from mastocytoma cells stimulated with calcium ionophore. Indeed, Murphy and colleagues needed to break the sulfur bridge between the lipid backbone and peptide adduct to characterize the lipid component as a triene (14). In a study with Robert Lewis, another long-time colleague, we used the purification scheme to identify the cellular biosynthesis of bioactive SRS-A before its release from human MCs (23). These findings predicted the export pathway for newly synthesized LTC4 described 15 years later. Human eosinophils loaded with LTA4 at 4◦ C formed but did not release LTC4 until the temperature was raised, thereby demonstrating an energy-dependent export pathway (24). When the effects of intravenously administered SRS-A, histamine, prostaglandin (PG) F2α, and bradykinin on lung function in guinea pigs were compared, SRS-A markedly reduced dynamic compliance with minimal effect on pulmonary resistance, whereas the reverse was true for the other agonists (25). These findings, which indicated that SRS-A had a unique preference for peripheral airways, were further examined by comparing the in vitro contractile activity of SRS-A with histamine for guinea pig tracheal spirals and parenchymal strips. Whereas the effect of histamine concentration was equal for contractions of both smooth muscle preparations, the sensitivity of the tracheal spirals to SRS-A was 100-fold less than that of the parenchymal strips. These findings with purified SRS-A predicted the novel selectivity of LTC4 and the other cys-LTs for peripheral airways when inhaled by human volunteers.
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Cysteinyl Leukotrienes LTC4 , LTD4 , and LTE4 On the basis of the composition of the SRS activity released by ionophore stimulation of mouse mastocytoma cells (14), E.J. Corey synthesized candidate stereoisomers with various sulfur-linked peptide adducts. In parallel bioassays of chemical moieties and the MCgenerated product by the Samuelsson group, LTC4 was established as 5(S)-hydroxy-6(R) glutathionyl-7, 9-trans, 11, 14-cis eicosatetraenoic acid (26). Corey provided our group with authentic LTC4 and related structures so that we could characterize biologic SRS-A generated from the rat peritoneal cavity and from human lung fragments. After a final RPHPLC step (19, 25), the SRS-A prepared from both sources had two activity peaks for contraction of the guinea pig ileum in units/pmol that were equivalent to LTC4 and LTD4 (27). LTD4 had been identified as the product of cleavage removal of glutamic acid from the glutathionyl adduct of LTC4 by Piper and colleagues (28). Two of five purified rat SRS-A preparations contained a previously undescribed activity peak by RP-HPLC that eluted after LTC4 and LTD4 and also exhibited a triene UV absorbance spectrum at 280 nm. The elution time corresponded to a candidate structure in which the glycine had been cleaved from LTD4 and left only the cysteinyl adduct, which we termed LTE4 . Synthetic and biologic LTE4 had the same specific contractile activity for guinea pig ileum and parenchymal strips (29). However, LTE4 was a log more potent than LTD4 in contracting tracheal spirals and a log less potent in contracting parenchymal strips (30). The possibility of two separate cys-LT receptors had already arisen because an antagonist, FPL 55712, blocked the low-dose, high-affinity parenchymal strip contractions produced by LTD4 but not the contractions initiated by LTC4 or high-dose LTD4 (31). Furthermore, after a contraction of parenchymal strips elicited by LTE4 but not LTC4 or LTD4 , followed by full relaxation, the response of the strip to
histamine was augmented due to the induced generation of a prostanoid (30), suggesting even a third response pathway. Because the cys-LTs are mediators generated during a local inflammatory response, we assessed the impact of the respiratory burst elicited in polymorphonuclear leukocytes (PMN) by phorbol myristate acetate (PMA) on their function, immunoreactivity, and integrity. By RP-HPLC with synthetic standards, each cys-LT was converted to a subclass-specific S-diastereoisomeric sulfoxide without function but with retained immunoreactivity and then, with disruption of the sulfur bridge, to an unreactive common end product, 6-trans-LTB4 . The metabolic inactivation was replicated with hydrogen peroxide, myeloperoxidase, and chloride anion, indicating an attack on the sulfur moiety by hypochlorous acid. Dose-response studies revealed LTE4 to be the most stable cys-LT in the presence of this inactivating pathway (32). Thus, in an integrated setting, the aggregate cellular effects of the cys-LTs reflect their relative individual stability and differential potency for expressed receptors on target cells.
LTC4 Synthase and the cys-LT Receptors With definition of LTC4 as the only biosynthetic intracellular cys-LT, we turned to isolation of the responsible enzyme, LTC4 S. Partial purification of LTC4 S solubilized from rat basophilic leukemia-1 cells or guinea pig lung revealed that it was an integral membrane protein that lacked the substrate specificity for xenobiotics characteristic of the glutathione S-transferases (GSTs) (33, 34). Homogeneous 18-kDa human LTC4 S was solubilized and isolated from 60 billion KG-1 cells, and an Nterminal sequence of 22 amino acids and an internal sequence of 14 residues were obtained (35, 36). For expression cloning, Bing Lam developed a high-throughput fluorescencelinked competitive immunoassay for detection of LTC4 generation by Cos cells www.annualreviews.org • Doing What I Like
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transfected with a cDNA library from KG-1 cells. The full-length cDNA that encoded the LTC4 S activity included the residues identified by amino acid sequencing of the purified protein (36). The N-terminal two-thirds of LTC4 S was 44% identical to FLAP at the protein level and 52% identical for the corresponding nucleotides. Both are integral perinuclear membrane proteins, and genomic cloning revealed that their intron/exon junctions align identically, suggesting their evolution by gene duplication (37). By fluorescence in situ hybridization, the gene for human LTC4 S is on chromosome 5q35 distal to the gene cluster for the cytokines that are central to the Th2 phenotype implicated in asthmatic and allergic inflammation. The cDNA for mouse LTC4 S is 87% homologous to the human cDNA (38), and genomic cloning revealed identical intron/exon boundaries. The mouse LTC4 S gene is located in a region syntenic to human 5q35 on chromosome 11 near to the Th2 gene cluster (39). The LTC4 S gene is the only one among the recently defined superfamily of membraneassociated proteins involved in eicosanoid and glutathione metabolism located on a chromosome with a Th2 gene cluster. That Th2 cytokines can regulate the pathway for cys-LT generation was recognized using human MCs derived from cord blood by culture in stem cell factor (SCF), interleukin (IL)-6, and IL-10 in studies with Joshua Boyce. Such MCs are deficient in LTC4 S, and priming them with IL-4 induced steady-state transcripts, protein, and function for LTC4 S but did not increase transcripts or protein for other pathway components such as cPLA2 , FLAP, or 5-LO (40). In addition, priming these MCs with IL-3 or IL-5 translocated 5LO to the outer nuclear membrane for FLAPdependent generation of LTA4 , thereby optimizing LTC4 generation when IL-4 was also present. IL-4 priming also enhanced the capacity of the cys-LTs to induce chemokine and cytokine expression by culture-derived human MCs. The cys-LTs did not cause exocytosis, and their action involved two receptors
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inasmuch as a CysLT1 receptor antagonist blocked induction of IL-5 but not IL-8 (41). Although site-directed mutagenesis of human LTC4 S has identified residues for substrate binding and the integrated conjugation function for GSH and LTA4 (42), crystallography is critical for a mechanistic model. Thus, human LTC4 S was overexpressed in fission yeast, purified to apparent homogeneity, and grown in 2D crystals in sheets and vesicles for electron crystallography. Projection maps at 4.5 and 7.5 A˚ show that the enzyme is a trimer and that each monomer contains at least four alpha helices that insert into the membrane (43). Analysis of the atomic structure of LTC4 S at 3.3-A˚ resolution by X-ray crystallography has revealed that the monomer has four transmembrane alpha helices and forms threefold symmetric trimers as a unit with functional domains across each interface. The residues conjugating GSH at C6 and generating a hydroxyl group at C5 are on opposing monomers (44). To examine the functions of the cys-LTs in complex models of inflammation, mouse strains with targeted disruption of LTC4 S and each of the known cys-LT receptors, CysLT1 and CysLT2 , were developed and extensively backcrossed by Yoshihide Kanaoka. Disruption of the LTC4 S gene abrogated the capacity of tissues to conjugate LTA4 methyl ester with GSH, establishing the dominant role of this enzyme rather than GSTs in LTC4 biosynthesis (45). IgE-dependent PCA in the ear of the LTC4 S-deficient and the CysLT1 and CysLT2 receptor–deficient strains was reduced by more than one-half, thereby revealing a role for cys-LTs at least equal to that of the MC secretory granule amines in eliciting the plasma leakage at this site. The plasma leak in the LTC4 S-deficient and CysLT1 receptor–deficient strains, but not the CysLT2 receptor–deficient strain, was also reduced by more than 50% after intraperitoneal injection of the microbial cell wall carbohydrate, zymosan (46–48). These studies reveal heterogeneity of the receptor expression of the microvasculature.
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In turning to more complex models, we began with bleomycin-induced pulmonary fibrosis for which the C57B/6 strain is optimal. Twelve days after intratracheal administration of bleomycin, the extent of macrophage and fibroblast accumulation with deposition of extracellular matrix proteins, including collagen, was much less in the LTC4 S-deficient strain. By digital image analysis, the septal thickening of the lower lobes was reduced to one-half that observed in wild-type (WT) littermates. The cys-LTs were absent from the bronchoalveolar lavage (BAL) fluid of the deficient strain and abundant in the BAL fluid of the WT littermates, while the quantities of LTB4 and PGE2 were similar. The CysLT2 receptor–deficient strain was as protected against bleomycin-induced pulmonary fibrosis as the LTC4 S-deficient strain but accumulated the same cys-LT content in the BAL fluid as the WT littermates (48). In contrast, the CysLT1 receptor–deficient strain had greater septal thickening than sufficient controls (49). That fibrosis is prevented by disruption of the pathway at different points, biosynthesis and receptor-mediated function, encoded by genes on different chromosomes, is strong evidence for the role of cys-LTs in this form of chronic inflammation.
THE MAST CELL The MC, which is derived from a hematopoietic stem cell, circulates as an immature monocyte-like progenitor (MCp) lacking cytoplasmic granules, is distributed to tissues as an immature progenitor, and matures and differentiates in a tissue-determined fashion. The major phenotypes of tissue MCs in mouse, rat, and human are the constitutive connective tissue type that surrounds microvasculature, often in proximity to nerve endings, and the T cell–dependent mucosal type at intraepithelial locations such as intestine and airways. In the rat and mouse, these MC phenotypes are distinguished by differences in their secretory granule proteoglycans, their profile of secretory granule pro-
teases, and their expression of eicosanoids with activation. These phenotypic distinctions are less perceptible in humans, although the T cell–dependence of the mucosal population is evident from their absence in patients with impaired T cell functions. In initial in vitro studies, we used MCs harvested from the rat peritoneal cavity and isolated on density gradients or human lung MCs obtained from surgical specimens. The MC numbers were limited and the preparation time was excessive. Thus, when knowledge of growth factors evolved through the studies of Ehud Razin and others, we changed to culturederived mouse bone marrow–derived MCs (BMMCs), which are abundant but immature, and human cord blood–derived MCs, which, although quite mature, are of limited number. We initially focused on the nature and number of the secretory granule neutral proteases and proteoglycans. With these markers for cell development, we moved in vivo to characterize the transendothelial migration of MCp to peripheral tissues, the phenotypic plasticity of tissue MCs with location and superimposed inflammation, and the tissue-based control of MC activation.
MCp: mast cell progenitor
Secretory Granule Proteases and Proteoglycans The secretory granule is best known as a source of histamine, a mediator of the nasal coryza and ocular/cutaneous pruritus in allergic disease. Both histamine and the neutral proteases bear positive charges, which interact with the anionic glycosaminoglycans polymerized onto a peptide core of the proteoglycan(s) in the secretory granule. An electron microscopic study of human lung MCs revealed that the secretory granules had a crystalline structure of defined periodicity with a lattice- or scroll-like distribution. With IgEdependent activation, the granules swelled, their crystalline structure dissolved, and in association with contractile elements they moved to the membrane for fusion and extracellular release of contents (50). The ionic www.annualreviews.org • Doing What I Like
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interactions of the released complex were disrupted at physiologic pH, and many of the cationic moieties including histamine diffused away, leaving a “ghost” composed of the proteoglycans and highly cationic proteases (51). We were surprised that the dominant human MC protease, which we termed tryptase, was a tetramer with four active sites (52). Although some considered the tetramer presentation to be a consequence of our protein isolation, the findings were confirmed by others with X-ray crystallography. Tryptase is the dominant neutral protease in both human MC phenotypes and can cleave human C3 to release the C3a anaphylatoxin (53). MC-carboxypeptidase A (MC-CPA) is a specific marker for connective tissue MCs in both mice and humans. MC-CPA is unique among carboxypeptidases in having a CPAlike substrate-binding pocket and enzymatic activity but an overall protein and gene structure more similar to carboxypeptidase B (54, 55). Recently, Rodewald and colleagues (56) reported that MC-CPA protected mice against snake venom sarafotoxin, identifying the specific protease responsible for a host defense MC function reported by others. On two occasions, transformed mouse cell lines developed in other laboratories profoundly advanced our program by solving a technical issue. The first was the derivation of connective tissue–like MC lines (KiSV-MC) by coculture of mouse splenocytes with fibroblasts that produce the Kirsten murine sarcoma virus. In contrast to earlier lines, some of the KiSV-MC lines exhibited maturation indistinguishable from that of mouse peritoneal MCs and provided enough secretory granule protein for isolation of the proteases (57). MC-CPA from KiSV-MCs and from peritoneal MCs were both 36 kDa and had identical N-terminal amino acid sequences; these cells, along with BMMCs, expressed the same transcript encoded by a single gene for MCCPA (58). The four other proteins obtained from KiSV-MCs, ranging from 28 to 32 kDa, were serine proteases based on [3 H]DFP binding (59). Their cDNAs indicated that
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mouse MC protease (mMCP)-2 (60), -4 (61), and -5 (62) were in the chymase gene family, whereas mMCP-6 was a tryptase (63). The tissue distribution of their mRNA indicated that mMCP-2 was prominent in mouse mucosal MCs, while mMCP-4, -5, and -6 and CPA characterized the connective tissue MC phenotype. We subsequently recognized a second secretory granule tryptase, mMCP-7, in the BALB/c but not the C57B/6 strain (64) and another chymase, mMCP-9, selectively expressed in mouse uterine MCs (65). The chymases are differently regulated in BMMCs, with mMCP-5 being induced by SCF (66) and the mucosal mMCP-1 and mMCP-2 by IL9 or IL-10 (67). By nuclear run-on analysis, all the beta chymases were being transcribed in the BMMCs, and the cytokines were simply stabilizing the transcripts to allow translation (68). Such a mechanism of transcript stabilization could account for the phenotypic diversity of the protease profile in different tissue MCs and for the further changes with inflammation by Trichinella spiralis infection (69). These seminal studies involved postdoctoral fellows Bill Serafin, Dale Reynolds, Patrick McNeil, and John Hunt and depended on a long-time colleague, Richard Stevens. The second transformed MC line from another laboratory that was essential to our progress was the v-abl immortalized MC line (V3-MC). Unlike the KiSV-MC, these cells did not shed virus and could be used to follow lineage maturation after adoptive transfer to a BALB/c recipient (70). The clonal line was immature and expressed protein for mMCP-5, mMCP-7, and mMC-CPA but not mMCP-2 or mMCP-6. After adoptive transfer and residence in the liver or spleen, the line expressed all proteases, as did the resident MCs. In contrast, the V3-MCs identified in the small intestine by the abl marker were agranular at day 6 after adaptive transfer and without detectable proteases, and by 14 days expressed only abundant mMCP-2, a marker for mucosal MCs. The distinct protease phenotypes of the V3-MCs in the two
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tissues reflecting additions and/or deletions elegantly demonstrated that protease expression was regulated by local factors. Because the proteases were bound in an active form in the secretory granule, we characterized the heparin moiety in rat peritoneal (71) and human lung MCs (72) after radiolabeling in vitro with [35 S]sulfate and [3 H]serine. This early work by Dean Metcalfe and Jerry Silbert showed that the rat proteoglycan was ten times larger than the human proteoglycan owing to the number and size of the glycosaminoglycans polymerized onto a glycine-/serine-rich small-core polypeptide (73). The proteoglycans in the BMMCs included heparin but were predominantly composed of chondroitin sulfate E glycosaminoglycans rich in Nacetylgalactosamine-4,6-disulfate sequences (74, 75). Irrespective of the size or nature of the glycosaminoglycans, the segment of the core polypeptide to which the glycosaminoglycans were attached was protease resistant. Cloning of the cDNA and gene that encode this peptide core in rat basophilic leukemia-1 cells (76), human promyelocytic HL-60 cells (77), and mouse BMMCs (78) revealed coding for a highly conserved N-terminal amino acid sequence and a stretch of alternating serine and glycine residues. Serglycin is the single peptide core for hematopoietic secretory granule proteoglycans, the selection of the types of glycosaminoglycan to be synthesized onto this peptide core is cell specific, and the protease resistance of serglycin allows storage association of active proteases to the glycosaminoglycans.
Development and Transendothelial Distribution of Mast Cell Progenitors (MCp) Investigations in the laboratories of Kitamura (79), Rodewald (80), and Schrader (81) indicated that MCp arise from bone marrow (BM) stem cells, circulate as agranular lineage progenitors, and settle into the small intestine at concentrations per million mononu-
clear cells (MNCs) that exceed the concentrations in other peripheral tissues. We assumed intestinal MCp to be the source of the Th2 cell–dependent MC hyperplasia that cleared adult worms (69), and Michael Gurish defined the MCp integrins that sustained the intestinal reservoir. MNCs were harvested from the small intestine, BM, spleen, and lung, and the MCp per million MNCs was determined by limiting dilution and clonal expansion. The absence of β7 (CD49d) but not αE (CD103) or β2 (CD18) integrins resulted in a marked reduction of MCp in the small intestine but not in the lung, spleen, or BM of naive mice. To confirm these findings, we eliminated MCp from WT mice by sublethal irradiation and introduced various monoclonal antibodies (mAbs) just after adoptive transfer of syngeneic BM. The administration of mAb to α4β7, α4, or β7 integrins and to their counterligands on the microvasculature, mucosal addressin cell adhesion molecule1 (MAdCAM-1) and vascular cell adhesion molecule-1 (VCAM-1), blocked reconstitution of the intestinal MCp, whereas mAb to αE or β1 integrins had no effect. The finding that blocking mAb to α4β7 was fully inhibitory even if administered four days after the syngeneic BM implied a priming phase for MC lineage development in recipient BM (82). This dynamic relationship between BM and the intestinal reservoir of MCp was confirmed by showing that administration of blocking mAb every other day for one week to nonirradiated naive mice profoundly depleted the intestinal pool of MCp by blocking the regular influx of new MCp (83). Furthermore, that the MCp reservoir was intact in mice null for the recombination activating (RAG)-2 and IL receptor common gamma chain genes indicated that this constitutive α4β7-dependent homing of MCp is independent of the Th2 cytokines needed to elicit mucosal MC hyperplasia (82). Finally, both mucosal and connective tissue MCs were deficient in the β7 integrin-null mouse, indicating that a single lineage of MCp gives rise to both tissue phenotypes. www.annualreviews.org • Doing What I Like
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Mouse lung has minimal numbers of baseline MCp, and their recruitment with sensitization and inhalation antigen challenge depends partially on α4β7 but also involves α4β1. As lung lacks MAdCAM-1, adhesion with pulmonary inflammation is entirely through upregulated VCAM-1, likely accounting for the role of both α4-based integrins (84). The fact that blocking mAb to integrins of MCp prevents the accumulation of MCp in lung indicates that even with inflammation the initial host response is recruitment, not proliferation. The appreciation that β7-integrin expression is a requirement for transendothelial migration by MCp led to the discovery of a new bifunctional progenitor for both the MC and the basophil lineages. Candidate MCp progenitors in BM, spleen, and small intestine were depleted of irrelevant lineages, sorted by membrane phenotype, and characterized by growth in a cytokine mixture suitable for all hematopoietic lineages. In the C57B/6 strain, the spleen contained a population of bipotent β7+ /c-Kit+ /FcεR1+ basophil/MC progenitors (BaMCp) that gave rise in single-cell culture to colonies of either MCp or basophil progenitors (Bap). MCp but not Bap retained and increased β7 integrin expression. BaMCp administered intravenously to genetically MC-deficient W/Wv mice reconstituted mature MCs in both spleen and stomach. The small intestine contained only MCp, suggesting that BaMCp do not leave the spleen. The granulocyte-related transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) played the major role in the fate decision of BaMCp, being retained by Bap and absent in MCp (85).
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IL-3. He entered our postdoctoral program for the purpose of unraveling the epitopes for these mAbs, of which one, gp49B1, has proven to be of particular interest as a constitutively expressed negative regulatory receptor. Immunoprecipitation of a membrane epitope on both BMMCs and peritoneal MCs by the IgM mAb/B23.1 revealed a heterogeneous protein with a mean molecular mass of 49 kDa (86). Purification of gp49 from a KiSV-MC clone provided the N-terminal amino acid sequence used to prepare oligonucleotides for screening a KiSV-MC library. Two of the fulllength cDNAs obtained, gp49A and gp49B1, were 97% homologous and encoded members of the Ig superfamily with two type 2 Ig-like extracellular domains, whereas the third, gp49B2, was identical to gp49B1 except for the lack of the entire transmembrane domain encoded by exon 6 (87, 88). That the putative tandem immunoreceptor tyrosine-based inhibition motifs (ITIMs) recognized in the cytosolic domain of gp49B1 were functional was established in vitro (89). Mice lacking the gp49B gene but not the g49A gene were generated and assessed for MC function by PCA (90). The net ear swelling of the sensitized ear due to MC activation and plasma extravasation was twofold greater in the gp49B1-deficient strain than in the sufficient WT littermates, and the number of MCs degranulated per unit area was also twofold greater. When the sensitizing dose of mAb IgE was reduced by one log, the net swelling of the sensitized ear in the deficient strain was equal to that obtained in the WT strain with the standard tenfold greater sensitizing dose. In active cutaneous anaphylaxis of mice systemically sensitized to OVA and showing similar levels of specific IgE, an intradermal dose of OVA that elicited a robust vascular leak in the gp49B1-deficient strain caused no measurable ear swelling in the WT mice. These studies not only uncovered a control receptor of IgE-dependent MC activation but, most important, recognized that such inflammation was normally dampened in situ by
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an innate constitutive mechanism. That the activation of ear MCs by SCF also led to a significantly greater vascular leak and MC degranulation in the gp49B1-deficient mice as compared to the sufficient littermates showed that regulation was not limited to adaptive immunity (91). There was yet a surprise. When lipopolysaccharide (LPS) was injected intradermally into the mouse ear to see if the gp49B1-null strain would have an exaggerated Toll-like receptor (TLR)-initiated MC-dependent swelling response, there was no early difference between the deficient and sufficient strains. Instead, by 24 h there was gross hemorrhage in the LPS-injected ear of the gp49B1-deficient strain but none in the ear of the sufficient littermates. The macroscopic bleeding visually apparent against the white fur of the gp49B1-deficient BALB/c strain was reminiscent (to someone who had been working in immunology in the late 1950s) of a Schwartzman reaction. The microangiopathy of a Schwartzman reaction is due to a coagulopathy, not a vasculitis. On microscopic analysis, we saw venules occluded by thrombi composed of neutrophils, platelets, and fibrin accompanied by a vascular margination and tissue infiltration by PMNs. The MCs were intact and not different in the deficient strain. The lesion was prevented by administration of mAbs that depleted PMNs or blocked the interaction of their β2 integrin with the intercellular adhesion molecule 1 (ICAM-1) or by therapeutic inhibition of coagulation. Unexpectedly, the PMN expressed gp49B1, which is upregulated by LPS in WT mice (92). The “one-shot” Schwartzman reaction occurred in the deficient strain owing to the absence of an innate control, gp49B1, of a TLR response on their PMNs. A member of the human leukocyte Ig-like receptor family (LIR-5) homologous to gp49B1 has been cloned (93) and renamed human LILRB4 to correspond to mouse LILRB4/gp49B1.
THE ALTERNATIVE COMPLEMENT PATHWAY In the 1950s, Pillemer and colleagues recognized that a plasma protein, designated properdin (P), was required for complementmediated bactericidal and hemolytic activity that was not antibody dependent (94). The properdin system/alternate complement pathway is composed of six proteins, of which four are specific to this pathway (P, factor B, factor D, and factor H) and two [C3 and C3b inactivator (C3bINA)] are shared with the classical antibody-dependent pathway. The most critical step in both activating pathways is the proteolytic cleavage of C3 to provide C3b for assembly of the amplification C3 convertase, C3bBb. The same alternative pathway proteins are used for formation of a weak alternative pathway-initiating C3 convertase built with uncleaved C3. Unraveling the relationship of the initiation and amplification phases of alternative pathway C3 cleavage followed the introduction of a quantitative, sensitive hemolytic assay for the assembly of C3bBb by my colleagues, Douglas Fearon and Shaun Ruddy (95). Sheep erythrocytes with affixed C3b interacted with B in the presence of D to generate C3bBb sites, and the number of these sites could be calculated by lysis with additional C3 and C5-9. The cell-based assay had linear stoichiometry for generation of the C3bBb sites with incremental inputs of B and a fixed dose of D, and a hemolytic efficiency comparable to cells bearing the classical C3 convertase. Our use of this assay included characterization of the proteins involved in the assembly, stabilization, and inactivation of C3bBb; recognition of the initiating alternative pathway C3 convertase, C3Bb; and demonstration of the integrated activation and amplification of the alternative pathway on an activating particle or cell. Most important to the understanding of the alternative pathway was our discovery of the stabilizing function of P and of the destabilizing protein H for C3bBb. Properdin
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bound to C3b to form a trimolecular complex from which the decay of Bb was markedly retarded (96). Conversely, H terminated C3bBb function by dissociation-decay of Bb even in the presence of P (97, 98). This counterregulatory action allowed inactivation of C3b by C3bINA to prevent regeneration of the hemolytic site. With these insights into amplification, we used the same proteins to seek the initiating alternative pathway C3 convertase, C3Bb, in the fluid phase by comparing the dose-response effects of C3 and C3b for D-mediated cleavage inactivation of B. The time-dependent sigmoidal inactivation curve for B with C3 and D was delayed relative to that with C3b and was not inhibited by addition of C3bINA, indicating that C3Bb provided the C3b for subsequent formation of the amplification convertase (99). Properdin dose-dependently augmented B inactivation with C3 and D, indicating stabilization of C3Bb. That D was a constitutively active serine protease (100) suggested a continuous low-grade cleavage of C3 in the presence of B and P and circumvention of the regulatory controls when C3b was deposited on an activating particle. To prove this mechanism, we used zymosan, the same insoluble polysaccharide derivative from yeast cell walls that Pillemer had used in recognizing the alternative complement-activating pathway (94). When zymosan was added to a mixture of C3, B, D, P, C3bINA, and H, an initial low-grade cleavage of C3 was followed by amplified cleavage that suggested a two-step process. Moreover, C3b bound to zymosan was relatively resistant to inactivation by C3bINA, and the hemolytic site, PC3bBb, assembled on zymosan was protected against H dissociation-decay, demonstrating that regulation of the amplification site was retarded by the character of an activating particle (101). In a parallel study with the same six proteins, the addition of rabbit, but not sheep, erythrocytes initiated consumption of B and C3 in the fluid phase and formation of lytic sites on the cell (102). Fearon then showed that enzymatic or chemical removal
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of membrane sialic acid groups from sheep erythrocytes converted these cells to activators of the alternative complement pathway while reducing the regulatory efficiency of C3bINA and H (103). Thus, the constitutive action of D to form C3Bb provides the C3b that, when affixed to a protective nonself surface, forms a stabilized amplification C3 convertase, PC3bBb, that provides diverse proinflammatory or host protective functions. The pattern recognition activation of the alternative complement pathway is a prime example of innate immunity. Our seminal insight that unraveled the activation and amplification of the alternative pathway was that it might not begin with recruitment of a proenzyme but rather that nonself might be recognized by circumvention of surveillance mechanisms, H and C3bINA, that protect self.
TRANSLATIONAL INVESTIGATIONS The linkage of our bench research in our three focal areas to the clinic was most dynamic in the early years, when less was known, and continued at a reduced level until the early 1990s. Each clinical application of an insight gained at the bench involved a critical collaboration with either an astute full-time clinician or an established clinical investigator.
The cys-LTs After toiling with SRS-A for two decades, I was immensely curious about whether the cys-LTs provided by E.J. Corey would have the smooth muscle actions in humans that we had observed in animals. My equally curious colleagues, Bob Lewis and Nick Soter, joined me in an initial dose-response study in ourselves to intradermal LTD4 . The magnitude and persistence of the elicited wheal and flare responses were so compelling that we initiated a second study with biopsies in which our cutaneous responses to the cys-LTs were compared with those to the other MCderived eicosanoids, LTB4 and PGD2 , and to
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buffer. Equimolar amounts of LTC4 , LTD4 , and LTE4 elicited a local erythema and wheal of 6 h and 2 h duration, respectively, whereas the similar response to a higher dose of PGD2 was less sustained. The tissue showed dermal edema with marked and uniform dilation of capillaries, superficial and deep venules, and arterioles as well as activation-related changes in the endothelium. There was no cellular infiltration in the cys-LT-injected sites. In contrast, LTB4 elicited a transient wheal and flare followed 3–4 h later by induration that was characterized by a dermal infiltration composed almost solely of neutrophils. The combination of LTB4 and PGD2 intensified the cellular infiltrate. The findings that nanomole amounts of leukotrienes were active in human skin and that each subclass gave the expected biology were immensely rewarding to us (104). The Human Studies Committee delayed our planned investigation of the airway smooth muscle actions of aerosolized cysLTs to be certain that the skin exposure had no adverse effects. The concentrations of aerosolized LTC4 that reduced by 30% the maximum expiratory flow rate (measured at 30% of vital capacity above residual volume) were in ug/ml, whereas those for histamine were in mg/ml, revealing a more than 1000fold greater potency for LTC4 in normal volunteers (105). LTC4 induced a fall in airflow that was slow in onset, prolonged, and associated with audible wheezing without a cough, whereas histamine acted rapidly and elicited a cough but not a wheeze. LTD4 was also three logs more potent than histamine, and the more biologically stable LTE4 was one log more potent as a bronchoconstrictor in normal human subjects. In contrast, in patients with bronchial asthma, the respective potencies of LTD4 and LTE4 relative to histamine were less than a log (106, 107). Although this finding would still classify the cys-LTs as potent bronchoconstrictors in individuals with bronchial asthma, it also suggests that their chronic overproduction somehow ameliorates receptor responses.
The Mast Cell In studies initiated in the clinic, a distinct form of physical allergy, exercise-induced anaphylaxis (EIA), was identified. When Al Sheffer described a number of patients “allergic to exercise” to the point of vascular collapse with jogging/running, indoor/outdoor team sports, tennis, and dancing, but without occurrence with every repetition of the exercise, it seemed reasonable to further expand the series. When the number reached 16, it was obviously a syndrome. EIA was defined by a premonitory feeling of body warmth and itching unrelated to ambient temperature and progression to cutaneous erythema, confluent hives, laryngeal edema with stridor or hoarseness, gastrointestinal cramps/colic, and frequently culmination in vascular collapse (108). Of seven patients with EIA who exercised on a treadmill with a moving grade while wearing an occlusive suit, four developed erythema and conventional-sized hives and two of these manifested laryngeal hoarseness. The four with symptoms showed a rise in blood histamine concentration, implicating MC activation (109), whereas the blood histamine concentration did not change in the subjects with EIA who did not respond to this challenge. In a repeat study, cutaneous biopsies of the patients with EIA with symptoms and signs showed classical MC degranulation that was absent in the nonresponders (110). In contrast to patients with cholinergic urticaria, who experienced punctate hives, elevations in blood histamine, and pulmonary symptoms with significantly altered pulmonary function with the exercise protocol (111), pulmonary mechanics were not altered in the challenged patients with EIA. Patients with EIA can abort an episode by stopping the exercise with the onset of premonitory symptoms and can ameliorate/prevent attacks by allowing a suitable interval after a meal and/or by using various MC-directed interventions before exercise. Studies from the bench to the clinic identified a new MC-derived mediator, PGD2 , that accounted for intractable hypotension in
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occasional patients with systemic mastocytosis. In collaboration with John Oates and Jack Roberts, we assessed the eicosanoid products of MC activation. Gas chromatography-mass spectroscopy (GC-MS) analysis of calcium ionophore-stimulated or anti-IgE-activated purified rat peritoneal MCs revealed net generation of PGD2 with only minimal quantities of other eicosanoids. Similarly, activation of dispersed human lung MCs by anti-IgE showed selective PGD2 generation relative to other prostanoids and a linear relationship to histamine release (112, 113). The failure of H1 and H2 antagonists to control the severe body flushing and hypotension in two patients with systemic mastocytosis led to a GC-MS analysis of urine and the structural identification of a metabolite of PGD2 that was not present in more than 200 urine samples from normal subjects or patients with other diseases (114). The hypotension in one of these patients was controlled by treatment with highdose aspirin in combination with H1 and H2 antagonists. The evidence that MCs in patients with systemic mastocytosis can spontaneously release more than preformed secretory granule mediators accounts for our use of cromolyn sodium, a MC-stabilizing agent, along with H1 and H2 antagonists and, when indicated by severe flushing, aspirin in their management (115).
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The Complement Pathways Disordered regulation of the complement system became a clinical focus because of our preclinical studies and ability to develop sensitive stoichiometric hemolytic assays for proteins whose absence or sustained presence defined the syndrome. Such studies included patients with inborn deficiency of C1INH and bouts of HAE and others with autoantibody-mediated C1INH deficiency; patients with autoantibody-mediated stabilization of the amplification C3 convertase by nephritic factor (NEF) and membranoproliferative glomerulonephritis; and patients with acquired clonal loss of decay18
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accelerating factor (DAF) and paroxysmal nocturnal hemoglobinuria (PNH). Once Al Sheffer learned that Donaldson & Evans (116) had recognized a C1INH deficiency in patients with HAE by screening serum for lack of ability to inhibit C1 esterase activity, he appeared in my laboratory to request a suitable assay for this potentially fatal disease among his patients. Stoichiometric hemolytic assays for C2 and C4, substrates of C1, showed their concentrations in HAE to be two standard deviations below the mean for normal in kindreds lacking the protein or those with a nonfunctional protein and to be further reduced by consumption with a clinical episode (117, 118). The finding by Spaulding (119) that androgen treatment could prevent attacks of angioedema in patients with HAE led us to use attenuated androgens, which reduced but did not eliminate the risk of androgen-related side effects (120). The concentrations of C1INH in untreated HAE patients during asymptomatic periods were less than one quarter normal even though inheritance is autosomal dominant, suggesting consumption of the product of the good gene by the uninhibited C1. Reasonable prevention or amelioration of attacks was achieved with a dose of attenuated androgen that increased the mean functional concentrations of C1INH and C4 to less than one-half of the lower limit of normal, demonstrating a modest dose threshold for clinical benefit (121). Acquired C1INH deficiency with clinical angioedema in patients with B cell proliferative disorders was recognized to be distinct from HAE because there was depletion of functional C1 and its binding subunit, C1q, as well as C4 and C2 (122). Analysis of three such patients showed circulating anti-idiotypes directed to the monoclonal Ig expressed on the surface of their lymph node B cells and on circulating B cells with fixed C1q (123). Patients with PNH have erythrocytes with an acquired abnormal membrane sensitivity to complement-mediated lysis (PNH-E) and experience spontaneous episodes of intravascular hemolysis, often at night. Two membrane
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control proteins, C3b receptor (CR1) and DAF, extracted and purified from human erythrocytes, can act exogenously to destabilize both the amplification (C3bBb) and classical (C4b2a) C3 convertases (124, 125). We found that specific immunoprecipitates of surfacelabeled PNH-E lacked a 70 MW DAF but expressed a 250 MW CR1. Further, PNH-E, unlike normal erythrocytes, failed to absorb the DAF-neutralizing activity of specific rabbit IgG (126). These findings provided the first in situ evidence that an endogenous membrane protein can downregulate the potential pathobiologic effects of amplification resulting from the low-grade turnover of C3 by identifying an acquired clonal deletion of DAF in PNH-E. Patients with chronic glomerulonephritis and a reduced serum C3 concentration have normal concentrations of C4 and reduced concentrations of B, implicating the alternative complement pathway, while patients with systemic lupus erythematosus and reduced C3 concentrations have reduced concentrations of C4 with or without reduced concentrations of B, implicating classical immune complex activation with or without amplification (127). C3 nephritic factor (C3 NeF) in serum of patients with low C3 concentrations and membranoproliferative glomerulonephritis was known to augment C3 consumption. Mohamed Daha and Doug Fearon found that chromatographically purified C3 NeF stabilized the hemolytic function of C3bBb on erythrocytes and interacted with C3, B, and D in the fluid phase to form a trimolecular 10S complex of C3bBb/C3NeF (128). The C3NeF recovered chromatographically after decay of the 10S convertase was highly purified, fully functional (129), and composed of heavy and light chains (130). Others had recognized that C3 NeF was an Ig by depletion of the activity from serum with particle-bound anti-IgG. We provided direct evidence that it was an autoantibody with specificity that stabilized the amplification convertase without a role for P and with resistance to induced decay by H (97).
EPILOGUE As physicians have entered my laboratory after experiencing a daily sense of accomplishment as house officers, it was critical that I help them endure the initial difficulties inherent to bench research. Most important, I have tried to convey that advice is not criticism and that failure is predictable if the projects chosen have merit. Over the years, postdoctoral fellows have been routinely designated as first author on manuscripts when a project reached fruition and as last author when they became faculty with mentoring responsibilities. I edited and rewrote many drafts of each manuscript, making sure that the literature was fully recognized and sometimes laying out an urgent set of additional experiments that we had not identified in laboratory meetings. Since 1966, the “final” text has been edited by Arlene Stolper Simon. She has edited every manuscript of which I am an author, the sections of every volume for which I served as an editor, and every grant application that I submitted. Colleagues often mention that they can recognize faculty who trained here by a certain consistency in their oral and written presentations. A few years ago, I titled my acceptance of the Kober medal “It Only Gets Better” (131) to convey that experience with focus provides insights and an inclination for measured risk that is productive for research in a setting with talented trainees and wise colleagues. Those individuals noted in this document have generally progressed to faculty level, thereby extending our period of collaboration. I have concentrated on areas with a longitudinal span and have not included descriptions for our studies of chemotaxis (Edward Goetzl, Stephen Wasserman), kinin generation (Allen Kaplan, Jocelyn Spragg), classical complement pathway (Irma Gigli, Michel Kazatchkine), eosinophils (Barry Kay, Marc Rothenberg), fish oil–derived leukotrienes (Tak Lee), and some of our early work on SRSA biology by Daniel Stechschulte and Martin Valentine, my first postdoctoral fellows. By being an administrative minimalist with an www.annualreviews.org • Doing What I Like
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open door and much sharing of tasks, I have been able to concentrate on my triad of interests with results beyond my expectations. The respect for each other’s laboratories that grew between Bengt Samuelsson, E.J. Corey, Jeffrey Drazen, and me enhanced progress in the SRS-A/cys-LT field and built long-term friendships. In the complement field, there were times when the laboratories of Fred Rosen, Hans Muller-Eberhard, and my own were in competition, but we managed those
occasions so as to sustain our collaborations and friendships. My wife, Joycelyn Chapman Austen, has been especially generous in tolerating my avocation, in indulging the intensity of the fiveyear grant renewals, and in meeting every responsibility to our four wonderful children in a manner that reflected our joint interests. These children, and now our eight grandchildren, take my efforts to provide guidance with humor and tolerance.
DISCLOSURE STATEMENT The author is not aware of any biases that might be perceived as affecting the objectivity of this review.
LITERATURE CITED 1. Austen KF. 1978. Homeostasis of effector systems which can also be recruited for immunologic reactions. Pres. Address Am. Assoc. Immunol. J. Immunol. 121:793–805 2. Austen KF, Koch-Weser J, Field RA. 1956. Cardiorespiratory problems in severe poliomyelitis observed during the recent epidemic. N. Engl. J. Med. 254:790–93 3. Drazen JM. 2004. Presentation of the Kober Medal to K. Frank Austen. J. Clin. Invest. 114:1174–76 4. Livingstone JB, Austen KF, Kunz LJ. 1957. A study of intercurrent bacterial respiratory infections in bulbospinal poliomyelitis. N. Engl. J. Med. 257:861–66 5. Austen KF, Carmichael MW, Adams RD. 1957. Neurologic manifestations of chronic pulmonary insufficiency. N. Engl. J. Med. 257:579–90 6. Austen KF, Rubini ME, Meroney WH, Wolff J. 1958. Salicylates and thyroid function. I. Depression of thyroid function. J. Clin. Invest. 37:1131–43 7. Wolff J, Austen KF. 1958. Salicylates and thyroid function. II. The effect on the thyroidpituitary interrelation. J. Clin. Invest. 37:1144–52 8. Austen KF. 1960. The differentiation of the chloroform, peptone and antigen antibody inducible esterase activities of human serum from plasmin. Immunology 3:152–73 9. Austen KF, Brocklehurst WE. 1961. Anaphylaxis in chopped guinea pig lung. I. Effect of peptidase substrates and inhibitors. J. Exp. Med. 113:521–39 10. Austen KF, Brocklehurst WE. 1961. Anaphylaxis in chopped guinea pig lung. II. Enhancement of the anaphylactic release of histamine and slow reacting substance by certain dibasic aliphatic acids and inhibition by monobasic fatty acids. J. Exp. Med. 113:541–57 11. Austen KF, Brocklehurst WE. 1961. Anaphylaxis in chopped guinea pig lung. III. Effect of carbon monoxide, cyanide, salicylaldoxine, and ionic strength. J. Exp. Med. 114:29– 42 12. Humphrey JH, Austen KF, Rapp HJ. 1963. In vitro studies of reversed anaphylaxis with rat cells. Immunology 6:226–45 13. Stroud RM, Austen KF, Mayer MM. 1965. Catalysis of C’2 fixation by C’1a: reaction kinetics, competitive inhibition by TAMe, and transferase hypothesis of the enzymatic action of C’1a on C’2, one of its natural substrates. Immunochemistry 2:219–34 20
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14. Murphy RC, Hammarstrom S, Samuelsson B. 1979. Leukotriene C: a slow-reacting substance from murine mastocytoma cells. Proc. Natl. Acad. Sci. USA 76:4275– 79 15. Stechschulte DJ, Austen KF, Bloch KJ. 1967. Antibodies involved in antigen-induced release of slow reacting substance of anaphylaxis (SRS-A) in the guinea pig and rat. J. Exp. Med. 125:127–47 16. Orange RP, Stechschulte DJ, Austen KF. 1970. Immunochemical and biologic properties of rat IgE. II. Capacity to mediate the immunologic release of histamine and slow reacting substance of anaphylaxis (SRS-A). J. Immunol. 105:1087–95 17. Ishizaka T, Ishizaka K, Orange RP, Austen KF. 1970. The capacity of human immunoglobulin E to mediate the release of histamine and slow reacting substance of anaphylaxis (SRS-A) from monkey lung. J. Immunol. 104:335–43 18. Morse HC, Bloch KJ, Austen KF. 1968. Biologic properties of rat antibodies. II. Timecourse of appearance of antibodies involved in antigen-induced release of slow reacting substance of anaphylaxis (SRS-arat ): association of this activity with rat IgGa. J. Immunol. 101:658–63 19. Orange RP, Murphy RC, Karnovsky ML, Austen KF. 1973. The physicochemical characteristics and purification of slow reacting substance of anaphylaxis. J. Immunol. 110:760– 70 20. Orange RP, Murphy RC, Austen KF. 1974. Inactivation of slow reacting substance of anaphylaxis (SRS-A) by arylsulfatases. J. Immunol. 113:316–22 21. Weller PF, Corey EJ, Austen KF, Lewis RA. 1986. Inhibition of homogeneous human eosinophil arylsulfatase B by sulfidopeptide leukotrienes. J. Biol. Chem. 261:1737–44 22. Jakschik BA, Falkenhein S, Parker CW. 1977. Precursor role of arachidonic acid in release of slow reacting substance from rat basophilic leukemia cells. Proc. Natl. Acad. Sci. USA 74:4577–81 23. Lewis RA, Wasserman SI, Goetzl EJ, Austen KF. 1974. Formation of slow-reacting substance of anaphylaxis in human lung tissue and cells before release. J. Exp. Med. 140:1133–46 24. Lam BK, Owen WF Jr, Austen KF, Soberman RJ. 1989. The identification of a distinct export step following the biosynthesis of leukotriene C4 by human eosinophils. J. Biol. Chem. 264:12885–89 25. Drazen JM, Austen KF. 1974. Effects of intravenous administration of slow reacting substance of anaphylaxis, histamine, bradykinin, and prostaglandin F2 on pulmonary mechanics in the guinea pig. J. Clin. Invest. 53:1679–85 26. Marfat A, Corey EJ. 1985. Synthesis and structure elucidation of leukotrienes. In Advances in Prostaglandin, Thromboxane, and Leukotriene Research, ed. JE Pike, DR Morton Jr, 14:155–228. New York: Raven 27. Lewis RA, Austen KF, Drazen JM, Clark DA, Marfat A, Corey EJ. 1980. Slow reacting substances of anaphylaxis: identification of leukotrienes C-1 and D from human and rat sources. Proc. Natl. Acad. Sci. USA 77:3710–14 28. Morris HR, Taylor GW, Piper PJ, Samhoun MN, Tippins JR. 1980. Slow reacting substances (SRSs); the structure identification of SRSs from rat basophil leukemia (RBL-1) cells. Prostaglandins 19:185–201 29. Lewis RA, Drazen JM, Austen KF, Clark DA, Corey EJ. 1980. Identification of the C(6)S-conjugate of leukotriene A with cysteine as a naturally occurring slow reacting substance of anaphylaxis (SRS-A). Importance of the 11-cis-geometry for biological activity. Biochem. Biophys. Res. Commun. 96:271–77 www.annualreviews.org • Doing What I Like
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30. Lee TH, Austen KF, Corey EJ, Drazen JM. 1984. Leukotriene E4 -induced airway hyperresponsiveness of guinea pig tracheal smooth muscle to histamine and evidence for three separate sulfidopeptide leukotriene receptors. Proc. Natl. Acad. Sci. USA 81:4922– 25 31. Drazen JM, Austen KF, Lewis RA, Clark DA, Goto G, et al. 1980. Comparative airway and vascular activities of leukotrienes C-1 and D in vivo and in vitro. Proc. Natl. Acad. Sci. USA 77:4354–58 32. Lee CW, Lewis RA, Tauber AI, Mehrotra M, Corey EJ, Austen KF. 1983. The myeloperoxidase-dependent metabolism of leukotrienes C4 , D4 and E4 to 6-transleukotriene B4 diastereoisomers and the subclass-specific S-diastereoisomeric sulfoxides. J. Biol. Chem. 258:15004–10 33. Yoshimoto T, Soberman RJ, Lewis RA, Austen KF. 1985. Isolation and characterization of leukotriene C4 synthetase of rat basophilic leukemia cells. Proc. Natl. Acad. Sci. USA 82:8399–403 34. Yoshimoto T, Soberman RJ, Spur B, Austen KF. 1988. Properties of highly purified leukotriene C4 synthase of guinea pig lung. J. Clin. Invest. 81:866–71 35. Penrose JF, Gagnon L, Goppelt-Struebe M, Myers P, Lam BK, et al. 1992. Purification of human leukotriene C4 synthase. Proc. Natl. Acad. Sci. USA 89:11603–6 36. Lam BK, Penrose JF, Freeman GJ, Austen KF. 1994. Expression cloning of a cDNA for human leukotriene C4 synthase, a novel integral membrane protein conjugating reduced glutathione to leukotriene A4 . Proc. Natl. Acad. Sci. USA 91:7663–67 37. Penrose JF, Spector J, Baldasaro M, Xu K, Boyce J, et al. 1996. Molecular cloning of the gene for human leukotriene C4 synthase: organization, nucleotide sequence, and chromosomal localization to 5q35. J. Biol. Chem. 271:11356–61 38. Lam BK, Penrose JF, Rokach J, Xu K, Baldasaro MH, Austen KF. 1996. Molecular cloning, expression, and characterization of mouse leukotriene C4 synthase. Eur. J. Biochem. 238:606–12 39. Penrose JF, Baldasaro MH, Webster M, Xu K, Austen KF, Lam BK. 1997. Molecular cloning of the gene for mouse leukotriene C4 synthase. Eur. J. Biochem. 248:807– 13 40. Hsieh FH, Lam BK, Penrose JF, Austen KF, Boyce JA. 2001. T helper cell type 2 cytokines coordinately regulate immunoglobulin E-dependent cysteinyl leukotriene production by human cord blood–derived mast cells: profound induction of leukotriene C4 synthase expression by interleukin 4. J. Exp. Med. 193:123–33 41. Mellor EA, Frank N, Soler D, Hodge MR, Lora JM, et al. 2003. Expression of the type 2 receptor for cysteinyl leukotrienes (CysLT2 R) by human mast cells: functional distinction from CysLT1 R. Proc. Natl. Acad. Sci. USA 100:11589–93 42. Lam BK, Penrose JF, Xu K, Baldasaro MH, Austen KF. 1997. Site-directed mutagenesis of human leukotriene C4 synthase. J. Biol. Chem. 272:13923–28 43. Schmidt-Krey I, Kanaoka Y, Mills DJ, Irikura D, Haase W, et al. 2004. Human leukotriene C4 synthase at 4.5 A˚ resolution in projection. Structure 12:2009– 14 44. Ago H, Kanaoka Y, Irikura D, Lam BK, Shimamura T, et al. 2007. Crystal structure of LTC4 synthase, the membrane protein for cysteinyl leukotriene biosynthesis. Nature 448:609–12 45. Kanaoka Y, Maekawa A, Penrose JF, Austen KF, Lam BK. 2001. Attenuated zymosaninduced peritoneal vascular permeability and IgE-dependent passive cutaneous anaphylaxis in mice lacking leukotriene C4 synthase. J. Biol. Chem. 276:22608–13
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46. Maekawa A, Kanaoka Y, Lam BK, Austen KF. 2001. Identification in mice of two isoforms of the cysteinyl leukotriene 1 receptor that result from alternative splicing. Proc. Natl. Acad. Sci. USA 98:2256–61 47. Maekawa A, Austen KF, Kanaoka Y. 2002. Targeted gene disruption reveals the role of cysteinyl leukotriene 1 receptor in the enhanced vascular permeability of mice undergoing acute inflammatory responses. J. Biol. Chem. 277:20820–24 48. Beller TC, Maekawa A, Friend DS, Austen KF, Kanaoka Y. 2004. Targeted gene disruption reveals the role of the cysteinyl leukotriene 2 receptor in increased vascular permeability and in bleomycin-induced pulmonary fibrosis in mice. J. Biol. Chem. 44:46129– 34 49. Beller TC, Friend DS, Maekawa A, Lam BK, Austen KF, Kanaoka Y. 2004. Cysteinyl leukotriene 1 receptor controls the severity of chronic pulmonary inflammation and fibrosis. Proc. Natl. Acad. Sci. USA 101:3047–52 50. Caulfield JP, Lewis RA, Hein A, Austen KF. 1980. Secretion in dissociated human pulmonary mast cells: evidence for solubilization of granule contents before discharge. J. Cell Biol. 85:299–312 51. Schwartz LB, Riedel C, Caulfield JP, Wasserman SI, Austen KF. 1981. Cell association of complexes of chymase, heparin proteoglycan, and protein after degranulation by rat mast cells. J. Immunol. 126:2071–78 52. Schwartz LB, Lewis RA, Austen KF. 1981. Tryptase from human pulmonary mast cells. Purification and characterization. J. Biol. Chem. 256:11939–43 53. Schwartz LB, Kawahara MS, Hugli TE, Vik D, Fearon DT, Austen KF. 1983. Generation of C3a anaphylatoxin from human C3 by human mast cell tryptase. J. Immunol. 130:1891– 95 54. Reynolds DS, Gurley DS, Stevens RL, Sugarbaker DJ, Austen KF, Serafin WE. 1989. Cloning of cDNAs that encode human mast cell carboxypeptidase A, and comparison of the protein with mouse mast cell carboxypeptidase A and rat pancreatic carboxypeptidases. Proc. Natl. Acad. Sci. USA 86:9480–84 55. Reynolds DS, Gurley DS, Austen KF. 1992. Cloning and characterization of the novel gene for mast cell carboxypeptidase A. J. Clin. Invest. 89:273–82 56. Schneider LA, Schlenner SM, Feyerabend TB, Wunderlin M, Rodewald H-R. 2007. Molecular mechanism of mast cell-mediated defense against endothelial and snake venom sarafotoxin. J. Exp. Med. 204:2629–39 57. Reynolds DS, Serafin WE, Faller DV, Wall DA, Abbas AK, et al. 1988. Immortalization of murine connective tissue-type mast cells at multiple stages of their differentiation by coculture of splenocytes with fibroblasts that produce Kirsten sarcoma virus. J. Biol. Chem. 263:12783–91 58. Reynolds DS, Stevens RL, Gurley DS, Lane WS, Austen KF, Serafin WE. 1989. Isolation and molecular cloning of mast cell carboxypeptidase A. J. Biol. Chem. 264:20094– 99 59. Reynolds DS, Stevens RL, Lane WS, Carr MH, Austen KF, Serafin WE. 1990. Different mouse mast cell populations express various combinations of at least six distinct mast cell serine proteases. Proc. Natl. Acad. Sci. USA 87:3230–34 60. Serafin WE, Reynolds DS, Rogelj S, Lane WS, Conder GA, et al. 1990. Identification and molecular cloning of a novel mouse mucosal mast cell serine protease. J. Biol. Chem. 265:423–29 61. Serafin WE, Sullivan TP, Conder GA, Ebrahimi A, Marcham P, et al. 1991. Cloning of the cDNA and gene for mouse mast cell protease 4: demonstration of its late transcription www.annualreviews.org • Doing What I Like
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63.
64.
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65.
66.
67.
68.
69.
70.
71. 72. 73. 74.
75.
76.
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in mast cell subclasses and analysis of its homology to subclass-specific neutral proteases of the mouse and rat. J. Biol. Chem. 266:1934–41 McNeil HP, Austen KF, Somerville LL, Gurish MF, Stevens RL. 1991. Molecular cloning of the mouse mast cell protease-5 gene: a novel secretory granule protease expressed early in the differentiation of serosal mast cells. J. Biol. Chem. 266:20316–22 Reynolds DS, Gurley DS, Austen KF, Serafin WE. 1991. Cloning of the cDNA and gene of mouse mast cell protease-6: transcription by progenitor mast cells and mast cells of the connective tissue subclass. J. Biol. Chem. 266:3847–53 Hunt JE, Stevens RL, Austen KF, Zhang J, Xia Z, Ghildyal N. 1996. Natural disruption of the mouse mast cell protease 7 gene in the C57BL/6 mouse. J. Biol. Chem. 271:2851–55 Hunt JE, Friend DS, Gurish MF, Feyfant E, Sali A, et al. 1997. Mouse mast cell protease 9, a novel member of the chromosome 14 family of serine proteases that is selectively expressed in uterine mast cells. J. Biol. Chem. 272:29158–66 Gurish MF, Ghildyal N, McNeil HP, Austen KF, Gillis S, Stevens RL. 1992. Differential expression of secretory granule proteases in mouse mast cells exposed to interleukin 3 and c-kit ligand. J. Exp. Med. 175:1003–12 Ghildyal N, Friend DS, Nicodemus CF, Austen KF, Stevens RL. 1993. Reversible expression of mouse mast cell protease 2 mRNA and protein in cultured mast cells exposed to interleukin-10. J. Immunol. 151:3206–14 Xia Z, Ghildyal N, Austen KF, Stevens RL. 1996. Post-transcriptional regulation of chymase expression in mast cells: a cytokine-dependent mechanism for controlling the expression of granule neutral proteases of hematopoietic cells. J. Biol. Chem. 271:8747– 53 Friend DS, Ghildyal N, Austen KF, Gurish MF, Matsumoto R, Stevens RL. 1996. Mast cells that reside at different locations in the jejunum of mice infected with Trichinella spiralis exhibit sequential changes in their granule ultrastructure and chymase phenotype. J. Cell Biol. 135:279–90 Gurish MF, Pear WS, Stevens RL, Scott ML, Sokol K, et al. 1995. Tissue-regulated differentiation and maturation of a v-abl-immortalized mast cell-committed progenitor. Immunity 3:175–86 Yurt RW, Leid RW Jr, Austen KF, Silbert JE. 1977. Native heparin from rat peritoneal mast cells. J. Biol. Chem. 252:518 Metcalfe DD, Lewis RA, Silbert JE, Rosenberg RD, Wasserman SI, Austen KF. 1979. Isolation and characterization of heparin from human lung. J. Clin. Invest. 64:1537–43 Metcalfe DD, Smith JA, Austen KF, Silbert JA. 1980. Polydispersity of rat mast cell heparin. Implications for proteoglycan assembly. J. Biol. Chem. 255:11753–58 Razin E, Stevens RL, Akiyama F, Schmid K, Austen KF. 1982. Culture from mouse bone marrow of a subclass of mast cells possessing a distinct chondroitin sulfate proteoglycan with glycosaminoglycans rich in N-acetylgalactosamine-4,6-disulfate. J. Biol. Chem. 257:7229–36 Serafin WE, Katz HR, Austen KF, Stevens RL. 1986. Complexes of heparin proteoglycans, chondroitin sulfate E proteoglycans, and [3 H]diisopropyl fluorophosphate-binding proteins are exocytosed from activated mouse bone marrow-derived mast cells. J. Biol. Chem. 261:15017–21 Avraham S, Stevens RL, Gartner MC, Austen KF, Lalley PA, Weis JH. 1988. Isolation of a cDNA that encodes the peptide core of the secretory granule proteoglycan of rat basophilic leukemia-1 cells and assessment of its homology to the human analogue. J. Biol. Chem. 263:7292–96
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77. Stevens RL, Avraham S, Gartner MC, Bruns GAP, Austen KF, Weis JH. 1988. Isolation and characterization of a cDNA that encodes the peptide core of the secretory granule proteoglycan of human promyelocytic leukemia HL-60 cells. J. Biol. Chem. 263:7287– 91 78. Avraham S, Austen KF, Nicodemus CF, Gartner MC, Stevens RL. 1989. Cloning and characterization of the mouse gene that encodes the peptide core of secretory granule proteoglycans and expression of this gene in transfected rat-1 fibroblasts. J. Biol. Chem. 264:16719–26 79. Kitamura Y, Go S, Hatanaka K. 1978. Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation. Blood 52:447–52 80. Rodewald HR, Dessing M, Dvorak AM, Galli SJ. 1996. Identification of a committed precursor for the mast cell lineage. Science 271:818–22 81. Crapper RM, Schrader JW. 1983. Frequency of mast cell precursors in normal tissues determined by an in vitro assay: antigen induces parallel increases in the frequency of P cell precursors and mast cells. J. Immunol. 131:923–28 82. Gurish MF, Tao H, Abonia JP, Arya A, Friend DS, et al. 2001. Intestinal mast cell progenitors require CD49dβ7 (α4β7 integrin) for tissue-specific homing. J. Exp. Med. 194:1243–52 83. Abonia JP, Austen KF, Rollins BJ, Joshi SK, Flavell RA, et al. 2005. Constitutive homing of mast cell progenitors to the intestine depends on autologous expression of the chemokine receptor CXCR2. Blood 105:4308–13 84. Abonia JP, Hallgren J, Jones T, Shi R, Xu Y, et al. 2006. Alpha-4 integrins and VCAM-1, but not MAdCAM-1, are essential for recruitment of mast cell progenitors to the inflamed lung. Blood 108:1588–94 85. Arinobu Y, Iwasaki H, Gurish MF, Mizuno S, Shigematsu H, et al. 2005. Developmental checkpoints of the basophil/mast cell lineages in adult murine hematopoiesis. Proc. Natl. Acad. Sci. USA 102:18105–10 86. Katz HR, Benson AC, Austen KF. 1989. Activation and phorbol ester-stimulated phosphorylation of a plasma membrane glycoprotein antigen expressed on mouse IL-3dependent mast cells and serosal mast cells. J. Immunol. 142:919–26 87. Arm JP, Gurish MF, Reynolds DS, Scott HC, Gartner CS, et al. 1991. Molecular cloning of gp49, a cell surface antigen that is preferentially expressed by mouse mast cell progenitors and is a new member of the immunoglobulin superfamily. J. Biol. Chem. 266:15966– 73 88. Castells MC, Wu X, Arm JP, Austen KF, Katz HR. 1994. Cloning of the gp49B gene of the immunoglobulin superfamily and demonstration that one of its two products is an early-expressed mast cell surface protein originally described as gp49. J. Biol. Chem. 269:8393–401 89. Katz HR, Vivier E, Castells MC, McCormick MJ, Chambers JM, Austen KF. 1996. Mouse mast cell gp49B1 contains two immunoreceptor tyrosine-based inhibition motifs and suppresses mast cell activation when coligated with the high affinity Fc receptor for IgE. Proc. Natl. Acad. Sci. USA 93:10809–14 90. Daheshia M, Friend DS, Grusby MJ, Austen KF, Katz HR. 2001. Increased severity of local and systemic anaphylactic reactions in gp49B1-deficient mice. J. Exp. Med. 194:227– 33 91. Feldweg AM, Friend DS, Zhou JS, Kanaoka Y, Daheshia M, et al. 2003. gp49B1 suppresses stem cell factor-induced mast cell activation-secretion and attendant inflammation in vivo. Eur. J. Immunol. 33:2262–68 www.annualreviews.org • Doing What I Like
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92. Zhou JS, Friend DS, Feldweg AM, Daheshia M, Li L, et al. 2003. Prevention of lipopolysaccharide-induced microangiopathy by gp49B1: evidence for an important role for gp49B1 expression on neutrophils. J. Exp. Med. 198:1243–51 93. Arm JP, Nwankwo C, Austen KF. 1997. Molecular identification of a novel family of human Ig superfamily members that possess immunoreceptor tyrosine-based inhibition motifs and homology to the mouse gp49B1 inhibitory receptor. J. Immunol. 159:2342–49 94. Pillemer L, Blum L, Lepow IH, Ross OA, Todd EW, Wardlaw AC. 1954. The properdin system and immunity. I. Demonstration and isolation of a new serum protein, properdin, and its role in immune phenomena. Science 120:279–85 95. Fearon DT, Austen KF, Ruddy S. 1973. Formation of a hemolytically active cellular intermediate by the interaction between properdin factors B and D and the activated third component of complement. J. Exp. Med. 138:1305–13 96. Fearon DT, Austen KF. 1975. Properdin: binding to C3b and stabilization of the C3bdependent convertase. J. Exp. Med. 142:856–63 97. Weiler JM, Daha MR, Austen KF, Fearon DT. 1976. Control of the amplification convertase of complement by the plasma protein β1H. Proc. Natl. Acad. Sci. USA 73:3268–72 98. Whaley K, Ruddy S. 1976. Modulation of the alternative complement pathways by beta 1H globulin. J. Exp. Med. 144:1147–63 99. Fearon DT, Austen KF. 1975. Initiation of C3 cleavage in the alternative complement pathway. J. Immunol. 115:1357–61 100. Fearon DT, Austen KF, Ruddy S. 1974. Properdin factor D: characterization of its active site and isolation of the precursor form. J. Exp. Med. 139:355–66 101. Fearon DT, Austen KF. 1977. Activation of the alternative complement pathway due to resistance of zymosan-bound amplification convertase to endogenous regulatory mechanisms. Proc. Natl. Acad. Sci. USA 74:1683–87 102. Fearon DT, Austen KF. 1977. Activation of the alternative complement pathway with rabbit erythrocytes by circumvention of the regulatory action of endogenous control proteins. J. Exp. Med. l46:22–33 103. Fearon DT. 1978. Regulation by membrane sialic acid of beta 1H-dependent decaydissociation of amplification C3 convertase of the alternative complement pathway. Proc. Natl. Acad. Sci. USA 75:1971–75 104. Soter NA, Lewis RA, Corey EJ, Austen KF. 1983. Local effects of synthetic leukotrienes (LTC4 , LTD4 , LTE4 and LTB4 ) in human skin. J. Invest. Dermatol. 80:115– 19 105. Weiss JW, Drazen JM, Coles N, McFadden ER Jr, Weller PF, et al. 1982. Bronchoconstrictor effects of leukotriene C in humans. Science 216:196–98 106. Griffin M, Weiss JW, Leitch AG, McFadden ER Jr, Corey EJ, et al. 1983. Effects of leukotriene D on the airways in asthma. N. Engl. J. Med. 308:436–39 107. Davidson AB, Lee TH, Scanlon PD, Solway J, McFadden ER Jr, et al. 1987. Bronchoconstrictor effects of leukotriene E4 in normal and asthmatic individuals. Am. Rev. Respir. Dis. 135:333–37 108. Sheffer AL, Austen KF. 1980. Exercise-induced anaphylaxis. J. Allergy Clin. Immunol. 66:106–11 109. Sheffer AL, Soter NA, McFadden ER Jr, Austen KF. 1983. Exercise-induced anaphylaxis: a distinct form of physical allergy. J. Allergy Clin. Immunol. 71:311–l6 110. Sheffer AL, Tong AKF, Murphy GF, Lewis RA, McFadden ER Jr, Austen KF. 1985. Exercise-induced anaphylaxis: a serious form of physical allergy associated with mast cell degranulation. J. Allergy Clin. Immunol. 75:479–84
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111. Soter NA, Wasserman SI, Austen KF, McFadden ER Jr. 1980. Release of mast cell mediators and alterations in lung function in patients with cholinergic urticaria. N. Engl. J. Med. 302:604–8 112. Roberts LJ II, Lewis RA, Oates JA, Austen KF. 1979. Prostaglandin, thromboxane, and 12-hydroxy-5,8,10,14-eicosatetraenoic acid production by ionophore-stimulated rat serosal mast cells. Biochim. Biophys. Acta 575:185–92 113. Lewis RA, Soter NA, Diamond PT, Austen KF, Oates JA, Roberts LJ II. 1982. Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE. J. Immunol. 129:1627–31 114. Roberts LJ II, Sweetman BJ, Lewis RA, Austen KF, Oates JA. 1980. Increased production of prostaglandin D2 in patients with systemic mastocytosis. N. Engl. J. Med. 303:1400–4 115. Soter NA, Austen KF, Wasserman SI. 1979. Oral disodium cromoglycate in the treatment of systemic mastocytosis. N. Engl. J. Med. 301:465–69 116. Donaldson VH, Evans RR. 1963. A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C’1-esterase. Am. J. Med. 35:37–44 117. Austen KF, Sheffer AL. 1965. Detection of hereditary angioneurotic edema by demonstration of a profound reduction in the second component of human complement. N. Engl. J. Med. 272:649–56 118. Ruddy S, Austen KF. 1967. A stoichiometric assay for the fourth component of complement in whole human serum using EAC’1agp and functionally pure human second component. J. Immunol. 99:1162–72 119. Spaulding WB. 1955. Hereditary angioneurotic oedema in two families. Can. Med. Assoc. J. 73:181–87 120. Sheffer AL, Fearon DT, Austen KF. 1979. Clinical and biochemical effects of impeded androgen (oxymethalone) therapy of hereditary angioedema (HAE). J. Allergy Clin. Immunol. 64:275–80 121. Sheffer AL, Fearon DT, Austen KF. 1981. Clinical and biochemical effects of stanozolol therapy for hereditary angioedema. J. Allergy Clin. Immunol. 68:181–87 122. Caldwell JR, Ruddy S, Schur PH, Austen KF. 1972. Acquired C1 inhibitor deficiency in lymphosarcoma. Clin. Immunol. Immunopathol. 1:39 123. Geha RS, Quinti I, Austen KF, Cicardi M, Sheffer A, Rosen FS. 1985. Acquired C1inhibitor deficiency associated with antiidiotypic antibody to monoclonal immunoglobulins. N. Engl. J. Med. 312:534–40 124. Fearon DT. 1980. Identification of the membrane glycoprotein that is the C3b receptor of the human erythrocyte, polymorphonuclear leukocyte, B lymphocyte, and monocyte. J. Exp. Med. 152:20–30 125. Nicholson-Weller A, Burge J, Fearon DT, Weller PF, Austen KF. 1982. Isolation of a human erythrocyte membrane glycoprotein with decay-accelerating activity for C3 convertases of the complement system. J. Immunol. 129:184–89 126. Nicholson-Weller A, March JP, Rosenfeld SI, Austen KF. 1983. Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria are deficient in the complement regulatory protein, decay accelerating factor. Proc. Natl. Acad. Sci. USA 80:5066– 70 127. Hunsicker LG, Ruddy S, Carpenter CB, Schur PH, Merrill JP, et al. 1972. Metabolism of third complement component (C3) in nephritis: role of the classical and alternate (properdin) pathways for complement activation. N. Engl. J. Med. 287:835–40 128. Daha MR, Fearon DT, Austen KF. 1976. C3 nephritic factor (C3NeF): stabilization of fluid phase and cell-bound alternative pathway convertase. J. Immunol. 116:1–7 www.annualreviews.org • Doing What I Like
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129. Daha MR, Austen KF, Fearon DT. 1977. The incorporation of C3 nephritic factor (C3NeF) into a stabilized C3 convertase, C3b, Bb (C3NeF) and its release after decay of convertase function. J. Immunol. 19:812–17 130. Daha MR, Austen KF, Fearon DT. 1978. Heterogeneity, polypeptide composition and antigenic reactivity of C3NeF. J. Immunol. 120:1389–94 131. Austen KF. 2004. Acceptance of the Kober Medal: It only gets better. J. Clin. Invest. 114:1177
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Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin Burnham Institute for Medical Research, La Jolla, California 92037; email:
[email protected],
[email protected],
[email protected],
[email protected],
[email protected],
[email protected] Annu. Rev. Immunol. 2008. 26:29–55
Key Words
First published online as a Review in Advance on October 11, 2007
LYP, PTPN22, CD45
The Annual Review of Immunology is online at immunol.annualreviews.org This article’s doi: 10.1146/annurev.immunol.26.021607.090418 c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0029$20.00
Abstract Protein tyrosine phosphatases (PTPs) are important regulators of many cellular functions and a growing number of PTPs have been implicated in human disease conditions, such as developmental defects, neoplastic disorders, and immunodeficiency. Here, we review the involvement of PTPs in human autoimmunity. The leading examples include the allelic variant of the lymphoid tyrosine phosphatase (PTPN22), which is associated with multiple autoimmune diseases, and mutations that affect the exon-intron splicing of CD45 (PTPRC). We also find it likely that additional PTPs are involved in susceptibility to autoimmune and inflammatory diseases. Finally, we discuss the possibility that PTPs regulating the immune system may serve as therapeutic targets.
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INTRODUCTION
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T regulatory (Treg) cells: specialized T cells (CD4+ CD25+ Foxp3+ ) that suppress activation of the adaptive immune system, contributing to self-tolerance and immune system homeostasis Tolerance: a state of unresponsiveness of cells of the adaptive immune system to self-antigens TCR: T cell antigen receptor
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Over 100 years ago Paul Ehrlich first proposed the concept of horror autotoxicus, the unthinkable possibility that an organism’s immune system would mount a response against itself. Today, we know that breakdown of self-tolerance is not uncommon and can result in serious immune-mediated damage and destruction of an individual’s own cells and tissues. There are currently over 80 diseases classified as autoimmune, affecting approximately 5% of the human population. Moreover, autoimmune disorders are among the top 10 leading causes of death and affect at least 10 million individuals in the United States alone. Autoimmunity develops through a combination of environmental and genetic factors resulting in a broad spectrum of human illnesses. Many genes identified as causing or predisposing to autoimmunity encode proteins that are involved in lymphocyte, macrophage, or dendritic cell signal transduction (1–7). Studies conducted with patient samples and with numerous animal models of autoimmune disease have demonstrated that subtle imbalances in the regulation of the activation and/or function of immune cells can precipitate the development of autoimmunity. Although several autoimmune diseases are characterized by the presence of autoantibodies produced by autoreactive B cells, genetic evidence [e.g., major histocompatibility complex (MHC) association] and animal models point to a central role of autoreactive T cells as the primary mediators of autoimmune disease. More recently, T cell subsets, such as CD4+ CD25+ Foxp3+ T regulatory (Treg) cells and T helper 17 (Th17) cells, have been implicated in the maintenance of peripheral tolerance (discussed below) and in promoting inflammation and tissue destruction (8, 9), respectively. Even though the etiology of each autoimmune disease is different (and often poorly understood), it appears that a common theme is a failure of immunologic tolerance, presumably by one or more lymphocyte subsets. Central tolerance is generated through mechanisms of Vang et al.
thymic negative selection wherein developing T cells with medium to high affinity for tissuespecific self-antigens are deleted, thereby eliminating putative autoreactive T cells from the peripheral T cell repertoire. Alternatively, thymocytes with T cell antigen receptors (TCRs) recognizing self-antigens can develop into Treg cells, which then function in the periphery to control self-reactive T cells that have escaped clonal deletion (10). Autoimmunity may develop if TCR signal strength is altered, for example by mutations in signaling proteins, leading to decreased effectiveness of negative selection allowing for the “escape” of autoreactive T cells and/or altering the development of Treg cells in the thymus. Analogous mechanisms are operative in B cells where high-affinity/avidity self-antigens induce rapid elimination (clonal deletion) of newly formed B cells in the bone marrow. Low-affinity/avidity interactions, by contrast, induce an anergic state where B cells are short lived and will succumb to apoptosis in the sustained presence of self-antigen (11, 12). Peripheral tolerance encompasses a myriad of mechanisms that include clonal anergy via activation by immature dendritic cells, clonal ignorance (13), clonal exhaustion, immune privilege, and regulation by Treg cells (14–16). Of note, Treg cells generated in the periphery, so-called adaptive Tregs, through the concerted actions of autoantigen and transforming growth factor-β (TGF-β), also function to suppress T cell activation. B cells can acquire self-reactivity as a consequence of V gene hypermutation during T cell–dependent differentiation in the germinal center. In such a case, altered antigen receptor specificity could lead to the efficient uptake and presentation of autoantigens as well as the generation of plasma cells producing autoantibodies. Together, the mechanisms of peripheral tolerance are aimed at preventing activation of autoreactive T cells, thereby avoiding immune responses against self and, ultimately, tissue damage. Because of the increasing prevalence of autoimmune diseases, particularly in the
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industrialized world, a better understanding of the molecular mechanisms of autoimmunity would be helpful for the development of more effective and specific treatments. Signaling molecules in immune cells are promising targets for such treatments. Protein tyrosine phosphatases (PTPs) constitute a group of signaling mediators playing important regulatory roles in immune cells and may prove useful as targets for medical treatment of autoimmune disorders. This review focuses on the known roles of PTPs in autoimmunity.
PROTEIN TYROSINE PHOSPHATASES The human genome contains a total of 107 genes encoding either experimentally verified PTPs or proteins with a domain homologous to the catalytic domain of these PTPs, i.e., probable PTPs (17). The corresponding gene products of 81 of these genes are predicted to be active protein phosphatases; 13 dephosphorylate inositol phospholipids, 2 dephosphorylate mRNA, and 11 are catalytically inactive. On the basis of the primary structure of the catalytic domains, PTPs can be divided into four evolutionarily distinct classes. Class I PTPs constitute the largest group with 99 members, including 38 classical PTPs and 61 VH1-like (dual-specific) phosphatases (DSPs). The classical PTPs can further be divided into receptor and nonreceptor PTPs. There are seven different subgroups of DSPs [MAPK phosphatases (MKPs), atypical DSPs, slingshots, PRLs, CDC14s, phosphatase and tensin homologs (PTENs), and myotubularins]. Class II contains only one member [low-molecular-weight phosphotyrosine phosphatase (LMPTP)], whereas class III has three members (CDC25 A, B, and C). All the members of these three classes of PTPs use a cysteine-based catalytic mechanism. In contrast, class IV PTPs are aspartate based and are currently represented by the four Eya genes. The expression patterns of individual PTPs vary from ubiquitous to strictly tissue
specific. Most cells express 30% to 60% of the entire complement of PTPs. Neuronal and hematopoietic cells tend to express a relatively high number of PTPs. T cells, for instance, contain between 60 and 70 different PTPs, and a similar set is found in B cells (18). Several PTPs are restricted to hematopoietic cells, for example LYP (lymphoid tyrosine phosphatase, also known as PTPN22); the mouse ortholog is called PEP [proline-, glutamicacid-, serine-, and threonine-rich (PEST)domain-enriched PTP)], SHP1 (Src homology 2-domain-containing PTP 1), CD45, and HePTP (hematopoietic PTP). Of the 60–70 PTPs expressed in T cells, approximately 20 regulate signaling events between the TCR and transactivation of the interleukin-2 (IL-2) gene (18). Most of these PTPs affect TCR signaling in an inhibitory manner, but a few (such as CD45, LMPTP, and SHP2) have a positive regulatory role. The importance of PTPs in immune cell signaling has recently been extensively reviewed (18, 19), and here we focus only on the involvement of PTPs in autoimmune disease (Table 1).
PTP: protein tyrosine phosphatase LYP: lymphoid tyrosine phosphatase Proline-rich motif/domain: a motif/domain that contains the proline-rich sequence PxxP and is found in numerous signaling proteins
LYMPHOID TYROSINE PHOSPHATASE (LYP; PTPN22) AND AUTOIMMUNITY Structure and Function of LYP The human PTPN22 gene is located on chromosome 1p13.3–13.1. It encodes an 807amino acid residue protein, LYP (20), which belongs to the PEST group of nonreceptor classical class I PTPs. The two other members of this family are PTP-PEST (PTP with PEST domain, genomic designation PTPN12) and PTP-HSCF (PTP hematopoietic stem-cell fraction, genomic designation PTPN18). LYP contains an N-terminal PTP domain, a central region of unknown function, and a C-terminal portion of approximately 200 amino acids containing four proline-rich motifs termed P1-P4. P4 is part of the so-called www.annualreviews.org • Phosphatases and Autoimmunity
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List of PTPs involved in autoimmunity, their mechanisms and phenotypesa
Common name
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Genomic designation
Synonyms
Molecular mechanism(s) for disease development
Cellular mechanism(s) for disease development
Phenotype(s)b
Gain-of-function mutation, reduced TCR signaling
Reduced negative selection in thymus? Reduced activity of Treg cells? Altered activity of other hematopoietic cells?
Associated with T1D, RA, JIA, SLE, Graves’ disease, myasthenia gravis, generalized vitiligo, Wegener’s granulomatosis
LYP (PEP in mouse)
PTPN22
PTP-PEST
PTPN12
PTPG1, PTP-P19
Mutations in CD2BP1 cause loss of PTP-PEST binding. Altered spatial regulation of PTP-PEST?
Exaggerated proliferation and infiltration of neutrophils. Altered activities of B or T cells?
Indirectly associated with the autoinflammatory condition FRA/PAPA syndrome
CD45
PTPRC
B220, Gp180, LCA, Ly5, T220
Aberrant CD45 activity due to abnormal splicing, the produced CD45RA isoforms are less likely to dimerize and hence are less likely to be autoinhibited
Altered B and/or T cell function? In mice with aberrant CD45 activity, B cells are hyperresponsive and hyperproliferative
Associated with autoimmune hepatitis and systemic sclerosis, and perhaps MS. In mice with aberrant CD45 activity, SLE-like disease and lymphoproliferative disorder are observed
IA-2
PTPRN
Islet cell antigen 512
The normal protein serves as autoantigen
Serves as autoantigen in pancreatic β-cells in T1D
T1D
Ia-2β
PTPRN2
Phogrin, PTPRP, RPTPπ
The normal protein serves as autoantigen
Serves as autoantigen in pancreatic β-cells in T1D
T1D
SHP1
PTPN6
HCP, Hcph, PTP1C, SH-PTP1
In mice, loss of expression or loss of function
In mice, inflammation caused by aberrant myeloid cells, B cell abnormalities
In mice, motheaten phenotype; B cells alone cause SLE-like disease
a The list includes the most relevant PTPs with regard to autoimmunity. The PTPs are listed in the order they appear in the text. Unless otherwise stated, the information given applies for humans. b Abbreviations: T1D, type 1 diabetes; RA, rheumatoid arthritis; JIA, juvenile idiopathic arthritis; SLE, systemic lupus erythematosus; FRA/PAPA, familial recurrent arthritis/pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome; MS, multiple sclerosis.
C-terminal homology (CTH) domain, which is found in all members of the PEST group of PTPs (21, 22). LYP may also exist as an alternatively spliced form called LYP2, which has a shorter C terminus, resulting in the absence of P2, P3, and P4 (CTH domain) (20), 32
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although this form has not been detected by others. The mouse ortholog of LYP is called PEP (23), and it was given the genomic designation PTPN8 because initially it was not clear that LYP and PEP were species orthologs. Both LYP and PEP are expressed exclusively
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in hematopoietic cells and share 89% identity between their PTP domains and 61% identity for their noncatalytic portions. Much of the current knowledge regarding LYP/PEP is derived from studies of PEP, and it should be stressed that data obtained with PEP may not necessarily apply completely to LYP, as these two PTPs show subtle biochemical differences in some assays (T. Vang & T. Mustelin, unpublished observations). The subcellular localization of LYP is mainly cytoplasmic, but some PEP can also be found in the nucleus (20, 24). Factors determining the localization of LYP/PEP in cells are poorly understood, but several binding partners have been identified. The best characterized is C-terminal Src kinase (Csk), which through its Src homology 3 (SH3) domain binds to the P1 region in LYP/PEP (25–27). This interaction is of relatively high stoichiometry: In mouse T cells, approximately 5% of total cellular Csk associates with 25% to 50% of total cellular PEP (25); the corresponding numbers for LYP in human cells are not known. Like other PEST group PTPs, both LYP and PEP contain a CTH domain at their C termini to which the coiled-coil domain of the cytoskeletalassociated protein proline-serine-threonine PTP-associated protein (PSTPIP) can bind (T. Vang, A.V. Miletic & T. Mustelin, unpublished observations). The human ortholog of PSTPIP is called CD2-binding protein 1 (CD2BP1). There are also reports that LYP can interact with the adaptor molecule Grb2 (28) as well as the adaptor molecule and the E3 ligase c-Cbl (20). Both PEP and LYP inhibit TCR signaling by acting immediately downstream of the TCR. Specifically, PEP has been implicated in the dephosphorylation of the positive regulatory tyrosine residue in the activation loop of the Src family kinases (SFKs) FynT (Y417) and Lck (Y394), as well as ZAP-70 (29, 30). PEP also negatively impacts TCR-induced phosphorylation of the tyrosines within the immunoreceptor tyrosinebased activation motifs (ITAMs) in CD3/ζ-
chains, but these effects may be indirect because SFKs (particularly Lck) are responsible for phosphorylation of ITAMs (29). A recent study using a substrate-trapping mutant version of LYP combined with mass spectrometry identified the following substrates: Lck (Y394), the ITAMs of CD3/ζ-chains, ZAP-70 (Y493), Vav, and valosin-containing protein (31). The ability of LYP/PEP to bind Csk may be important. Although PEP dephosphorylates the positive regulatory tyrosine in the activation loop of Lck (Y394) and FynT (Y417), Csk phosphorylates the C-terminal negative regulatory tyrosine in Lck (Y505) and FynT (Y528) (29, 30). However, recent data contradict the notion that Csk association promotes LYP/PEP function in TCR signaling. First, PEP cannot bind Csk when the latter interacts with the membrane protein Cbp/PAG (Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched membrane domains), which exclusively partitions into lipid rafts and contributes to raft targeting of Csk (32). Second, PEP is in fact not found in lipid rafts (32). Therefore, at present it is unclear how PEP targets lipid raft–resident proteins such as Lck and FynT. In comparison, in human T cells, a small fraction of LYP partitions into lipid rafts, but this partitioning is independent of Csk binding, highlighting interesting differences between PEP and LYP (T. Vang, A.V. Miletic & T. Mustelin, unpublished observations). Mice deficient in PEP have normal resting T cell numbers and subpopulations but exhibit enhanced memory T cell responses (33). Furthermore, restimulation of T cells from these animals is associated with elevated and sustained TCR-induced phosphorylation of both Lck-Y394 and of ZAP-70, as well as augmented proliferation. The lack of a noticeable phenotype in naive T cells from PEP−/− mice may be due to redundancy with PTP-PEST (Y. Arimura & T. Mustelin, unpublished observations). A recent study found that microRNA-181a targets and downregulates PEP expression, resulting in elevated www.annualreviews.org • Phosphatases and Autoimmunity
C-terminal homology (CTH) domain: a proline-rich sequence found at the C terminus of PEST group PTPs Csk: C-terminal Src kinase Src homology 3 (SH3) domain: a protein domain of approximately 60 amino acids capable of binding proline-rich motifs SFK: Src family kinase
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Single-nucleotide polymorphism (SNP): one nucleotide in a gene differs between members of a species or between paired chromosomes in an individual causing a DNA sequence variation T1D: type 1 diabetes RA: rheumatoid arthritis
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Lck-Y394 phosphorylation in resting T cells and rendering the cells hyperresponsive to TCR stimulation (34). In addition to PEP, microRNA-181a also targets DUSP6, a MAP kinase-specific phosphatase, which may contribute to the downstream response (34). In accordance with these observations for PEP, acute elimination of LYP in Jurkat T cells using RNA interference resulted in increased TCR-mediated activation of nuclear factor κB (35). Although most of our knowledge about LYP/PEP is derived from studies on T cells, LYP/PEP is also expressed in all other leukocyte lineages. In PEP-deficient mice, the germinal center B cell population and IgG production are elevated, but it remains to be determined whether these effects are B cell intrinsic or secondary to defects in the T cell compartment (33).
Association of the C1858T Polymorphism in PTPN22 with Autoimmune Diseases In 2004, we reported that the C1858T single-nucleotide polymorphism (SNP) in the PTPN22 gene was associated with increased risk of type 1 diabetes (T1D) in two independent populations (6). The following year, association of T1D with the T1858 allele was confirmed in additional large population samples (36–38). Furthermore, the same association was found for rheumatoid arthritis (RA) (35, 39–42), juvenile idiopathic arthritis ( JIA) (42, 43), systemic lupus erythematosus (SLE) (39, 41, 44), Graves’ disease (36, 45), myasthenia gravis (46), generalized vitiligo (47), and Wegener’s granulomatosis (48). Interestingly, some diseases were demonstrated not to be associated with the T1858 allele, including multiple sclerosis (MS) (41, 43, 49), inflammatory bowel diseases such as Crohn’s disease (50– 52) and ulcerative colitis (52, 53), celiac disease (42, 54), primary sclerosing cholangitis (42), primary biliary cirrhosis (55), psoriasis (43), and psoriatic arthritis (43). In addition, several other disorders (such as Hashimoto’s 34
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thyroiditis, primary Sjogren’s syndrome, and systemic sclerosis) have been investigated with regard to involvement of the C1858T SNP, but these data are somewhat conflicting, and more studies are required. A recent metaanalysis confirmed the association between the T1858 allele and the diseases T1D, RA, JIA, SLE, and Graves’ disease, while there was no association with MS, inflammatory bowel disease, psoriasis, or Addison’s disease (56). In general, PTPN22 appears to be coupled to the collection of autoimmune diseases that typically are characterized by circulating autoantibodies. On the basis of many genetic studies conducted with different populations, there is a clear geographic gradient with regard to the frequency of the disease-associated T1858 allele in Europe. Even though this allele is relatively rare in southern European populations (2% in Italy, 6% in Spain), the frequency increases northward through Europe (8% in the United Kingdom, 12% in Sweden, 15.5% in Finland). Interestingly, in African American and Asian populations, the T1858 allele is virtually absent, suggesting a northern European origin and/or selective advantage for the T1858 allele in this region. Nevertheless, an adequate number of studies have now been conducted to demonstrate that the autoimmune disease association with the T1858 allele is population independent. In addition to the C1858T SNP (rs2476601), there are numerous other SNPs in the human PTPN22 gene. An initial investigation of the role of these other SNPs in RA patients confirmed that C1858T is the major disease-associated SNP in PTPN22, but also suggested minor involvement of at least one other SNP (rs3789604) (57). Subsequent studies have supported the notion that C1858T is the only SNP in PTPN22 associated with RA (58–60). Similarly, T1D patients have also been investigated with regard to other SNPs in PTPN22. Whereas one report suggested that a promoter SNP in PTPN22 (-G1123C, rs2488457) confers increased risk
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of T1D (61), a later study could not confirm this connection (62), again supporting a role for C1858T as the major T1D-associated SNP in PTPN22 (63). However, it is still possible that additional polymorphisms may be discovered for PTPN22 and that these are independently related to different and/or overlapping groups of autoimmune disorders. For instance, one recent study suggested that the C1858T SNP was not associated with psoriasis but that there was evidence for a susceptibility locus for this disease somewhere else in PTPN22 or in its vicinity (64). The involvement of PTPN22 in multiple human autoimmune disorders places this gene in company of general autoimmunity genes (such as MHC and CTLA4) that increase the risk for numerous autoimmune diseases. The MHC locus (HLA variants) has the greatest impact among these genes, followed by PTPN22 and CTLA4 susceptibility variants. For T1D, HLA contributes approximately 40% to the familial clustering, while the corresponding number for PTPN22 is about 2% (65). Even so, the odds ratio is typically ∼1.5 for the T1858 allele in T1D, and that is substantially greater than the 1.1 value calculated for the CTLA4 variant predisposing for T1D (66). Obviously, the presence of many susceptibility loci and other factors, although of little impact on their own, can add up and contribute a significant portion to the genetic predisposition for T1D. To better predict the risk for autoimmune disorders, MHC haplotype could perhaps be combined with PTPN22 genotype and an additional set of nongenetic factors. Studies published so far have not revealed firm genetic interactions between PTPN22 and MHC in RA or T1D, but two recent reports demonstrated a strong connection between the disease-associated T1858 allele and the occurrence of anticyclic citrullinated peptide antibodies in RA (67, 68). When combined, these two factors led to an up to 350-fold increased risk of developing RA (67, 68). The concurrent presence of these two factors also predicted
the later development of RA with extremely high accuracy (68). Similarly, the T1858 allele confers increased risk for development of insulin autoantibodies (as well as of other autoantibodies) and progression from insulitis to clinical T1D (69). For other autoimmune diseases, additional factors may likewise enhance the predictive power of PTPN22 C1858T. The C1858T SNP may also potentially serve as a prognostic factor. A link between the T1858 allele and the course of disease or other variables of autoimmune disorders has been reported. For instance, the T allele is preferentially associated with rheumatoid factor (RF)-positive RA and probably not with RFnegative disease (35, 40, 70), although there are some conflicting results (43, 50). There also seems to be a dose-dependent effect of the T allele because two copies of this allele give a much higher risk for RF-positive RA compared with one copy alone (40). Furthermore, a recent study demonstrated that RA disease progression rate (evaluated as tissue damage) was increased in patients carrying the T allele (71). The C1858T SNP is also associated with an earlier age at RA onset (67). A similar pattern is observed for other diseases. For example, Graves’ disease will debut at a younger age in T1858/T1858 homozygous patients compared with patients with C1858/C1858 genotype, whereas heterozygous patients develop the disease at an intermediate age (72). In contrast, no correlation between the T allele and severity of Graves’ disease has been demonstrated (72). Likewise, the age at onset for T1D is lower for patients with the T1858/T1858 genotype compared with the C1858/C1858 genotype, but no difference has been seen with regard to autoantibodies (38, 73). Clearly, more work is required to clarify whether and how the C1858T SNP is associated with the clinical course and severity of autoimmune diseases. Such studies will also answer the question of whether determination of a patient’s PTPN22 genotype will be useful for evaluation of disease prognosis and treatment. www.annualreviews.org • Phosphatases and Autoimmunity
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Effects of the Disease-Associated LYP∗ W620 Allele at the Molecular Level
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The C1858T SNP changes amino acid 620 in LYP from an arginine to a tryptophan (6). We refer to the two forms as LYP∗ R620 (encoded by the C1858 allele) and LYP∗ W620 (encoded by the T1858 allele). Residue 620 is located within the P1 region, which interacts with the SH3 domain of Csk. The structure of the Csk SH3 domain with a bound peptide, including the P1 region from PEP (this peptide sequence differs only by one amino acid residue from the corresponding human sequence), was solved by NMR (27). Interestingly, the Csk SH3 domain contains two peptide recognition surfaces: the usual polyproline helix-binding surface of SH3 domains as well as a hydrophobic patch that interacts with hydrophobic residues C-terminal to the polyproline helix of the PEP P1 region. In the P1 sequence PPLPERTPESFIV, the underlined residues are responsible for the binding to the polyproline helix-binding surface, and the two C-terminal residues (I and V) mediate the interaction with the hydrophobic patch. Both of these sets of interactions contribute to the binding affinity. The P1 region in the human LYP∗ R620 (PPLPVRTPESFIV, R620 in bold) differs from the mouse sequence only in residue V619, which corresponds to a glutamic acid in the mouse. However, this residue is not involved in SH3 binding, and because the amino acid sequences of the Csk SH3 domain in humans and mice are identical, it is likely that the PEP-P1/Csk-SH3 and LYP∗ R620P1/Csk-SH3 interactions are virtually identical. These structures also strongly predict that the R620W change in LYP will severely impair the formation of the LYP-Csk complex. This model was confirmed experimentally, both with recombinant and endogenous proteins. Thus, although LYP∗ R620 bound strongly to the SH3 domain of Csk, the corresponding interaction between LYP∗ W620 and Csk was undetectable (5, 6, 35).
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Because of earlier reports that PEP and Csk in complex downmodulate TCR signaling in a cooperative manner (29, 30), we and others expected that the inability of LYP∗ W620 to bind Csk would result in less efficient inhibition of TCR signaling by LYP∗ W620 compared with LYP∗ R620. However, all experimental data clearly demonstrated that the opposite was the case. When expressed in either Jurkat T cells or in primary human T cells, both LYP∗ R620 and LYP∗ W620 reduced TCR signaling in a dosedependent manner, but at equivalent expression levels LYP∗ W620 was consistently more potent (5). This was observed for all TCRsignaling parameters tested, including LckY394 phosphorylation, ζ-chain phosphorylation, LAT phosphorylation, intracellular calcium flux, Erk1/2 phosphorylation, activation of the proximal IL-2 promoter (containing NFAT and AP1 sites), as well as IL-2 secretion. Furthermore, T cells from the peripheral blood of T1D patients with LYP∗ W620 (heterozygous T1858/C1858 genotype) secreted less IL-2 in response to TCR/CD28 costimulation than T cells from patients homozygous for LYP∗ R620. All T cell subsets were similar between the two groups, excluding the possibility that the reduced IL-2 secretion levels were due to a skewing in T cell subsets. Importantly, when T cells from the two patient groups were stimulated with a combination of phorbol ester and ionomycin to bypass proximal TCR signaling, IL-2 secretion levels were indistinguishable, demonstrating that the only differences between the two groups were present in signaling events immediately downstream of the TCR. These findings raise the question: What is/are the mechanism(s) by which LYP∗ W620 is a stronger inhibitor of TCR signaling? There are several possibilities. Although residue 620 is more than 300 amino acid residues C-terminal to the PTP domain, LYP∗ W620 is approximately 1.5-fold more active a PTP than LYP∗ R620 (5). Although this increase in activity may not seem significant, it is consistent with our observation that
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even a modest overexpression of LYP in T cells has a profound inhibitory effect on TCR signaling. It remains unclear, however, how a mutation so far away from the PTP domain can affect the PTP activity. In the absence of crystal structures of the two LYP variants, one can only speculate that the noncatalytic portion of LYP may play a regulatory role in the function of the catalytic domain. In support of this notion, we found that deletion of the C-terminal half of PEP resulted in a fivefold increase in its PTP activity (30), suggesting an interaction between the N and C termini of PEP. Thus, it is possible that binding of ligands to the C-terminal part of LYP may affect the catalytic activity of LYP/PEP, perhaps in a manner reminiscent of the way SH2 domain ligands activate SHP1 or SHP2. Even though Csk coimmunoprecipitated with LYP∗ R620 in the above-mentioned PTP assays, no coimmunoprecipitation was seen between LYP∗ W620 and Csk (5). Theoretically, the absence of Csk binding per se could enhance the catalytic activity of LYP (in what would be the opposite type of regulation compared with SHP1). However, such a model is less likely because the two LYP variants expressed and purified from a Csk-deficient system did not exhibit changes in PTP activities when increasing amounts of Csk were added (T. Vang & T. Mustelin, unpublished observations). Another possibility is that the R620W mutant confers upon the P1 region of LYP the capacity to interact more strongly with other proteins and that these proteins can induce a more catalytically preferable conformation of the LYP PTP domain. However, in the absence of any experimental evidence, all of these possibilities remain completely speculative. It is reasonable to assume that there is an equilibrium between free LYP and LYP bound to known (Csk, Grb-2, c-Cbl, PSTPIP) or unknown proteins. Any skewing of this equilibrium may have profound cellular effects. In murine T cells, 25% to 50% of total cellular PEP are bound to Csk (25) in what appears to be a high-affinity interaction with a Kd =
0.8 μM (27). This is probably also true for human LYP∗ R620 and Csk. In comparison, most SH3 domain-mediated interactions have a Kd ≥ 10 μM. Thus, a disruption of the LYPCsk interaction, as is the case for LYP∗ W620, may result in a more than 1.5-fold increase in the pool of free LYP (i.e., not bound to Csk), which may bind other proteins. Such a mechanism, combined with altered ligand properties for the P1 region of LYP∗ W620, may contribute to make LYP∗ W620 a stronger inhibitor of TCR signaling compared with LYP∗ R620. We currently have some experimental evidence in support for this model (T. Vang & T. Mustelin, unpublished data). Another explanation for the augmented inhibitory effect of LYP∗ W620 on TCR signaling is altered subcellular localization, which may be tightly connected with a new set of interacting partners for LYP∗ W620 compared with LYP∗ R620. There appear to be subtle differences between the two LYP variants as evaluated by subcellular localization analyses and biochemical fractionation studies (T. Vang, A.V. Miletic & T. Mustelin, unpublished data), but more studies are required to clarify these issues. A final explanation for the increased inhibitory potential of LYP∗ W620 is an alteration in the substrate specificities and/or substrate affinities compared with LYP∗ R620, although this has yet to be experimentally tested.
Src homology 2 (SH2) domain: a protein domain of approximately 100 amino acids capable of binding tyrosine phosphorylated proteins
Effects of the Disease-Associated LYP∗ W620 at the Cellular and Systemic Level A simplistic model of autoimmunity would predict that T cells with abnormalities augmenting TCR signaling would be likely to cause disease. However, there is emerging evidence that the picture is much more complex. For instance, peripheral T cells from T1D patients are hyporesponsive rather than hyperresponsive to TCR stimulation in vitro (74). Furthermore, thymocytes from nonobese diabetic mice are also hyporesponsive with regard to TCR-mediated activation www.annualreviews.org • Phosphatases and Autoimmunity
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and proliferation (75–77). Indirect evidence also suggests that thymocyte hyporesponsiveness because of abnormalities in early TCR signaling can play a causative role in autoimmune disorders (2). Together, these findings may explain why LYP∗ W620 as a more potent inhibitor of TCR signaling can still enhance the risk for a variety of autoimmune diseases. This also explains why patients with the T1858/T1858 genotype are at a higher risk for autoimmune diseases than heterozygotes (T1858/C1858), because there is a dosedependent effect of LYP∗ W620. Another question is how LYP∗ W620 affects T cells so that autoimmunity develops. At present, there is a lack of experimental data covering this field. However, one can envision two possibilities, and they are not mutually exclusive. First, the reduced signal transduction ability downstream of the TCR, caused by LYP∗ W620, may result in a skewing of the TCR repertoire toward generation of more autoreactive TCRs in the thymus. The resulting failure in deleting these autoreactive thymocytes by negative selection gives rise to a peripheral T cell population with enhanced ability for self-recognition. Second, the presence of LYP∗ W620 in Treg cells may inhibit signaling in these cells so that they become insufficient in their ability to control the activity of autoreactive T cells in peripheral blood and tissues. Interestingly, a recent report demonstrated that PTPN22 is a direct Foxp3 target gene and that, although stimulation of Foxp3− hybridoma cells resulted in upregulation of PTPN22, this increase was not observed in Foxp3+ hybridoma cells or in ex vivo Treg cells (78). There are still several unanswered questions. All our knowledge about the cellular effects of LYP∗ W620 comes from studies on Jurkat T cells or on primary T cells (mainly CD4+ T helper cells). It is possible that LYP∗ W620 affects the development of autoimmunity through more complex mechanisms involving other immune cell lineages. The potential role for Treg cells has already been mentioned. Furthermore, some of the
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autoimmune disorders associated with the T1858 allele of PTPN22 are not regarded as primarily T cell mediated. A possible role in B cell biology has been suggested by the association of the T allele with RF-positive RA but not with RF-negative RA (35, 40, 70). In contrast, in T1D, there is no significant correlation between the T allele and the appearance or levels of autoantibodies. Also, the role of LYP in the autoantibody response may not necessarily be intrinsic to B cells but rather a consequence of altered T cell help. The uncertainty regarding which cells are phenotypically affected by LYP∗ W620 in different disease settings is further exemplified by a recent study demonstrating that carriers of the T1858 allele are more prone to certain infectious diseases, such as invasive pneumococcal infections and Gram-positive empyema (79). These findings may reflect reduced antibody responses owing to the presence of LYP∗ W620 in B cells, or they may even be caused by the effects of LYP∗ W620 in neutrophils. To make the picture even more complex, T cells have also been shown to play an important protective role in the early phase of the immune response toward pneumococcal lung infection (80). LYP∗ W620 may also simultaneously exert effects in all these cell lineages. Moreover, because LYP is found in all leukocytes, it may play a role in the function of dendritic cells, macrophages, and natural killer cells. Certainly, more studies are required to clarify which hematopoietic cells are responsible for the different effects of LYP∗ W620. On the basis of current knowledge, we favor a model wherein LYP∗ W620 functions primarily in T cell–mediated autoimmunity by reducing TCR signaling in the thymus and/or periphery, although we are aware that effects in other immune cell lineages are likely. Our model is supported by the role T cells play during the initiation phase of the autoimmune diseases associated with the C1858T SNP. In addition, altered TCR signaling has been reported in both T1D and RA as well as in animal models of these diseases, for
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instance the nonobese diabetic mouse model in which peripheral T cells exhibit hyporesponsiveness to TCR engagement in the early phase of the autoimmune disease (75, 77). Interestingly, diminished TCR signaling in developing thymocytes owing to a mutation in ZAP-70 (which serves as a substrate for LYP) also results in autoimmune disease in mice (2). Finally, the two other shared autoimmunity genes, MHC and CTLA4, play a role in antigen recognition by T cells and in negative regulation of TCR signaling, respectively.
Why Has Evolution Kept the C1858T SNP? A fascinating question is why evolution has kept the C1858T SNP. From a historical perspective, the relatively high prevalence of autoimmune disorders currently seen is a characteristic trait of modern society. Although it is evident that the T1858 allele is tightly associated with several autoimmune disorders, some of which have a relatively poor prognosis, the negative effects of the C1858T SNP on the immune system of the modern human being may have been beneficial in ancient times. Interestingly, a recent report demonstrated that the T allele is associated with increased risk of atherosclerosis in men as evaluated by intima-media thickness of the carotid artery (81). A corresponding association was not found in women, but here there was an association between the T1858 allele and several risk factors for atherosclerosis, including body mass index (BMI), waist circumference, waist-to-hip ratio, and elevated serum levels of triglycerides and C-reactive protein. Like autoimmunity, atherosclerosis is a disease that has reached epidemic levels in the modern world. However, individuals with typical syndrome X characteristics (high BMI, elevated hip-to-waist ratio, big waist circumference, and elevated serum lipids) probably had a survival advantage in ancient times because they could easily gain weight when food supplies were adequate and survive for longer periods of times when food supplies were low. It was
also recently reported that carriers of the T allele are less susceptible to developing clinically significant tuberculosis (82). Given the worldwide epidemic of tuberculosis in historical times, individuals with protection against this disease may have had a survival advantage. However, carriers of the T allele have not always had an advantage in fighting infections, as carriers of the T allele are at higher risk for certain infectious diseases, such as invasive pneumococcal infections and Gram-positive empyema (79). Taken together, the data suggest that the T1858 allele has been a selection factor. Because the T allele is found in Europeans but is virtually absent in Africans and Asians, there may have been a regional advantage of the T allele. Alternatively, the T allele may have originated in northern Europe, but did not provide sufficient advantage to spread worldwide.
INVOLVEMENT OF OTHER PEST GROUP PTPs IN AUTOIMMUNITY In addition to LYP, there are two other PEST group PTPs in humans, namely PTPPEST (PTPN12) and PTP-HSCF (PTPN18) (19). These PTPs share certain structural features, including an N-terminal PTP domain and a noncatalytic C-terminal portion containing different sequence motifs. All PEST group PTPs also contain a proline-rich CTH domain. However, the sequence motifs within the noncatalytic parts of the three family members differ to a certain degree, thereby providing a basis for shared as well as unique interaction partners. PTP-PEST is ubiquitously expressed, whereas PTP-HSCF is primarily found in brain, stem cells, and hematopoietic cells where expression tends to be higher in primitive cells compared with mature cells. In immune cells, there may be a certain degree of redundancy between the different PEST group PTPs ( Y. Arimura & T. Mustelin, unpublished observations), and this can explain the seemingly mild phenotype observed in PEP-deficient mice (33). That www.annualreviews.org • Phosphatases and Autoimmunity
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LYP/PEP act primarily on SFKs and their substrates (CD3/ζ-chain ITAMs and ZAP70) suggests that PTP-PEST and/or PTPHSCF may target the same proteins. However, these two PTPs also seem to have unique functions. For instance, PTP-PEST dephosphorylates several cytoskeletal and focal adhesion proteins (83, 84), and PTP-HSCF may play a role in regulation of the Tec family protein tyrosine kinases (PTKs) (85). To date, there are no reports of a direct involvement of PTP-PEST or PTP-HSCF in autoimmune disease. Because LYP∗ W620 is a gain-of-function variant and there are likely redundant functions between LYP and at least PTP-PEST, one could envision that activating mutations in the PTPN12 gene could also be associated with autoimmunity. Indeed, there are several SNPs in PTPN12, but no disease association with one or more of these SNPs has been published. It is also worth mentioning that the PTPN12 gene is located on chromosome 7q in a region that exhibits evidence of linkage to inflammatory bowel disease (86). PTP-PEST, LYP, and PTP-HSCF may be indirectly involved in an autoimmunityrelated group of disorders called autoinflammatory diseases, which are conditions involving inflammation due to breakdown in self-tolerance but where detection of antigenspecific T cells and/or autoantibodies fails (87). The autoinflammatory condition familial recurrent arthritis (FRA)/PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) is caused by mutations in the coiled-coil domain of a cytoskeletalassociated protein called CD2BP1 (in humans) or PSTPIP (in mice) (88). All PEST group PTPs can normally through their CTH domain bind the coiled-coil domain of CD2BP1/PSTPIP (19) (T. Vang, A.V. Miletic & T. Mustelin, unpublished data), but the disease-associated mutated form of CD2BP1 exhibits more than 90% reduction in its ability to interact with PTP-PEST (88). Most likely, the binding between disease-associated CD2BP1 and LYP/PTP-HSCF is affected
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PTK: protein tyrosine kinase
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in a similar way. C-terminal to the coiledcoil domain, CD2BP1 contains an SH3 domain that interacts with CD2, Abl, and WASP (Wiskott-Aldrich syndrome protein). Notably, the CD2/CD2BP1/PTP-PEST complex negatively affects T cell responses (89). Similarly, the CD2BP1/PTP-PEST complex also exists in other hematopoietic cells, and the disruption of this complex in neutrophils from FRA/PAPA syndrome patients is most likely the underlying cause for the accumulation of dysfunctional neutrophils in the affected organs in this disease (88). Furthermore, CD2BP1 can also bind to pyrin, which is primarily expressed in myeloid cells and is mutated in familial Mediterranean fever, another autoinflammatory disease (90).
CD45 AND AUTOIMMUNITY CD45 (PTPRC ) is expressed in all nucleated hematopoietic cells and consists of a highly glycosylated extracellular part, a single transmembrane domain, and a cytoplasmic portion containing two consecutive PTP domains (called D1 and D2) (91). The membrane distal D2 is catalytically inactive but necessary to support the PTP activity of the membrane proximal D1. Different isoforms of CD45 are expressed owing to alternative splicing of exons 4 (gives rise to CD45RA), 5 (gives CD45RB), and 6 (gives CD45RC); CD45RABC includes all three exons. The isoform CD45RO is a result of exons 4–6 spliced out. Different CD45 isoforms are expressed during the life span of immune cells. For instance, naive peripheral T cells primarily express CD45RB, and memory T cells predominantly express CD45RO. CD45 is extremely abundant in T cells. In fact, it constitutes 10% of all surface protein. With regard to TCR signaling, CD45 has a nonredundant positive regulatory role, which involves activation of the SFKs Lck and FynT through dephosphorylation of the C-terminal tyrosine residues Y505 and Y528, respectively (18). Consistent with this function, patients lacking CD45 suffer from severe combined immunodeficiency
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(92). In the peripheral blood of these patients, B cell numbers are normal, but the T cell population is greatly diminished, and these few T cells are unresponsive to mitogenic stimulation (92). CD45-deficient mice exhibit similar B and T cell phenotypes to that which is observed in patients lacking CD45 (93). Interestingly, although B cells are generated in CD45−/− mice, BCR-mediated positive and negative selection events are impaired (94). With respect to autoimmunity, autoreactive B cells are generated in CD45−/− mice as a consequence of altered threshold signaling by self-antigen, but autoantibodies are not generated because of impairments in late B cell differentiation (95). In T cells, CD45 activity is regulated at several levels, including spatiotemporal mechanisms, phosphorylation, and autoinhibition by dimerization (18) (Figure 1). Notably, CD45 splice variants with a smaller extracellular portion (CD45RO) homodimerize more easily compared with those with a larger extracellular domain (CD45RA, CD45RAB, and CD45RABC) (96). Because naive and memory T cells express different repertoires of CD45 isoforms, such a mechanism may allow differential regulation of CD45 between subsets of T cells. The molecular basis for autoinhibition by dimerization was proposed to involve a wedge-like structure in CD45, blocking the catalytic site in the other CD45 molecule of the dimer (97). This model was supported by the finding that disruption of the function of the putative wedge by mutating a key residue (from glutamic acid to arginine at position 624) abolished dimerizationinduced inhibition of CD45 (97). Moreover, knockin mice with a corresponding mutation (from glutamic acid to arginine at position 613, hereafter called CD45-E613R) in CD45 developed a phenotype characterized by a lymphoproliferative syndrome as well as autoimmune disease (such as lupus nephritis), suggesting aberrant CD45 activity in these animals (98). However, the authors found no evidence for activation of Lck in CD45E613R knockin T cells, and these cells exhib-
ited the same proliferative responses in vitro compared with wild-type T cells, indicating that the wedge model cannot explain important features of CD45 regulation in T cell biology (98). Furthermore, the crystal structure of CD45 is incompatible with the wedge model for several reasons (99). First, even when highly concentrated, the CD45 cytoplasmic region does not dimerize. Second, the intramolecular D1-D2 interaction appeared very tight and may not allow the deformation needed for an intermolecular D1-D1 interaction. And finally, the wedge region is not involved in any intermolecular interactions. At present, there is some debate regarding the role of the CD45 wedge. On the basis of the published coordinates for the CD45 structure, the researchers behind the CD45E613R knockin mice conducted a re-analysis of the CD45 structure (100). They confirmed the existence of the wedge, but its involvement in CD45 regulation is still an open question. The latter study also encompassed a more thorough investigation of the CD45E613R knockin mice, demonstrating that the observed phenotype in these mice (lymphoproliferative disorder) is due to hyperresponsive B cells, whereas T cells do not play any role (100). CD45 has also been linked to several autoimmune disorders in humans. The C77G SNP in PTPRC (the gene encoding CD45) was initially reported to associate with MS (101). This mutation disrupts an exonic splicing silencer for exon 4 in the PTPRC gene, with the consequence that high levels of exon 4–encoded CD45 isoforms are produced (i.e., CD45RA) in all cell lineages (102). As already mentioned, CD45RA isoforms do not dimerize as easily as CD45RO. Therefore, according to the model for autoinhibition by dimerization, patients with the C77G mutation should have aberrant CD45 activity in cells that normally only would express CD45RO, thereby suggesting a mechanism for disease development. However, subsequent studies have not been able to confirm the association between the C77G SNP and MS (103, 104). www.annualreviews.org • Phosphatases and Autoimmunity
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a Lipid raft
FN SH3
D1 SH2
Lck
D2 Phosphorylated Y505
b
CD45RABC
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CD45R0
More active
Less active
More active
CD45RABC
c
Less active
d
CD45R0
CD45AP
Fodrin
CK2, PKC, Csk
Figure 1 CD45 activity in T cells is regulated at several levels. (a) While Lck preferentially partitions into lipid rafts, approximately 95% of all CD45 molecules are excluded from rafts. Therefore, it remains controversial whether CD45-mediated activation of Lck (through dephosphorylation of Y505 in Lck) occurs within lipid rafts or outside. (b) CD45 activity is inhibited by homodimerization. Because CD45 isoforms with smaller extracellular portions (such as CD45RO) tend to homodimerize more easily compared with isoforms with larger extracellular parts (such as CD45RABC), the PTP activity of the former will be lower. (c) CD45 isoform–specific interactions with other transmembrane proteins may affect the juxtapositioning of CD45 with its substrates (such as Lck). (d ) CD45 may be regulated by numerous other proteins, for instance by binding CD45-associated protein (CD45AP) or fodrin (a cytoskeletal protein). CD45 can also be phosphorylated by casein kinase 2 (CK2), protein kinase C (PKC), and Csk. FN, fibronectin-like; SH, Src homology.
Nevertheless, there seems to be a connection between the C77G mutation and increased risk for systemic sclerosis (105) and autoimmune hepatitis (106), but not with T1D or 42
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Graves’ disease (107). Another mutation in PTPRC, C59A, has also been reported to interfere with alternative splicing in several members of a MS multiplex family (i.e., a large
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family in which several members have MS), leading to CD45RA expression on memory T cells (108).
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INVOLVEMENT OF OTHER TRANSMEMBRANE PTPs IN AUTOIMMUNITY In addition to CD45, there are 20 other transmembrane (or receptor-like) PTPs in humans. A large number of these are found in leukocytes, and there is currently limited evidence for an involvement of these PTPs in autoimmune diseases. Because LYP most likely is associated with autoimmunity through regulation of SFKs, we can speculate that transmembrane PTPs acting on SFKs are connected as well; in addition to CD45, those would include PTPα and PTPε. Interestingly, two other transmembrane PTPs have been implicated as major autoantigens in pancreatic β-cells in connection with T1D, namely PTPRN (IA-2) and PTPRN2 (IA-2β, phogrin) (109, 110).
SHP1 AND SHP2 IN AUTOIMMUNITY SHP1 (PTPN6 ) consists of two N-terminal SH2 domains, a PTP domain, and a Cterminal tail. It is expressed in hematopoietic cells and is a well-characterized PTP that negatively regulates immune cell activation through recruitment to immunoreceptor tyrosine-based inhibition motifs (ITIMs) in signaling molecules. SHP1 catalyzes dephosphorylation of ITAMs, the Syk family kinases Syk and ZAP-70, SLP-76, PI3 kinase, and Vav, to name a few. The association of SHP1 with autoimmunity was first revealed in motheaten and viable motheaten mice in which mutations cause abnormal splicing of SHP1 transcripts. As a result, motheaten mice lack SHP1 protein, while viable motheaten mice express catalytically defective protein (111, 112). Motheaten and viable motheaten mice (hereafter referred to as motheaten mice) display aggressive hyperinflammation characterized by hyperactive T
and B cells, as well as myeloid and phagocytic cells. Moreover, motheathen mice express autoantibodies and display glomerulonephritis (113). Notably, SHP1-deficient mice show a two- to threefold increase in the percentage of Treg cells, potentially explaining the minimal contribution of T cells compared with myeloid cells in the inflammation displayed by motheaten mice (114). Importantly, conditional deletion of SHP1 in B cells causes autoantibody production and glomerulonephritis, demonstrating that these hallmarks of the motheaten phenotype are B cell intrinsic and not secondary to dysregulated macrophage activity (19). Polymorphisms in the gene encoding SHP1 (PTPN6 ) have been found in humans, but unlike PTPN22, no association with autoimmune disease has been found. Of note, it has been reported that some SLE patients express lower levels of SHP1 as well as of CD45 (115). It is also worth mentioning that SHP1 mutations have been demonstrated in numerous hematological diseases, including myelodysplastic syndrome (116), and in certain types of lymphoma (117). SHP2 (PTPN11) is widely expressed and, similar to SHP1, contains two SH2 domains, a PTP domain, and a C-terminal tail. SHP2 is generally a positive regulator of signaling through receptor tyrosine kinases and cytokine receptors as well as of integrin signaling. TCR signaling is also positively regulated by SHP2 (118). Our preliminary findings from the analysis of mice lacking SHP2 in B cells indicates that it has a minimal role in BCR signaling but negatively regulates germinal center formation (R.V. Kolla, F. Princen, D. Ostertag, G.S. Feng & R.C. Rickert, in preparation). Although there are no reports of involvement of SHP2 in autoimmune diseases, mutations in the gene encoding SHP2 (PTPN11) are associated with Noonan syndrome (NS), a disorder characterized by multiple developmental defects, and LEOPARD (multiple lentigines, electrocardiographic-conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, www.annualreviews.org • Phosphatases and Autoimmunity
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and sensorineural deafness) syndrome, a rare, autosomal dominant disorder that shares many of the clinical features of NS. Interestingly, mutations in NS code for gainof-function proteins, whereas LEOPARD syndrome is characterized by a dominantnegative, loss-of-function SHP2 protein (119). Mutations in PTPN11 have also been associated with Helicobacter pylori-induced gastric atrophy/cancer (120) and in numerous myeloid leukemias and lymphomas (121, 122). Annu. Rev. Immunol. 2008.26:29-55. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
OTHER NONRECEPTOR PTPs IN AUTOIMMUNITY Although no PTPs aside from the aforementioned PTPs have been linked to autoimmunity, it is conceivable that mutations altering the function of other PTPs, perhaps combined with genetic or environmental factors, may precipitate autoimmune disease. Gene knockout studies are beginning to reveal the roles of many nonreceptor PTPs in lymphocyte development and activation. Mice lacking expression of TCPTP (PTPN2) show defects in T and B cell development and activation (123), which may be caused by its function in regulation of STAT1 signaling in the nucleus (124). In contrast, PTPH1 (PTPN3)deficient mice displayed no discernible defects in TCR signaling despite a proposed function of PTPH1 in the dephosphorylation of ITAMs (125). Like PTPH1, PTPMEG1 (PTPN4) and HePTP (PTPN7) have been implicated in negative regulation of TCR signaling (126). Although HePTP expression is induced by IL-2, suggesting that it may be involved in contraction of T cell responses following activation (127–129), and HePTP functions to regulate Erk and p38, the knockout mice displayed no noticeable phenotype aside from a two- to fivefold increase in Erk1/2 and p38 activation. PTPD1 (PTPN21) reportedly associates with Tec kinases and functions to activate Tec and Itk (130). The precise function of PTP-BAS (FAP-1, PTPN13) in T lymphocytes is unknown; however, it may function to regulate 44
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apoptosis of developing or activated T cells as it associates with, and inhibits, cell surface expression of FAS (131). Future studies, including SNP analysis, may reveal roles for these and other PTPs in human autoimmunity.
DUSPs IN AUTOIMMUNITY—FOCUS ON MAPK PHOSPHATASES MAPK (mitogen-activated protein kinase) phosphatases (MKPs, a subgroup of the DUSPs) are important for regulation of MAPKs, which can function either to amplify or to attenuate innate immune responses and are essential for lymphocyte development, activation, and homeostasis (132). In this regard, at least 10 MKPs are expressed in developing thymocytes, and MKP expression levels vary at different stages of T cell development and can be modulated by TCR signaling (133). Together, these data suggest that MKPs potentially play an important role in thymic selection and/or Treg cell development. Gene-targeting studies have revealed the specificity, redundancy, and cross talk between MKPs in both innate and adaptive immunity (134). MKP-1 (DUSP1) is a phosphatase that primarily regulates activation of p38 and JNK1/2, with little effect on Erk1/2 activation (135). Mice lacking MKP-1 revealed a critical function for MKP-1 in regulation of innate immune responses to microbial components via a negative-feedback loop that includes p38 and JNK. Moreover, compared with wild-type controls, MKP-1-deficient mice showed increased severity of collagen-induced arthritis resulting from increased levels of systemic TNF-α and IL-6, as well as high levels of antitype II collagen antibodies, suggesting that in addition to an important function in innate immune cells, MKP-1 may also be critical in regulation of T and/or B lymphocytes. Although a MKP-1 SNP has been identified in ovarian cancer to date, no associations have been made between MKP-1 and autoimmune disease (136).
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PAC-1 (DUSP2) expression is induced in T cells in response to antigen receptor stimulation and functions to negatively regulate JNK activation but augments both p38 and ERK1/2 activation. Unlike MKP-1−/− mice, PAC-1-deficient mice show decreased inflammatory cytokine production by myeloid cells following stimulation with Toll-like receptor ligands (137). PAC-1−/− CD4+ T cells have diminished proliferation and cytokine production, indicating that PAC-1 is a positive regulator of both innate and adaptive immune cell signaling. In addition, PAC-1 is a direct transcriptional target of p53 in response to cell stress, suggesting that PAC-1 may be important in cellular apoptosis and growth suppression, both of which are critical in contraction of immune responses and are aberrant in many autoimmune disorders (138). MKP-5 (DUSP10) is constitutively expressed in naive CD4+ T cells and is downregulated following TCR activation (139). Following mitogenic stimulation, MKP-5deficient T cells display diminished proliferation but increased cytokine production by both Th1 and Th2 cells, as well as increased IFN-γ and TNF-α production by cytolytic CD8+ T cells in vitro. Notably, although primary responses to lymphocytic choriomeningitis virus infection were similar between wild-type and MKP-5−/− mice, upon secondary infection, MKP-5−/− CD4+ and CD8+ T cells had increased cytokine production. Thus, MKP5 functions to diminish T cell responses, thereby preventing excessive, and potentially harmful, T cell activation during an immune response. Several other MKPs have been implicated in regulation of T cell activation and homeostasis; however, the precise function and association with autoimmunity of these MKPs are not yet established. For example, MKP-2 (DUSP4), MKP-3 (DUSP6 ), hVH3 (DUSP5), MKP-7 (DUSP16 ), and LMWDSP20 (DUSP18) are all implicated in regulation of ERK1/2 and/or JNK1/2 activation (140–143). VHR (DUSP3) is a negative regulator of TCR signaling whose activation is,
in part, mediated by ZAP-70 phosphorylation (144), and expression of VHR controls cell cycle, differentiation, or senescence through regulation of ERK1/2 and JNK1/2 MAPKs (145). VHX (DUSP22), like VHR, is implicated in negative regulation of TCR signaling (146), whereas MKP-6 (DUSP14) associates with CD28 and negatively regulates CD28 signals (147). Interestingly, MGC1136 (DUSP24) is upregulated in tolerant T cells and thus could function in induction or maintenance of lymphocyte tolerance (148).
POTENTIAL FOR TREATMENT OF AUTOIMMUNE DISORDERS USING PTP INHIBITORS? PTPs have recently been implicated in an increasing number of human diseases. That, in turn, has begun to elicit a growing interest in PTPs as drug targets and the development of potent and selective PTP inhibitors (149). The spark that truly ignited the quest for PTP inhibitors with great market potential was the paper reporting the PTP1B knockout mouse, which indicated that PTP1B acts as a negative regulator of insulin signaling (123). Inhibition of PTP1B would conceivably alleviate insulin resistance in type 2 diabetes and would improve the effects of insulin on both glucose balance and fatty acid metabolism. Although the enthusiasm for PTP inhibitors was initially dampened by the notions that PTPs were less specific than, for example, PTKs and that the structure of the active site of PTPs did not allow for the generation of selective inhibitors, it has now become increasingly clear that PTPs indeed have unique, nonredundant, important functions and a great deal of specificity in vivo. The question of how selective small-molecule inhibitors can be developed is perhaps not quite resolved, but many promising examples have been published. The crystallization of many PTPs has revealed that the surface topology surrounding the catalytic pocket of each PTP has numerous unique features that can be utilized for the rational structure-based design of highly selective www.annualreviews.org • Phosphatases and Autoimmunity
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compounds (149). The highest affinity and the most selective inhibitors reported so far have been those that interact with several such distinct surface features. These features together with new techniques in PTP inhibitor design (150) provide great opportunities for the development of sufficiently selective and efficient PTP inhibitors. In our view, specific criteria have to be fulfilled for selecting a particular PTP as a drug target for the treatment of autoimmune disease. First, the target enzyme should have higher activity in autoimmunity than in healthy subjects. Second, the protein should be expressed mostly in immune cells. Third, the biological function of the PTP should be reasonably well known. At this point, only LYP fulfills these criteria, although the biology of this PTP is only partially understood. Most importantly, the activity of the disease-associated LYP∗ W620 enzyme is
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about 50% higher than the nonmutated form (LYP∗ R620) (5), and the protein is found only in hematopoietic cells (20). Thus, in theory, a selective small-molecule LYP inhibitor could eliminate the effects of LYP∗ W620 on TCR signaling. Such an inhibitor would need to reduce the activity of LYP∗ W620 only to a certain extent. Under these conditions, TCR signaling should be corrected to normal levels, and the autoimmunity-inducing process precipitated by LYP∗ W620 would be neutralized. However, because of the complexity and plasticity of the immune system and the many different roles that signaling molecules can have, the timing and strategy of such a treatment would need to be carefully evaluated. Once suitable small-molecule PTP inhibitors with viable pharmacological properties have been developed, their potential for treatment of autoimmune disorders can be experimentally evaluated.
DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS This work was supported by grants from the U.S. National Institutes of Health (AI53585 to T.M.), the Oxnard Foundation (to T.M.), and the Norwegian Cancer Society (to T.V.). We apologize to all colleagues whose papers we could not cite owing to space constraints.
NOTE ADDED IN PROOF A recent study demonstrated no association between Graves’ disease and individual SNPs in PTPN12, but some of these SNPs were associated with ophthalmopathy and/or interacted with a previously associated thyrotropin hormone receptor SNP (151). Another study has shown that mice with specific deletion of SHP1 in B cells develop an SLE-like condition, suggesting that SHP1 deficiency in B cells alone is sufficient to cause autoimmune disease (152).
LITERATURE CITED 1. Rose NR, Mackay IR. 1999. The Autoimmune Diseases. London: Academic 2. Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T, et al. 2003. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426:454–60 3. Sakaguchi S, Sakaguchi N, Yoshitomi H, Hata H, Takahashi T, Nomura T. 2006. Spontaneous development of autoimmune arthritis due to genetic anomaly of T cell signal transduction: Part 1. Semin. Immunol. 18:199–206 46
Vang et al.
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ANRV338-IY26-02
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4. Chang TT, Kuchroo VK, Sharpe AH. 2002. Role of the B7-CD28/CTLA-4 pathway in autoimmune disease. Curr. Dir. Autoimmun. 5:113–30 5. Vang T, Congia M, Macis MD, Musumeci L, Orru V, et al. 2005. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat. Genet. 37:1317–19 6. Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, et al. 2004. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat. Genet. 36:337–38 7. Bottini N, Vang T, Cucca F, Mustelin T. 2006. Role of PTPN22 in type 1 diabetes and other autoimmune diseases. Semin. Immunol. 18:207–13 8. Nomura T, Sakaguchi S. 2007. Foxp3 and Aire in thymus-generated Treg cells: a link in self-tolerance. Nat. Immunol. 8:333–34 9. Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, et al. 2007. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445:648–51 10. Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE, et al. 2001. Thymic selection of CD4+ CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2:301–6 11. Gauld SB, Benschop RJ, Merrell KT, Cambier JC. 2005. Maintenance of B cell anergy requires constant antigen receptor occupancy and signaling. Nat. Immunol. 6:1160–67 12. Grimaldi CM, Hicks R, Diamond B. 2005. B cell selection and susceptibility to autoimmunity. J. Immunol. 174:1775–81 13. Stockinger B. 1999. T lymphocyte tolerance: from thymic deletion to peripheral control mechanisms. Adv. Immunol. 71:229–65 14. Fontenot JD, Gavin MA, Rudensky AY. 2003. Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat. Immunol. 4:330–36 15. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. 2005. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22:329–41 16. Kim JM, Rasmussen JP, Rudensky AY. 2007. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8:191–97 17. Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, et al. 2004. Protein tyrosine phosphatases in the human genome. Cell 117:699–711 18. Mustelin T, Vang T, Bottini N. 2005. Protein tyrosine phosphatases and the immune response. Nat. Rev. Immunol. 5:43–57 19. Pao LI, Badour K, Siminovitch KA, Neel BG. 2007. Nonreceptor protein-tyrosine phosphatases in immune cell signaling. Annu. Rev. Immunol. 25:473–523 20. Cohen S, Dadi H, Shaoul E, Sharfe N, Roifman CM. 1999. Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood 93:2013–24 21. Spencer S, Dowbenko D, Cheng J, Li W, Brush J, et al. 1997. PSTPIP: a tyrosine phosphorylated cleavage furrow-associated protein that is a substrate for a PEST tyrosine phosphatase. J. Cell Biol. 138:845–60 22. Cote JF, Chung PL, Theberge JF, Halle M, Spencer S, et al. 2002. PSTPIP is a substrate of PTP-PEST and serves as a scaffold guiding PTP-PEST toward a specific dephosphorylation of WASP. J. Biol. Chem. 277:2973–86 23. Matthews RJ, Bowne DB, Flores E, Thomas ML. 1992. Characterization of hematopoietic intracellular protein tyrosine phosphatases: description of a phosphatase containing an SH2 domain and another enriched in proline-, glutamic acid-, serine-, and threoninerich sequences. Mol. Cell. Biol. 12:2396–405 www.annualreviews.org • Phosphatases and Autoimmunity
47
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24. Gjorloff-Wingren A, Saxena M, Han S, Wang X, Alonso A, et al. 2000. Subcellular localization of intracellular protein tyrosine phosphatases in T cells. Eur. J. Immunol. 30:2412–21 25. Cloutier JF, Veillette A. 1996. Association of inhibitory tyrosine protein kinase p50csk with protein tyrosine phosphatase PEP in T cells and other hemopoietic cells. EMBO J. 15:4909–18 26. Gregorieff A, Cloutier JF, Veillette A. 1998. Sequence requirements for association of protein-tyrosine phosphatase PEP with the Src homology 3 domain of inhibitory tyrosine protein kinase p50(csk). J. Biol. Chem. 273:13217–22 27. Ghose R, Shekhtman A, Goger MJ, Ji H, Cowburn D. 2001. A novel, specific interaction involving the Csk SH3 domain and its natural ligand. Nat. Struct. Biol. 8:998–1004 28. Hill RJ, Zozulya S, Lu YL, Ward K, Gishizky M, Jallal B. 2002. The lymphoid protein tyrosine phosphatase Lyp interacts with the adaptor molecule Grb2 and functions as a negative regulator of T-cell activation. Exp. Hematol. 30:237–44 29. Cloutier JF, Veillette A. 1999. Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J. Exp. Med. 189:111–21 30. Gjorloff-Wingren A, Saxena M, Williams S, Hammi D, Mustelin T. 1999. Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP. Eur. J. Immunol. 29:3845–54 31. Wu J, Katrekar A, Honigberg LA, Smith AM, Conn MT, et al. 2006. Identification of substrates of human protein-tyrosine phosphatase PTPN22. J. Biol. Chem. 281:11002–10 32. Davidson D, Bakinowski M, Thomas ML, Horejsi V, Veillette A. 2003. Phosphorylationdependent regulation of T-cell activation by PAG/Cbp, a lipid raft-associated transmembrane adaptor. Mol. Cell. Biol. 23:2017–28 33. Hasegawa K, Martin F, Huang G, Tumas D, Diehl L, Chan AC. 2004. PEST domainenriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. Science 303:685–89 34. Li QJ, Chau J, Ebert PJ, Sylvester G, Min H, et al. 2007. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129:147–61 35. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, et al. 2004. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75:330–37 36. Smyth D, Cooper JD, Collins JE, Heward JM, Franklyn JA, et al. 2004. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 53:3020–23 37. Onengut-Gumuscu S, Ewens KG, Spielman RS, Concannon P. 2004. A functional polymorphism (1858C/T) in the PTPN22 gene is linked and associated with type I diabetes in multiplex families. Genes Immun. 5:678–80 38. Ladner MB, Bottini N, Valdes AM, Noble JA. 2005. Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes. Hum. Immunol. 66:60– 64 39. Orozco G, Eerligh P, Sanchez E, Zhernakova S, Roep BO, et al. 2005. Analysis of a functional BTNL2 polymorphism in type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Hum. Immunol. 66:1235–41 40. Lee AT, Li W, Liew A, Bombardier C, Weisman M, et al. 2005. The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status. Genes Immun. 6:129–33
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41. Criswell LA, Pfeiffer KA, Lum RF, Gonzales B, Novitzke J, et al. 2005. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am. J. Hum. Genet. 76:561–71 42. Viken MK, Amundsen SS, Kvien TK, Boberg KM, Gilboe IM, et al. 2005. Association analysis of the 1858C>T polymorphism in the PTPN22 gene in juvenile idiopathic arthritis and other autoimmune diseases. Genes Immun. 6:271–73 43. Hinks A, Barton A, John S, Bruce I, Hawkins C, et al. 2005. Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: further support that PTPN22 is an autoimmunity gene. Arthritis Rheum. 52:1694–99 44. Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, et al. 2004. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am. J. Hum. Genet. 75:504–7 45. Velaga MR, Wilson V, Jennings CE, Owen CJ, Herington S, et al. 2004. The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease. J. Clin. Endocrinol. Metab. 89:5862–65 46. Vandiedonck C, Capdevielle C, Giraud M, Krumeich S, Jais JP, et al. 2006. Association of the PTPN22∗ R620W polymorphism with autoimmune myasthenia gravis. Ann. Neurol. 59:404–7 47. Canton I, Akhtar S, Gavalas NG, Gawkrodger DJ, Blomhoff A, et al. 2005. A singlenucleotide polymorphism in the gene encoding lymphoid protein tyrosine phosphatase (PTPN22) confers susceptibility to generalised vitiligo. Genes Immun. 6:584–87 48. Jagiello P, Aries P, Arning L, Wagenleiter SE, Csernok E, et al. 2005. The PTPN22 620W allele is a risk factor for Wegener’s granulomatosis. Arthritis Rheum. 52:4039–43 49. Begovich AB, Caillier SJ, Alexander HC, Penko JM, Hauser SL, et al. 2005. The R620W polymorphism of the protein tyrosine phosphatase PTPN22 is not associated with multiple sclerosis. Am. J. Hum. Genet. 76:184–87 50. van Oene M, Wintle RF, Liu X, Yazdanpanah M, Gu X, et al. 2005. Association of the lymphoid tyrosine phosphatase R620W variant with rheumatoid arthritis, but not Crohn’s disease, in Canadian populations. Arthritis Rheum. 52:1993–98 51. Wagenleiter SE, Klein W, Griga T, Schmiegel W, Epplen JT, Jagiello P. 2005. A casecontrol study of tyrosine phosphatase (PTPN22) confirms the lack of association with Crohn’s disease. Int. J. Immunogenet. 32:323–24 52. Martin MC, Oliver J, Urcelay E, Orozco G, Gomez-Garcia M, et al. 2005. The functional genetic variation in the PTPN22 gene has a negligible effect on the susceptibility to develop inflammatory bowel disease. Tissue Antigens 66:314–17 53. Prescott NJ, Fisher SA, Onnie C, Pattni R, Steer S, et al. 2005. A general autoimmunity gene (PTPN22) is not associated with inflammatory bowel disease in a British population. Tissue Antigens 66:318–20 54. Rueda B, Nunez C, Orozco G, Lopez-Nevot MA, de la Concha EG, et al. 2005. C1858T functional variant of PTPN22 gene is not associated with celiac disease genetic predisposition. Hum. Immunol. 66:848–52 55. Milkiewicz P, Pache I, Buwaneswaran H, Liu X, Coltescu C, et al. 2006. The PTPN22 1858T variant is not associated with primary biliary cirrhosis. Tissue Antigens 67:434–37 56. Lee YH, Rho YH, Choi SJ, Ji JD, Song GG, et al. 2007. The PTPN22 C1858T functional polymorphism and autoimmune diseases—a meta-analysis. Rheumatology 46:49–56 57. Carlton VE, Hu X, Chokkalingam AP, Schrodi SJ, Brandon R, et al. 2005. PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis. Am. J. Hum. Genet. 77:567–81 www.annualreviews.org • Phosphatases and Autoimmunity
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58. Wesoly J, Hu X, Thabet MM, Chang M, Uh H, et al. 2007. The 620W allele is the PTPN22 genetic variant conferring susceptibility to RA in a Dutch population. Rheumatology 46:617–21 59. Ikari K, Momohara S, Inoue E, Tomatsu T, Hara M, et al. 2006. Haplotype analysis revealed no association between the PTPN22 gene and RA in a Japanese population. Rheumatology 45:1345–48 60. Hinks A, Eyre S, Barton A, Thomson W, Worthington J. 2007. Investigation of genetic variation across the protein tyrosine phosphatase gene in patients with rheumatoid arthritis in the UK. Ann. Rheum. Dis. 66:683–86 61. Kawasaki E, Awata T, Ikegami H, Kobayashi T, Maruyama T, et al. 2006. Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): association between a promoter polymorphism and type 1 diabetes in Asian populations. Am. J. Med. Genet. Part A 140:586–93 62. Cinek O, Hradsky O, Ahmedov G, Slavcev A, Kolouskova S, et al. 2007. No independent role of the –1123 G>C and +2740 A>G variants in the association of PTPN22 with type 1 diabetes and juvenile idiopathic arthritis in two Caucasian populations. Diabetes Res. Clin. Pract. 76:297–303 63. Onengut-Gumuscu S, Buckner JH, Concannon P. 2006. A haplotype-based analysis of the PTPN22 locus in type 1 diabetes. Diabetes 55:2883–89 64. Huffmeier U, Steffens M, Burkhardt H, Lascorz J, Schurmeier-Horst F, et al. 2006. Evidence for susceptibility determinant(s) to psoriasis vulgaris in or near PTPN22 in German patients. J. Med. Genet. 43:517–22 65. Concannon P, Erlich HA, Julier C, Morahan G, Nerup J, et al. 2005. Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1435 multiplex families. Diabetes 54:2995–3001 66. Ueda H, Howson JM, Esposito L, Heward J, Snook H, et al. 2003. Association of the Tcell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–11 67. Plenge RM, Padyukov L, Remmers EF, Purcell S, Lee AT, et al. 2005. Replication of putative candidate-gene associations with rheumatoid arthritis in >4000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am. J. Hum. Genet. 77:1044–60 68. Johansson M, Arlestig L, Hallmans G, Rantapaa-Dahlqvist S. 2006. PTPN22 polymorphism and anticyclic citrullinated peptide antibodies in combination strongly predicts future onset of rheumatoid arthritis and has a specificity of 100% for the disease. Arthritis Res. Ther. 8:R19 69. Hermann R, Lipponen K, Kiviniemi M, Kakko T, Veijola R, et al. 2006. Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes. Diabetologia 49:1198–208 70. Dieude P, Garnier S, Michou L, Petit-Teixeira E, Glikmans E, et al. 2005. Rheumatoid arthritis seropositive for the rheumatoid factor is linked to the protein tyrosine phosphatase nonreceptor 22-620W allele. Arthritis Res. Ther. 7:R1200–7 71. Lie BA, Viken MK, Odegard S, van der Heijden D, Landewe R, et al. 2007. Associations between the PTPN22 1858C>T polymorphism and radiographic joint destruction in patients with rheumatoid arthritis: results from a 10-year longitudinal study. Ann. Rheum. Dis. 66:1604–9 72. Skorka A, Bednarczuk T, Bar-Andziak E, Nauman J, Ploski R. 2005. Lymphoid tyrosine phosphatase (PTPN22/LYP) variant and Graves’ disease in a Polish population: association and gene dose-dependent correlation with age of onset. Clin. Endocrinol. 62:679–82
Annu. Rev. Immunol. 2008.26:29-55. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-02
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73. Fedetz M, Matesanz F, Caro-Maldonado A, Smirnov II, Chvorostinka VN, et al. 2006. The 1858T PTPN22 gene variant contributes to a genetic risk of type 1 diabetes in a Ukrainian population. Tissue Antigens 67:430–33 74. Salojin KV, Zhang J, Madrenas J, Delovitch TL. 1998. T-cell anergy and altered T-cell receptor signaling: effects on autoimmune disease. Immunol. Today 19:468–73 75. Salojin K, Zhang J, Cameron M, Gill B, Arreaza G, et al. 1997. Impaired plasma membrane targeting of Grb2-murine son of sevenless (mSOS) complex and differential activation of the Fyn-T cell receptor (TCR)-zeta-Cbl pathway mediate T cell hyporesponsiveness in autoimmune nonobese diabetic mice. J. Exp. Med. 186:887–97 76. Delovitch TL, Singh B. 1997 . The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 7:727–38. Erratum. 1998. Immunity 8(4):531 77. Rapoport MJ, Lazarus AH, Jaramillo A, Speck E, Delovitch TL. 1993. Thymic T cell anergy in autoimmune nonobese diabetic mice is mediated by deficient T cell receptor regulation of the pathway of p21ras activation. J. Exp. Med. 177:1221–26 78. Marson A, Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, et al. 2007. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445:931– 35 79. Chapman SJ, Khor CC, Vannberg FO, Maskell NA, Davies CW, et al. 2006. PTPN22 and invasive bacterial disease. Nat. Genet. 38:499–500 80. Kadioglu A, Andrew PW. 2004. The innate immune response to pneumococcal lung infection: the untold story. Trends Immunol. 25:143–49 81. Pertovaara M, Raitala A, Juonala M, Kahonen M, Lehtimaki T, et al. 2007. Autoimmunity and atherosclerosis: functional polymorphism of PTPN22 is associated with phenotypes related to the risk of atherosclerosis. The Cardiovascular Risk in Young Finns Study. Clin. Exp. Immunol. 147:265–69 82. Gomez LM, Anaya JM, Martin J. 2005. Genetic influence of PTPN22 R620W polymorphism in tuberculosis. Hum. Immunol. 66:1242–47 83. Cote JF, Charest A, Wagner J, Tremblay ML. 1998. Combination of gene targeting and substrate trapping to identify substrates of protein tyrosine phosphatases using PTPPEST as a model. Biochemistry 37:13128–37 84. Garton AJ, Flint AJ, Tonks NK. 1996. Identification of p130(cas) as a substrate for the cytosolic protein tyrosine phosphatase PTP-PEST. Mol. Cell. Biol. 16:6408–18 85. Aoki N, Ueno S, Mano H, Yamasaki S, Shiota M, et al. 2004. Mutual regulation of protein-tyrosine phosphatase 20 and protein-tyrosine kinase Tec activities by tyrosine phosphorylation and dephosphorylation. J. Biol. Chem. 279:10765–75 86. Satsangi J, Parkes M, Louis E, Hashimoto L, Kato N, et al. 1996. Two stage genomewide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nat. Genet. 14:199–202 87. Galon J, Aksentijevich I, McDermott MF, O’Shea JJ, Kastner DL. 2000. TNFRSF1A mutations and autoinflammatory syndromes. Curr. Opin. Immunol. 12:479–86 88. Wise CA, Gillum JD, Seidman CE, Lindor NM, Veile R, et al. 2002. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum. Mol. Genet. 11:961–69 89. Yang H, Reinherz EL. 2006. CD2BP1 modulates CD2-dependent T cell activation via linkage to protein tyrosine phosphatase (PTP)-PEST. J. Immunol. 176:5898–907 90. Shoham NG, Centola M, Mansfield E, Hull KM, Wood G, et al. 2003. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc. Natl. Acad. Sci. USA 100:13501–6 www.annualreviews.org • Phosphatases and Autoimmunity
51
ARI
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91. Hermiston ML, Xu Z, Weiss A. 2003. CD45: a critical regulator of signaling thresholds in immune cells. Annu. Rev. Immunol. 21:107–37 92. Kung C, Pingel JT, Heikinheimo M, Klemola T, Varkila K, et al. 2000. Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease. Nat. Med. 6:343–45 93. Kishihara K, Penninger J, Wallace VA, Kundig TM, Kawai K, et al. 1993. Normal B lymphocyte development but impaired T cell maturation in CD45-exon6 protein tyrosine phosphatase-deficient mice. Cell 74:143–56 94. Cyster JG, Healy JI, Kishihara K, Mak TW, Thomas ML, Goodnow CC. 1996. Regulation of B-lymphocyte negative and positive selection by tyrosine phosphatase CD45. Nature 381:325–28 95. Huntington ND, Xu Y, Puthalakath H, Light A, Willis SN, et al. 2006. CD45 links the B cell receptor with cell survival and is required for the persistence of germinal centers. Nat. Immunol. 7:190–98 96. Xu Z, Weiss A. 2002. Negative regulation of CD45 by differential homodimerization of the alternatively spliced isoforms. Nat. Immunol. 3:764–71 97. Majeti R, Bilwes AM, Noel JP, Hunter T, Weiss A. 1998. Dimerization-induced inhibition of receptor protein tyrosine phosphatase function through an inhibitory wedge. Science 279:88–91 98. Majeti R, Xu Z, Parslow TG, Olson JL, Daikh DI, et al. 2000. An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity. Cell 103:1059–70 99. Nam HJ, Poy F, Saito H, Frederick CA. 2005. Structural basis for the function and regulation of the receptor protein tyrosine phosphatase CD45. J. Exp. Med. 201:441–52. Erratum. 2005. J. Exp. Med. 201(6):1019 100. Hermiston ML, Tan AL, Gupta VA, Majeti R, Weiss A. 2005. The juxtamembrane wedge negatively regulates CD45 function in B cells. Immunity 23:635–47 101. Jacobsen M, Schweer D, Ziegler A, Gaber R, Schock S, et al. 2000. A point mutation in PTPRC is associated with the development of multiple sclerosis. Nat. Genet. 26:495–99 102. Lynch KW, Weiss A. 2001. A CD45 polymorphism associated with multiple sclerosis disrupts an exonic splicing silencer. J. Biol. Chem. 276:24341–47 103. Barcellos LF, Caillier S, Dragone L, Elder M, Vittinghoff E, et al. 2001. PTPRC (CD45) is not associated with the development of multiple sclerosis in U.S. patients. Nat. Genet. 29:23–24 104. Vorechovsky I, Kralovicova J, Tchilian E, Masterman T, Zhang Z, et al. 2001. Does 77C–>G in PTPRC modify autoimmune disorders linked to the major histocompatibility locus? Nat. Genet. 29:22–23 105. Schwinzer R, Witte T, Hundrieser J, Ehlers S, Momot T, et al. 2003. Enhanced frequency of a PTPRC (CD45) exon A mutation (77C–>G) in systemic sclerosis. Genes Immun. 4:168–69 106. Vogel A, Strassburg CP, Manns MP. 2003. 77 C/G mutation in the tyrosine phosphatase CD45 gene and autoimmune hepatitis: evidence for a genetic link. Genes Immun. 4:79–81 107. Wood JP, Pani MA, Bieda K, Meyer G, Usadel KH, Badenhoop K. 2002. A recently described polymorphism in the CD28 gene on chromosome 2q33 is not associated with susceptibility to type 1 diabetes. Eur. J. Immunogenet. 29:347–49 108. Jacobsen M, Hoffmann S, Cepok S, Stei S, Ziegler A, et al. 2002. A novel mutation in PTPRC interferes with splicing and alters the structure of the human CD45 molecule. Immunogenetics 54:158–63
Annu. Rev. Immunol. 2008.26:29-55. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-02
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ANRV338-IY26-02
ARI
16 February 2008
11:8
109. Passini N, Larigan JD, Genovese S, Appella E, Sinigaglia F, Rogge L. 1995. The 37/40kDa autoantigen in insulin-dependent diabetes mellitus is the putative tyrosine phosphatase IA-2. Proc. Natl. Acad. Sci. USA 92:9412–16 110. Lu J, Li Q, Xie H, Chen ZJ, Borovitskaya AE, et al. 1996. Identification of a second transmembrane protein tyrosine phosphatase, IA-2beta, as an autoantigen in insulindependent diabetes mellitus: precursor of the 37-kDa tryptic fragment. Proc. Natl. Acad. Sci. USA 93:2307–11 111. Shultz LD, Schweitzer PA, Rajan TV, Yi T, Ihle JN, et al. 1993. Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell 73:1445–54 112. Tsui HW, Siminovitch KA, de Souza L, Tsui FW. 1993. Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nat. Genet. 4:124–29 113. Westhoff CM, Whittier A, Kathol S, McHugh J, Zajicek C, et al. 1997. DNA-binding antibodies from viable motheaten mutant mice: implications for B cell tolerance. J. Immunol. 159:3024–33 114. Carter JD, Calabrese GM, Naganuma M, Lorenz U. 2005. Deficiency of the Src homology region 2 domain-containing phosphatase 1 (SHP-1) causes enrichment of CD4+ CD25+ regulatory T cells. J. Immunol. 174:6627–38 115. Huck S, Le Corre R, Youinou P, Zouali M. 2001. Expression of B cell receptor-associated signaling molecules in human lupus. Autoimmunity 33:213–24 116. Mena-Duran AV, Togo SH, Bazhenova L, Cervera J, Bethel K, et al. 2005. SHP1 expression in bone marrow biopsies of myelodysplastic syndrome patients: a new prognostic factor. Br. J. Haematol. 129:791–94 117. Zhang Q, Wang HY, Marzec M, Raghunath PN, Nagasawa T, Wasik MA. 2005. STAT3and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Proc. Natl. Acad. Sci. USA 102:6948–53 118. Nguyen TV, Ke Y, Zhang EE, Feng GS. 2006. Conditional deletion of Shp2 tyrosine phosphatase in thymocytes suppresses both pre-TCR and TCR signals. J. Immunol. 177:5990–96 119. Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG. 2006. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J. Biol. Chem. 281:6785–92 120. Kawai S, Goto Y, Ito LS, Oba-Shinjo SM, Uno M, et al. 2006. Significant association between PTPN11 polymorphism and gastric atrophy among Japanese Brazilians. Gastric Cancer 9:277–83 121. Chan RJ, Feng GS. 2007. PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. Blood 109:862–67 122. Mohi MG, Neel BG. 2007. The role of Shp2 (PTPN11) in cancer. Curr. Opin. Genet. Dev. 17:23–30 123. You-Ten KE, Muise ES, Itie A, Michaliszyn E, Wagner J, et al. 1997. Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatasedeficient mice. J. Exp. Med. 186:683–93 124. Zhu W, Mustelin T, David M. 2002. Arginine methylation of STAT1 regulates its dephosphorylation by T cell protein tyrosine phosphatase. J. Biol. Chem. 277:35787–90 125. Bauler TJ, Hughes ED, Arimura Y, Mustelin T, Saunders TL, King PD. 2007. Normal TCR signal transduction in mice that lack catalytically active PTPN3 protein tyrosine phosphatase. J. Immunol. 178:3680–87 www.annualreviews.org • Phosphatases and Autoimmunity
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126. Han S, Williams S, Mustelin T. 2000. Cytoskeletal protein tyrosine phosphatase PTPH1 reduces T cell antigen receptor signaling. Eur. J. Immunol. 30:1318–25 127. Saxena M, Williams S, Brockdorff J, Gilman J, Mustelin T. 1999. Inhibition of T cell signaling by mitogen-activated protein kinase-targeted hematopoietic tyrosine phosphatase (HePTP). J. Biol. Chem. 274:11693–700 128. Saxena M, Williams S, Gilman J, Mustelin T. 1998. Negative regulation of T cell antigen receptor signal transduction by hematopoietic tyrosine phosphatase (HePTP). J. Biol. Chem. 273:15340–44 129. Adachi M, Torigoe T, Sekiya M, Minami Y, Taniguchi T, et al. 1995. IL-2-induced gene expression of protein-tyrosine phosphatase LC-PTP requires acidic and serine-rich regions within IL-2 receptor beta chain. FEBS Lett. 372:113–18 130. Jui HY, Tseng RJ, Wen X, Fang HI, Huang LM, et al. 2000. Protein-tyrosine phosphatase D1, a potential regulator and effector for Tec family kinases. J. Biol. Chem. 275:41124–32 131. Ivanov VN, Lopez Bergami P, Maulit G, Sato TA, Sassoon D, Ronai Z. 2003. FAP-1 association with Fas (Apo-1) inhibits Fas expression on the cell surface. Mol. Cell. Biol. 23:3623–35 132. Liu Y, Shepherd EG, Nelin LD. 2007. MAPK phosphatases—regulating the immune response. Nat. Rev. Immunol. 7:202–12 133. Tanzola MB, Kersh GJ. 2006. The dual specificity phosphatase transcriptome of the murine thymus. Mol. Immunol. 43:754–62 134. Owens DM, Keyse SM. 2007. Differential regulation of MAP kinase signalling by dualspecificity protein phosphatases. Oncogene 26:3203–13 135. Abraham SM, Clark AR. 2006. Dual-specificity phosphatase 1: a critical regulator of innate immune responses. Biochem. Soc. Trans. 34:1018–23 136. Suzuki C, Unoki M, Nakamura Y. 2001. Identification and allelic frequencies of novel single-nucleotide polymorphisms in the DUSP1 and BTG1 genes. J. Hum. Genet. 46:155– 57 137. Jeffrey KL, Brummer T, Rolph MS, Liu SM, Callejas NA, et al. 2006. Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nat. Immunol. 7:274–83 138. Yin Y, Liu YX, Jin YJ, Hall EJ, Barrett JC. 2003. PAC1 phosphatase is a transcription target of p53 in signalling apoptosis and growth suppression. Nature 422:527–31 139. Zhang Y, Blattman JN, Kennedy NJ, Duong J, Nguyen T, et al. 2004. Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5. Nature 430:793–97 140. Kovanen PE, Rosenwald A, Fu J, Hurt EM, Lam LT, et al. 2003. Analysis of gamma c-family cytokine target genes. Identification of dual-specificity phosphatase 5 (DUSP5) as a regulator of mitogen-activated protein kinase activity in interleukin-2 signaling. J. Biol. Chem. 278:5205–13 141. Mandl M, Slack DN, Keyse SM. 2005. Specific inactivation and nuclear anchoring of extracellular signal-regulated kinase 2 by the inducible dual-specificity protein phosphatase DUSP5. Mol. Cell. Biol. 25:1830–45 142. Masuda K, Shima H, Katagiri C, Kikuchi K. 2003. Activation of ERK induces phosphorylation of MAPK phosphatase-7, a JNK specific phosphatase, at Ser-446. J. Biol. Chem. 278:32448–56 143. Wu Q, Huang S, Sun Y, Gu S, Lu F, et al. 2006. Dual specificity phosphatase 18, interacting with SAPK, dephosphorylates SAPK and inhibits SAPK/JNK signal pathway in vivo. Front. Biosci. 11:2714–24 144. Alonso A, Rahmouni S, Williams S, van Stipdonk M, Jaroszewski L, et al. 2003. Tyrosine phosphorylation of VHR phosphatase by ZAP-70. Nat. Immunol. 4:44–48
Annu. Rev. Immunol. 2008.26:29-55. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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145. Cerignoli F, Rahmouni S, Ronai Z, Mustelin T. 2006. Regulation of MAP kinases by the VHR dual-specific phosphatase: implications for cell growth and differentiation. Cell Cycle 5:2210–15 146. Alonso A, Merlo JJ, Na S, Kholod N, Jaroszewski L, et al. 2002. Inhibition of T cell antigen receptor signaling by VHR-related MKPX (VHX), a new dual specificity phosphatase related to VH1 related (VHR). J. Biol. Chem. 277:5524–28 147. Marti F, Krause A, Post NH, Lyddane C, Dupont B, et al. 2001. Negative-feedback regulation of CD28 costimulation by a novel mitogen-activated protein kinase phosphatase, MKP6. J. Immunol. 166:197–206 148. Perco P, Blaha P, Kainz A, Mayer B, Hauser P, et al. 2006. Molecular signature of mice T lymphocytes following tolerance induction by allogeneic BMT and CD40-CD40L costimulation blockade. Transpl. Int. 19:146–57 149. Tautz L, Pellecchia M, Mustelin T. 2006. Targeting the PTPome in human disease. Expert Opin. Ther. Targets 10:157–77 150. Pellecchia M, Becattini B, Crowell KJ, Fattorusso R, Forino M, et al. 2004. NMR-based techniques in the hit identification and optimisation processes. Expert Opin. Ther. Targets 8:597–611 151. Syed AA, Simmonds MJ, Brand OJ, Franklyn JA, Gough SC, Heward JM. 2007. Preliminary evidence for interaction of PTPN12 polymorphism with TSHR genotype and association with Graves’ ophthalmopathy. Clin. Endocrinol. In press 152. Pao LI, Lam KP, Henderson JM, Kutok JL, Alimzhanov M, et al. 2007. B cell-specific deletion of protein-tyrosine phosphatase Shp1 promotes B-1a cell development and causes systemic autoimmunity. Immunity 27:35–48
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:29-55. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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Contents
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Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity∗ Rosanne Spolski and Warren J. Leonard Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892-1674; email:
[email protected],
[email protected] Annu. Rev. Immunol. 2008. 26:57–79
Key Words
First published online as a Review in Advance on November 8, 2007
cytokine, Blimp-1, plasma cell differentiation, Stat3, antitumor, adaptive immunity, innate immunity
The Annual Review of Immunology is online at immunol.annualreviews.org This article’s doi: 10.1146/annurev.immunol.26.021607.090316 c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0057$20.00 ∗ The U.S. Government has the right to retain a nonexclusive, royalty-free license in and to any copyright covering this paper.
Abstract Interleukin-21 (IL-21), a potent immunomodulatory four-α-helicalbundle type I cytokine, is produced by NKT and CD4+ T cells and has pleiotropic effects on both innate and adaptive immune responses. These actions include positive effects such as enhanced proliferation of lymphoid cells, increased cytotoxicity of CD8+ T cells and natural killer (NK) cells, and differentiation of B cells into plasma cells. Conversely, IL-21 also has direct inhibitory effects on the antigen-presenting function of dendritic cells and can be proapoptotic for B cells and NK cells. IL-21 is also produced by Th17 cells and is a critical regulator of Th17 development. The regulatory activity of IL-21 is modulated by the differentiation state of its target cells as well as by other cytokines or costimulatory molecules. IL-21 has potent antitumor activity but is also associated with the development of autoimmune disease. IL-21 transcription is dependent on a calcium signal and NFAT sites, and IL-21 requires Stat3 for its signaling. The key to harnessing the power of IL-21 will depend on better understanding its range of biological actions, its mechanism of action, and the molecular basis of regulation of expression of IL-21 and its receptor.
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INTRODUCTION
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Immune responses to foreign antigens have evolved to comprise the two interacting arms of cellular and humoral responses: the innate and adaptive immune systems. The cellular components of the innate immune system, including dendritic cells (DCs), natural killer (NK) cells, macrophages, and granulocytes, possess pattern recognition receptors capable of detecting conserved structural components of pathogens whose recognition then initiates immediate responses. One of the key responses of the innate immune system is the production of cytokines that then regulate the antigen-driven differentiation of the adaptive immune system, composed of naive lymphoid B and T cells, which then results in the development of antigen-specific effector responses. Cytokines produced by the innate immune system as well as cytokines produced by activated T cells drive the expansion and effector functions of the adaptive immune response as well as the downregulation of responses once the offending agent has been eradicated. Much attention has been paid over the past several decades to the array of cytokines that are produced by these immune cells and play such an important role in the amplification and control of responses to pathogens. Understanding the mechanisms involved in the production and function of these cytokines is key to predicting and employing clinical strategies for controlling these responses. One of the most important families of cytokines includes the type I four-α-helicalbundle cytokines, which comprise many of the interleukins and colony-stimulating factors as well as a range of other molecules such as erythropoietin, growth hormone, and prolactin. In one subfamily of this set of cytokines, the receptors share the common cytokine receptor γ chain, γc , which is mutated in humans with X-linked severe combined immunodeficiency (XSCID) (1), a disease characterized by the absence of T and NK cells but the presence of nonfunctional B cells. This set of cytokines includes IL-2, IL-4, IL-7, IL-9, IL-
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15, and IL-21, the most recently discovered member (2, 3) (see Figure 1). The IL-21 receptor was discovered in 2000 as an orphan receptor, first denoted as NILR for novel interleukin receptor and now as IL21R (4, 5). IL-21 was cloned as the ligand for this novel receptor (5) and was first observed to be produced by CD4+ T cells and to modulate the proliferation and effector function of other lymphoid cells. Subsequently, however, IL-21 was observed to act on multiple nonlymphoid lineages as well and to be produced by innate immune natural killer T (NKT) cells and the more recently identified Th17 lineage. This has expanded our understanding of the broad potential roles for this cytokine in the development and control of immune responses. Moreover, IL-21 has been shown to have strong antitumor action via its effects on both NK and CD8+ T cells and also has been identified as a key component in the development of autoimmune disease. The dissection of these beneficial and pathogenic effects of IL-21 has begun to offer a new appreciation of the complexity of the interaction between the innate and adaptive immune responses.
IL-21 Receptor and Ligand Structure The IL-21 receptor (IL-21R) was first discovered by genomic and cDNA sequencing projects as an open reading frame that putatively encoded a type I cytokine receptor (4, 5). Its predicted amino acid sequence was most related to the IL-2 receptor β chain, and like IL-2Rβ, IL-21R appeared to be lymphohematopoietic restricted. Moreover, IL-21R was located immediately downstream of IL4Rα on human chromosome 16 (4). Thus, IL-21R was clearly related to the γc family of cytokines. Indeed, when identified, the ligand for this novel type I receptor was most similar to IL-2, IL-4, and IL-15 (5). The functional receptor for IL-21 is IL-21R + γc (6, 7). IL-21R was observed initially to be expressed on T, B, and NK cells (4, 8).
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IL-2Rα α
IL-15Rα IL-4
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• B cell proliferation • Th2 T cell development
• B cell development in mice
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• Ig class switch • T cell proliferation • Antigen-induced cell death • Boosting of cytolitic activity of NK cells • Development of Treg cells
• NK cell development • CD8+ memory T cell homeostasis
• T cell development in humans and mice
• Memory T cell development
• Mucus production • Mast cell proliferation
• Comitogen for T cell proliferation • Cooperative expansion of CD8+ T cells • Antitumor agent • Plasma cell differentiation • Implicated in autoimmunity (see Fig. 4)
Figure 1 Cytokine receptors containing the common cytokine receptor γ chain (γc ). The IL-21 receptor is a member of a family of receptors that share γc . In addition to γc , each of these receptors has one or more distinctive receptor components. Mutations in γc result in X-linked severe combined immunodeficiency (XSCID); the severity of this disease results from defective signaling through all these receptors.
Expression on B cells was the highest, even on resting cells, with constitutive expression in a number of cell lines (4, 8). Low-level IL-21R expression on T cells was also observed but was significantly increased following T cell receptor (TCR) stimulation (4, 8). Interestingly, like that of IL-2Rβ, expression of IL21R was also augmented in cells transformed with HTLV-I (4). Recently, the three-dimensional structure of human IL-21 has been solved by heteronuclear NMR spectroscopy (9). As anticipated, it is a typical up-up-down-down four-α-helicalbundle cytokine. A segment of the molecule involving helix C that is important for receptor binding is relatively unstable, and stabilization of this region in a human IL-21 analog results in a tenfold increase in biological potency (9).
The Molecular Basis for IL-21 Signaling Like other type I cytokines, IL-21 signals via the Jak-STAT pathway (see Figure 2). Analogous to IL-2, IL-4, IL-7, IL-9, and IL-15, Jak1 and Jak3 are the Janus family tyrosine kinases that are activated by IL-21 (4, 6, 7). IL21 can activate Stat1, Stat3, and both Stat5a and Stat5b (10, 11). However, the activation of Stat5a and Stat5b is relatively weak and transient, whereas the activation of Stat3 is the most sustained. Stat3 appears to be the most important STAT protein for IL-21 signaling. Indeed, there is defective signaling to IL-21 in T cells that lack expression of Stat3 (11). The IL-21R cytoplasmic domain contains six tyrosine residues. One of these, Tyr 510, is phosphorylated and serves as a critical docking site for both Stat1 and Stat3. On the basis
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MEK
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Co
Co TF
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IL-21 target genes Granzyme A, Bcl-3, Jak3, granzyme B
Figure 2 Signaling pathways for the IL-21 receptor (IL-21R). Upon IL-21 binding, Jak1 and Jak3, which interact with IL-21R and γc , respectively, are activated and then phosphorylate Stat3 and Stat1 and weakly phosphorylate Stat5 proteins. This leads to STAT dimerization and translocation to the nucleus, with subsequent binding to target gene regulatory elements. A critical tyrosine in the IL-21R cytoplasmic domain (Y510) is primarily responsible for the docking of Stat1 and Stat3. Five other cytoplasmic tyrosines are not shown. Additionally, ligand binding to the IL-21R can lead to activation of the MAP kinase (MAPK) and the PI 3-kinase (PI 3-K) pathways. Target genes activated by IL-21 have been identified, but the involvement of each of these signaling pathways in the regulation of these genes remains to be determined. Co, co-activator; POL, RNA polymerase; TF, transcription factor.
of analysis using the chemical inhibitors wortmannin and PD98059, we can conclude that PI 3-kinase and MAP kinase pathways also contribute to IL-21 signaling. These different signaling pathways may function in distinct phases of lineage development and function.
IL-21 Ligand and Receptor Regulation IL-21 is produced by CD4+ T cells (5) as well as by NKT cells (13). Although the genes encoding IL-21 and IL-2 are adjacent to each other, the regulation of these genes is signifi60
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cantly distinct. Both cytokines can be induced in CD4+ T cells by signaling via the TCR, but IL-21 mRNA can be induced by a calcium signal alone in preactivated T cells, whereas IL-2 mRNA induction requires both a calcium signal and protein kinase C (14). Nuclear factor of activated T cells (NFAT) binding sites in the IL-21 promoter region contribute to the regulation of IL-21 transcription (14, 15). Interestingly, NFATC2 binds in vivo, but mice lacking NFATC2 still express IL-21, indicating functional redundancy with other NFAT family proteins (14). Mycobacterial antigens
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(BCG) upregulate levels of IL-21 in NKT cells in both mouse and human systems (16), revealing that innate immune signals can also induce IL-21 production. IL-21 receptor expression has been detected on CD4+ T cells, CD8+ T cells, B cells, NK cells, DCs, macrophages, and keratinocytes (4, 5, 8, 17–19), suggesting that IL21 has a broad range of actions. Although IL-21 is not required for hematopoiesis, as demonstrated by analysis of IL-21R knockout (KO) mice (20), IL-21R mRNA has also been detected on a population of bone marrow progenitors, and IL-21 can expand hematopoietic progenitor cells both in vivo and in vitro (20a). Within the T cell lineage, IL-21R expression is induced as cells differentiate from double negative (CD4− CD8− ) thymocytes to double positive (CD4+ CD8+ ) thymocytes (8), but this expression may not be absolutely essential for thymocyte differentiation because there is normal thymic development in IL-21R KO mice (20). Low but detectable levels of IL21R are found on mature CD4+ and CD8+ T cells (8), and these levels are upregulated in response to either TCR or IL-21 (8, 21). TCRmediated IL-21R expression is regulated in part by the induction and dephosphorylation of the transcription factor Sp1 (21). Within the B cell lineage, IL-21R is expressed at a low level at the pre–B cell stage of development; this level persists through the first transitional (T1) stage but then increases at the second transitional (T2) stage (22). Mature follicular B cells express higher basal levels of IL-21R than are found on mature T cells (8), and these levels are further increased by signals either through the B cell receptor (BCR) or through CD40 (23). Marginal zone B cells respond to IL-21 but have lower IL-21R expression than do follicular B cells (22). Plasma cells have no detectable surface IL-21R (23), in keeping with their terminally differentiated and nonproliferative state. Interestingly, however, myeloma plasmacytoma cells do express surface IL-21R (24), which may provide a distinct survival advantage for these cells in vivo.
IL-21 AND B CELL FUNCTION IL-21 Plays a Critical Role in Immunoglobulin Production The role of IL-21 in B cell function has been investigated in both in vitro studies and in vivo systems employing IL-21R KO and IL-21 transgenic mice. IL-21 is not essential for B cell development; no defects in B cell subsets within bone marrow or periphery have been observed in IL-21R KO mice (20). B cells from IL-21R KO mice normally proliferate in response to lipopolysaccharide (LPS), anti-CD40, or the combination of IL4 plus anti-IgM (20). The most striking defect in naive IL-21R KO mice is a reduced level of serum IgG1, yet an increased level of IgE (20). Upon immunization with T cell– dependent antigens, IL-21R KO mice have strikingly impaired production of antigenspecific IgG1 and significantly higher levels of antigen-specific IgE (20), an unexpected result given that IgG1 and IgE are usually coordinately regulated. These elevated levels of IgE in IL-21R KO mice were consistent with experiments demonstrating that IL-21 administered to wild-type (WT) mice at the time of immunization can lead to reduced IgE responses, as well as with in vitro experiments showing that IL-21 can reduce levels of germline Cε transcripts, leading to reduced IgEspecific switching (25). Interestingly, in vitro experiments using human peripheral blood B cells revealed that IL-21 can both positively and negatively regulate IgE production, depending on the context. For example, IL-21 in combination with PHA and IL-4 inhibited IgE, whereas IL-21 in combination with anti-CD40 plus IL-4 led to increased IgE levels (26). The precise molecular mechanism(s) by which IL-21 regulates IgE production remains to be fully delineated, particularly because IL-21 can also be proapoptotic for B cells (see below). IL-4 is required for IgE production, and as expected, IL-4/IL-21R double-knockout (DKO) mice could not produce IgE,
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confirming that IL-4 is indeed necessary for the enhanced levels of IgE seen in the IL-21R KO mice. But surprisingly, the DKO mice exhibited a pan-hypogammaglobulinemia, with essentially absent levels of IgG1, IgG2a, IgG2b, and IgG3 and greatly reduced levels of IgM (20). Thus, IL-21 and IL-4 cooperatively regulate immunoglobulin (Ig) production. These observations may also explain the B cell phenotype in humans with XSCID (2, 20). In this severe immunodeficiency, B cells develop normally but are nonfunctional; patients exhibit a severe pan-hypogammaglobulinemia. In the mouse, elimination of γc results in a loss not only of T cells but also of B cells, given a critical role in the mouse, but not human, for IL-7 signaling in B cell development (27). By keeping IL-7 signaling intact and thus allowing B cells to develop but by eliminating signaling by IL-4 and IL-21, we apparently have mimicked in mice the human XSCID B cell phenotype (20).
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IL-21 Induces B Cell Apoptosis in a Context-Dependent Manner One of the most puzzling aspects of IL-21 biology is that, in contrast to other members of the γc -dependent cytokines, IL-21 can be potently proapoptotic for B cells. Initially, IL21 was found to augment anti-CD40-induced human B cell proliferation but inhibit proliferation to anti-IgM and IL-4 (5). The inhibition of LPS-induced proliferation by IL-21 results at least in part from a strong proapoptotic signal from IL-21 (8, 28, 29). The degree of IL-21-induced apoptosis is dependent on the context of B cell activation: Apoptosis dominates when B cells are activated with Toll-like receptor (TLR) signals such as LPS or CpG but augments proliferation when B cells are activated with BCR signals (antiIgM) plus T cell–derived costimulatory signals such as those provided by anti-CD40 (8, 28, 29). The apoptotic signal is caspase dependent because it can be inhibited with caspase inhibitors (28). Although apoptosis can
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be prevented by the overexpression of the antiapoptotic Bcl-2 protein (28, 29), IL-21 has no effect on Bcl-2 protein levels in B cells (29). Analysis of genes involved in apoptosis revealed that IL-21 increases mRNA and protein levels of the proapoptotic mitochondrial protein Bim and decreases levels of Bcl-xL (8). IL-21-induced apoptosis was eliminated in B cells from Bim KO mice, confirming that Bim-1 plays a role in the IL-21-mediated death of B cells. Other antiapoptotic proteins may be involved in the rescue from IL-21mediated apoptosis. For example, IL-4 can rescue B cells from LPS + IL-21-induced cell death through upregulation of Bcl-xL, and this rescue is dependent on the presence of Bcl-6 (30). IL-21-mediated induction of apoptosis may in part also account for the inhibitory effects of IL-21 on IgE production. Vaccination with Mycobacterium bovis bacillus (BCG) activated Vα14 NKT cells to express high levels of IL-21, which in turn preferentially induced apoptosis of IgE-expressing B cells but not apoptosis of other Ig-isotypeexpressing B cells (16). The mechanism for this specific apoptosis seems to involve IL21-induced formation of a complex between Bcl-2 and the proapoptotic molecule Bcl-2modifying factor (Bmf), which is specifically expressed in the IgE-expressing population of B cells. Bmf thereby inhibits the usual antiapoptotic activity of Bcl-2, leading to specific apoptosis of IgE-producing B cells and the subsequent loss of IgE production. The above results indicate that IL-21 can differentially influence the outcome of an antibody response, depending on the costimulatory signals present at the time that B cells encounter antigen (see Figure 3). B cells receiving a polyclonal, nonspecific signal such as those mediated by the TLRs would thus potentially produce nonantigen-specific Igs, including autoreactive Igs. Expansion of this potentially deleterious population would be prevented by the presence of IL-21 at the time of encounter. In contrast, a B cell that interacts specifically via its BCR and receives specific
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Without BCR signal or T cell interaction
With BCR signal and/or T cell interaction IL-21
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IL-21R
IL-21
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Figure 3 Effects of IL-21 on B cell differentiation and survival. Signaling through the IL-21 receptor (IL-21R) has two potential outcomes for naive B cells. (Left) In the absence of a B cell receptor (BCR) or T cell interaction signal or in the presence of a Toll-like receptor (TLR)-dependent signal, IL-21 induces apoptosis of a naive B cell. (Right) In the presence of a BCR signal and/or costimulatory interactions with T cells, IL-21 induces proliferation, isotype class switching, and differentiation to either memory B cells or terminally differentiated plasma cells. Memory B cells maintain IL-21R and respond to IL-21 plus antigen signals to differentiate into plasma cells, with subsequent downregulation of IL-21R expression.
T cell help would receive a positive costimulatory signal from IL-21.
IL-21 Drives Terminal Differentiation of B Cells to Plasma Cells The analysis of IL-21R KO mice had indicated a critical role for IL-21 in Ig production. The role of IL-21 in antibody responses was further investigated through the use of IL-21 transgenic mice as well as through hydrodynamic transfection of mice with an IL21 expression plasmid (29). In both systems, IL-21-induced apoptosis could be detected by annexin V staining of naive B cells ex vivo. Surprisingly, in both mouse models, there
were increased numbers of total splenic B cells rather than the expected decrease resulting from IL-21-induced apoptosis. Most of the increase in B cell numbers resulted from increases in the number of immature B cells and in the number of postswitch B cells and plasma cells. However, there was no change in the number of mature B cells. This was consistent with the increased concentrations of serum IgM and IgG1. In vitro experiments using murine splenic B cells showed that IL-21 in combination with anti-IgM could directly induce the differentiation and accumulation of Syndecan-1+ plasma cells in these cultures (29). The ability of IL-21 to promote differentiation to plasma cells was explained by its potent induction of B lymphocyte–induced www.annualreviews.org • Interleukin-21
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maturation protein-1 (Blimp-1) (29), a transcription factor that acts as a master switch for the program of transcriptional changes involved in terminal differentiation of B cells to plasma cells (31). Surprisingly, in both primary splenic B cells as well as in a B cell line, IL-21 also induced the production of the transcription factor Bcl-6 (29). Blimp-1 and Bcl-6 function as mutually exclusive transcription factors that negatively regulate the expression of each other and correlate with the plasma cell and the memory cell phenotype, respectively (31, 32). It is not yet clear whether both transcription factors are induced by IL21 within the same individual cells; if so, their coinduction by IL-21 may be limited to a specific stage of B cell development prior to the commitment to either memory cell or plasma cell lineages. Corresponding to its effects on mouse B cells, IL-21 also plays a major role in stimulating the differentiation of human B cells. Naive cord blood B cells as well as postswitch memory B cells can be driven to differentiate to plasma cells by IL-21 in combination with either BCR and/or CD40 signals (33). IL-21 costimulation of human B cells also induced high levels of Blimp-1 as well as activation-induced cytidine deaminase (AID), but surprisingly this did not induce somatic hypermutation (33). Although IL-21 acted as a switch factor for production of both IgG1 and IgG3 by human peripheral B cells (34), costimulation of naive cord blood B cells with IL-21 plus anti-CD40 induced predominantly the IgG3 isotype (33), suggesting that molecular differences in the responding populations can account for switch preferences. Interestingly, although IL-21 and IL-4 cooperate in the production of Ig, as seen in the absence of Ig responses in IL-4/IL-21R DKO mice (20), these two cytokines appear antagonistic in their effects in both murine and human B cell differentiation into plasma cells: IL-4 inhibited IL-21-mediated plasma cell differentiation by B cells stimulated with either anti-IgM or anti-IgM plus anti-CD40 but did not inhibit B cells stimulated with anti-
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CD40 alone (29, 33). The functional interaction between IL-4 and IL-21 is thus complex and dependent on the nature of costimulatory signals as well as the developmental stage of the target B cell. Although IL-21R levels are higher on naive than on memory B cells (23), IL-21 can also induce rapid plasma cell differentiation in a population of human marginal zone memory B cells (35). This differentiation occurs in response to the combination of IL21 plus BAFF/BLyS, a TNF family cytokine produced by the local DC population (36). The combination of IL-21 with BAFF leads to the synergistic induction of both Blimp-1 and AID, providing a possible mechanism for rapid upregulation of IgG-secreting plasma cells in an antigen-independent manner (35).
IL-21 EFFECTS ON CD4+ T CELL FUNCTION IL-21 Is Produced by Multiple T Helper Populations The functional capacity of CD4+ T cell populations is highly dependent on the cytokines that are available in the environment at the time of TCR priming. Th1 cells arise in response to DC-derived IL-12, produce IFNγ and TNF-α, and are involved in mediating strong inflammatory responses to intracellular pathogens. IL-4-mediated Th2 cell differentiation results in cells that produce cytokines, including IL-4, IL-5, and IL-13, which mediate antibody responses to extracellular pathogens. Th17 cells, the most recently identified CD4+ T cell subset, differentiate in response to TGF-β and IL-6 signals and produce IL-17, which mediates neutrophil differentiation and infiltration during various infections (37). Each of these CD4+ T cell populations can produce IL-21, although to different extents, and can respond to IL-21 with distinct differentiative responses. Nevertheless, the subset(s) of cells responsible for IL-21 production at specific phases of various in vivo immune responses is not yet fully clear.
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Several laboratories originally examined the Th subset expression of IL-21 and obtained ostensibly inconsistent results. One study reported that IL-21 mRNA and protein are produced by Th2-polarized cells but not by Th1polarized cells (38), but another used a DNA array analysis of expression in human Th1and Th2-polarized CD4 T cells and showed that IL-21 mRNA was expressed predominantly in Th1 cells (39). Furthermore, IL-21 mRNA expression was highest in a population of follicular Th cells that could augment B cell antibody responses to antigen (39). Recent work has identified Th17 cells as producing significantly higher levels of IL-21 mRNA and protein than either Th1 or Th2 cells do (40, 41). IL-21 itself and IL-6 were identified as essential for the upregulation of IL-21 in this lineage (40–42); Stat3 signaling was essential (41, 42). In the committed Th17 cell, TCR signaling can further upregulate IL21 production. The functional significance of Th17 expression of IL-21 is further discussed below.
Regulation of Th1 versus Th2 Differentiation In Vitro by IL-21 Although both Th1 and Th2 cells produce IL-21, the effects of IL-21 on differentiation within these subsets are only beginning to be delineated. Analogous to effects of IL-21 on B cell proliferation and function, the end result may depend on other cytokines or immune populations as well as on the developmental stage of the target cell. The initial observation that IL-21 can function as a Th2 cytokine was based in part on in vitro experiments showing that IL-21 could inhibit IFN-γ expression only when IL-21 was present at the time of naive CD4+ T cell priming under Th1 conditions (38). There was not, however, a general downregulation of the Th1 program in that IL-21 had no effect on T-bet or IL-12Rβ2 expression, both of which are induced in Th1 cells even when Th1 cells are primed in the presence of IL-21. The specific decrease of IFN-γ by IL-21 was mediated by the direct
repression of Eomesodermin, a T-box transcription factor important for IFN-γ induction (43). Moreover, in populations of human peripheral blood T cells that were preactivated with TCR, IL-21 could induce the expression of a panel of Th1 genes, including those encoding IFN-γ, T-bet, and IL-12Rβ2, suggesting that the effects of IL-21 on already activated cells may be distinct from those on naive T cells (44).
Regulation of Th1 versus Th2 Responses In Vivo by IL-21 The role that IL-21 plays in the in vivo regulation of Th1 versus Th2 polarization has been studied via the use of IL-21R KO mice in a number of immunization and infection models. IL-21R KO mice exhibit normal development of CD4+ T cells both in the thymus and in the periphery (20). Additionally, in vitro stimulation of naive CD4+ T cells under Th1- or Th2-polarized conditions showed no differences in WT versus IL-21R KO levels of IFN-γ or IL-4, suggesting that IL-21 is not essential for the normal differentiation of these two subsets (20). When IL21R KO mice were examined in a delayedtype hypersensitivity model in which footpad swelling was measured after an antigenic challenge, these KO mice had higher inflammatory responses than did WT mice (38). Ex vivo antigen-specific challenge of CD4+ T cells in these challenged mice revealed higher production of IFN-γ by KO than by WT cells. Another group examined the expression of IL-21 during the time course of infection with Schistosoma mansoni, a parasite that induces a Th2-dependent granuloma formation (45). IL-21 levels were measured in strains of mice that developed massive Th1 (IL-4/IL-10 DKO) or Th2 (IL-12/IL-10 DKO) responses to the parasite. Although infection of these mice with schistosome eggs induced highly polarized responses in the lungs, as evaluated by the production of IL-13 and IFN-γ, IL21 was produced during the infection in both strains of mice, indicating that IL-21 does not www.annualreviews.org • Interleukin-21
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behave as a classical Th1 or Th2 cytokine (45). When IL-21R KO mice were infected with S. mansoni, there was not a corresponding increase in Th1 cytokine production, despite a reduced Th2 response (i.e., decreased production of IL-4, IL-10, and IL-13) to the parasite in the granulomatous tissues of the lungs. Consistent with the decreased Th2 response in the IL-21R KO mice, there was more rapid resolution of the lung granulomas in these mice, indicating that IL-21 plays a role in the initiation and maintenance of a granulomatous inflammatory response. In spite of the reduced Th2 responses in the S. mansoni– infected mice, there was no difference in the cytokine profile of CD4+ T cells stimulated ex vivo with antigen, suggesting that in vivo IL21 deficiency may not alter the Th priming of CD4+ T cells per se but rather may lead to a depressed Th2 response through mechanisms that are not yet clear. In a separate study, IL21R KO mice that were infected with Heligmosomoides polygyrus intestinal parasites developed fewer and smaller granulomas and had a reduced eosinophilia in the blood, suggesting a defective Th2 type response (46). However, analysis of ex vivo cytokine production from infected mice revealed no differences in levels of IFN-γ or IL-4 (46).
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IL-21 Critically Regulates Th17 Development IL-17-producing Th17 cells have distinctive developmental and functional properties that differ from those ascribed to Th1 and Th2 CD4+ effector T cells (47, 48). TGF-β, an immunosuppressive cytokine with a role in the generation of T regulatory (Treg) cells (49), also plays a key role in the induction of the Th17 differentiation pathway (50). However, Treg and Th17 cells are induced by TGF-β in a mutually exclusive manner; IL-6 shifts the balance in favor of Th17 cells and decreases the development of Treg cells (51). An analysis of TCR-stimulated CD4+ T cells revealed that the IL-21 gene was one of the genes most highly induced by IL-6 (42). 66
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Indeed, IL-21 mRNA and protein are very highly expressed in Th17 cells, at levels approximately fivefold higher than in Th1- and Th2-polarized cells (40, 41). The induction of IL-21 leads to a further autocrine upregulation of IL-21 (42). Interestingly, IL-21 induced IL-23R expression on these CD4+ T cells (41, 42). IL-23R forms dimers with the IL-12Rβ1 subunit, which is shared by both IL-12R and IL-23R (52). Although IL-23 is an important factor in inflammatory disease in both mice and humans, its receptor is not present on naive T cells, and IL-23 may play a role in the expansion of already differentiated Th17 cells (53). The induction of IL-23R by IL-21 in naive CD4+ T cells is therefore a critical step in the differentiation and possibly in the expansion of Th17 cells in vivo. IL-21 and IL-23 both upregulated expression of the orphan nuclear receptor RORγt, which is essential for Th17 differentiation (54) and which leads to further upregulation of IL-21 (42). IL-17 production was significantly lower in CD4+ T cells from IL-21R KO mice that were induced in vitro with TGF-β and IL-6, demonstrating that the induction of IL-21 by IL-6 leads to an amplification of this differentiation pathway (41, 42). In fact, no IL-23R was induced by TGF-β + IL-6 in CD4+ T cells from IL-21 KO or IL-21R KO mice, indicating a critical role for IL-21 in controlling IL-23R expression (41, 42). The initial induction of IL-21 in Th17 cells therefore is critical for the establishment of an autocrine amplification pathway for maximal IL-17 production.
IL-21 and Treg Induction IL-21 also plays an indirect role in the regulation of Treg differentiation. Interestingly, IL6 is critical in the inhibition of Treg differentiation by TGF-β and in the induction of Th17 differentiation (51). Indeed, IL-6 KO mice do not produce Th17 cells but produce a dominant FoxP3+ Treg population (40). However, in mice that are deficient in both IL-6 and FoxP3+ Treg cells, Th17 cells are once again
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present, and these cells are produced in response to IL-21 in combination with TGFβ, demonstrating the presence of an IL-6independent pathway for Th17 production. The negative effects of IL-21 on Treg production are further demonstrated by the presence of a three- to fourfold increased FoxP3+ CD4+ T cell population in IL-21 KO mice (41).
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IL-21 Regulates Proliferation and Effector Function of CD8+ T Cells IL-21 is produced by CD4+ T cells and, as indicated above, influences the development of specific functional subsets within this lineage; however, the CD8+ T cell lineage is perhaps the primary target of the proliferative effects of IL-21. Nevertheless, CD8+ T cell development appears normal in the IL21R KO mice (20), indicating compensatory redundancy of these proliferative effects. In vitro experiments demonstrate that IL-21 by itself has very little if any effect on naive or memory phenotype CD8+ T cell proliferation and expansion but that it has a profound synergistic effect on proliferation in combination with either IL-7 or IL-15 (55), cytokines previously identified as playing major roles in homeostatic expansion of naive or memory CD8+ T cells (56, 57). This synergistic effect is especially evident when CD8+ T cells are stimulated in the absence of TCR signals (55), suggesting that IL-21 may play a role in antigen-independent expansion of this lineage in vivo. Gene expression analysis by DNA microarrays reveals that subsets of mRNAs are regulated individually by IL-21 or IL-15, but an additional set of mRNAs are cooperatively or distinctively regulated by the combination of IL-21 and IL-15, including granzyme B, which is important in cytolytic function of CD8+ T cells, as well as c-jun, which plays a role in the control of proliferative responses (55). The molecular mechanism of this synergistic transcriptional activity by these two cytokines remains to be determined. It is interesting that IL-21 activates Stat1 and Stat3
whereas IL-15 activates Stat5; however, differential STAT protein activation alone cannot be the full explanation given that the cooperative effect of IL-15 with IL-21 cannot be mimicked by IL-2, even though, like IL15, IL-2 is an activator of Stat5 proteins. Despite the ability of IL-21 to synergistically upregulate proliferation in combination with either IL-7 or IL-15, IL-21 has distinct effects on the differentiation of CD8+ T cells. IL-15 treatment of naive CD8+ T cells induces an effector phenotype in CD8+ T cells characterized by reduced CD28 and CD62L surface proteins, but IL-21 acts to prevent the downregulation of these proteins and potentially serves to maintain the important costimulatory function mediated by them (58). Although IL-21 alone can lead to the downregulation of CD44 expression on CD8+ T cells, the combination of IL-21 with IL-15 enhanced the accumulation of CD44high CD8+ T cells (55). With regard to cytokine production by naive CD8+ T cells, IL-21 alone induced no accumulation of IFN-γ-producing cells, and IL-15 alone could induce these cells, but the combination led to a further increase in the number of IFN-γ-producing cells (55). The effects of IL-21 on antigen-specific CD8+ T cell proliferation and effector function have been examined in several experimental systems. Primary immunization of mice with vaccinia virus expressing HIV gp160 antigen induced significantly lower expansion and cytolytic activity in IL-21R KO mice than in WT mice (55), indicating a role for IL-21 in antigen-specific expansion and functional differentiation of naive CD8+ T cells in vivo. When naive human CD8+ T cells were stimulated in vitro with mature DCs presenting a tumor-associated peptide, there was a greatly augmented proliferation when IL-21 was added, leading to the accumulation of a population of cytotoxic cells characterized by a CD28high surface phenotype and a tenfold higher affinity for antigen and a significantly increased production of IL-2, as compared with cells stimulated in the absence of IL21 (59). In contrast to the ability of IL-21 to www.annualreviews.org • Interleukin-21
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augment the antigen-independent proliferation of both naive and memory CD8+ T cells, IL-21 augmented proliferative and differentiative effects of antigen-dependent stimulation with naive but not with memory CD8+ T cells. The basis for this difference is not yet known. A study of the effects of IL-21 on CD8+ effector T cells in HIV-infected patients revealed that IL-21 could upregulate perforin production in the absence of cell activation or proliferation, whereas IL15-mediated upregulation of perforin was less substantial and occurred only in the presence of proliferation (60). This induction of perforin by IL-21 in memory T cells was greater in cells from HIV patients than from normal controls. Thus, the proliferative and functional effects of IL-21 differ for naive and memory CD8+ T cells.
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Actions of IL-21 on Natural Killer Cells NK cell development depends on the function of γc cytokines; γc KO mice are devoid of mature NK cells (61, 62). IL-21R KO mice have normal numbers of fully functional NK cells (20, 63), indicating that IL21 is not required for NK cell development, but it has become clear that IL-21 plays a role in NK cell maturation and functional development and that the actions of IL-21 on this lineage are stage specific. The original observation of an effect of IL-21 on NK cells was that IL-21 enhanced in vitro generation of NK cells from bone marrow precursors (5). Although γc KO mice lack mature NK cells, bone marrow NK cell precursors (CD122+ NK1.1− CD49b− ) develop even in the absence of γc -mediated signals, and a small subset of these precursors expresses IL21R (64). Increases in IL-21R levels on these precursors depended on IL-15, suggesting that IL-15 may regulate the ability of NK precursors to respond to IL-21 (64). Although IL-21 has not been found to affect NK cell generation, experiments using human cord blood NK cell precursors showed that these 68
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cells progressed further along the maturation pathway if IL-21 was added to the combination of IL-15, Flt3, stem cell factor, and IL-7, a set of cytokines required for in vitro generation of NK cells (65). Once committed immature NK cells are generated, IL-21 can also enhance their proliferative response to suboptimal IL-2 or IL-15 concentrations while having no effect on proliferation by itself (66). Interestingly, IL-21 had a biphasic effect on the growth of immature NK cells: Low doses of IL-21 enhance proliferation and high doses inhibit proliferation, even in the presence of IL-2 or IL-15 (66). IL-21 also has effects on mature NK cells, including effects on both proliferation and survival as well as on NK cell–specific cell surface receptors. IL-21 had a negative effect on the proliferation of NK cells that had been activated by IL-15, either inhibiting proliferation or increasing their apoptosis (67). In spite of the reduced proliferative and survival effects of IL-21 on NK cells, these cells exhibited enhanced cytolytic function, increased IFN-γ production, and conversion to a large granular phenotype, all indicative of enhanced effector function of these cells (63, 67). In addition, IL-21 inclusion in the in vitro–generated NK cell cultures resulted in changes in the expression of several NK cell inhibitory and activating receptors. For example, IL-2 and IL-15 could induce inhibitory Ly49 receptors on mature NK cells, but the inclusion of IL-21 downregulated these receptors (68). The NKG2D receptor was similarly downregulated by IL21 in cultures of human NK cells (69). This decreased expression was mediated by transcriptional repression of the DAP10 adaptor through which NKG2D signals. Consistent with these changes in NK receptor expression, IL-21 modestly inhibited NK cell lysis of NKG2D-sensitive targets (69). Although IL21 repressed NKG2D expression on mature peripheral blood NK cells, IL-21 enhanced NKG2D expression on murine bone marrow– derived NK cells, which represent a less mature population of NK cells. This underscores
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the stage-specific effects of IL-21 on NK cells (67). Thus, although IL-21 is not required for NK cell development, it influences the proliferation and functional activity of this lineage.
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IL-21 Effects on Natural Killer T Cells NKT cells are a population of T cells expressing a restricted TCR repertoire; they recognize glycolipids presented by CD1d as well as inhibitory and activating NK receptors (70). NKT cells have immunoregulatory activity on other subsets that is related to their secretion of cytokines and their potent cytotoxic activity. Similar to its effect on NK cells, IL-21 can increase the proliferation of NKT cells in response to in vitro stimulation with antiCD3 but only when combined with either IL2 or IL-15 (13). IL-21 can also stimulate the in vitro release of increased levels of IL-4 and IL13 by NKT cells. In addition, IL-21 upregulated effector function in NKT cells through the induction of granzyme B and conversion to a large granular cell morphology similar to what was found for NK cells (13). Interestingly, NKT cells are also potent producers of IL-21 when stimulated in vitro with anti-CD3 or in vivo with α-GalCer, a stimulatory glycolipid specific for NKT cells (13). Levels of IL-21 protein secreted by NKT were significantly higher than those produced by splenic CD4+ T cells in response to anti-CD3 stimulation. The ability of NKT cells to produce large amounts of IL-21 in response to microbial stimuli opens the possibility that these innate immune cells can regulate the initial steps in the formation of an adaptive immune response by B and T cells.
IL-21 Inhibits Dendritic Cell Maturation and Function DCs are peripheral myeloid cells that have the capacity to recognize microbial components via surface receptors, endocytose these microbes, and then undergo maturation in response to some of these microbial compo-
nents. Subsequent to this maturation, DCs migrate to lymphoid organs, where they function as antigen-presenting cells for T cells. The initial evidence that IL-21 can affect the proliferation or differentiation of myeloid cells came from the observation that injection of an IL-21-encoding plasmid into WT mice led to increases in the numbers of both CD11b+ and Gr1+ cells in the periphery (71). Although most of the effects of IL-21 on lymphoid cells are stimulatory, involving enhanced proliferation or effector function, effects of IL-21 on DCs are largely inhibitory. DCs can be generated and expanded in vitro by culturing bone marrow precursor cells with GM-CSF. When DC cultures were expanded in this manner in the presence of either IL21 or IL-15, differences in their phenotype and function were evident (17). Although IL15-treated DCs behaved as mature DCs and could present antigen in both in vivo and in vitro assays, IL-21-treated DCs maintained an immature phenotype that was characterized by low MHC class II expression accompanied by increased uptake of antigen and lowlevel expression of CC-chemokine receptor 7 (CCR7) (17). When IL-21-primed DCs were stimulated with LPS, there was no upregulation of MHC class II, CD86, or CD80 costimulatory proteins, in contrast to the upregulation that is seen with IL-15-primed DCs, and the IL-21-primed DCs had inhibitory effects on T cell responses. Even when DCs were treated for only 2 h in vitro with IL-21 plus ovalbumin antigen and then adoptively transferred in vivo, they could inhibit T cell– mediated contact hypersensitivity responses (17). IL-21 can also exert proinflammatory effects on immune responses through the induction of the neutrophil chemoattractant CXCchemokine ligand 8 (CXCL8) in macrophages (72). Neutrophils apparently lack IL-21R but can be recruited to sites of inflammation indirectly through IL-21-mediated CXCL8 induction on macrophages. Additionally, the critical role played by IL-21 in the differentiation and expansion of Th17 cells leads to the www.annualreviews.org • Interleukin-21
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production of IL-17 family cytokines that affect neutrophil recruitment and function (40– 42). Thus, IL-21 can either dampen immune responses or exacerbate them, depending on the myeloid population that is targeted and the timing of exposure to IL-21 during the course of an immune response.
IL-21 Mediates Potent Antitumor Responses
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The ability of IL-21 to regulate both T cell– mediated and NK cell–mediated immune responses suggested possible antitumor effects. Indeed, IL-21 has been examined in a number of in vivo tumor models, and these studies have confirmed the potent effects of IL21 as an antitumor agent in animal models. The success in these models has led to the use of IL-21 in several phase I clinical trials in advanced-stage melanoma patients. The mechanisms of the antitumor action of IL-21 involve augmented NK cell and CD8+ T cell cytotoxicity. Systemic expression of IL-21 by plasmidmediated in vivo delivery led to an inhibition of the growth of large preestablished melanomas and fibrosarcomas (71). These effects were mediated predominantly by NK cells; ablation of this population reduced the antitumor effect, with only minimal effects seen by ablation of the CD8+ T cell population. Significantly, there were no major in vivo toxic effects, even at high doses of IL-21 (71), unlike the severe toxicity observed with similar doses of IL-2 or IFN-α. In another study that used a different approach to achieve high systemic levels of cytokine, IL-21 and IL23 were constitutively expressed in pancreatic carcinomas, leading to retarded tumor growth in nude mice, an effect that was again predominantly mediated by NK cells (73). IL-21 overexpression in mammary adenocarcinoma cells also led to the prevention of tumor initiation, although in this system there was no role for NK cells, and the tumor prevention was completely dependent on CD8+ T cells (74). 70
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NK cell–mediated killing of tumors after treatment with IL-21 appears to depend on the presence of NKG2D ligands on the tumor target because there was no IL-21-mediated enhancement of rejection of tumors that did not express these ligands and killing could be blocked by antibodies to NKG2D (75). IL-21 could enhance killing of ligand-positive tumors even in Rag2 KO mice, demonstrating that this is an NK cell–mediated event not requiring an adaptive immune response. These experiments suggest that the action of IL-21 on NK cells may be limited to tumors involving the NKG2D recognition system. Although this study found no effects of IL-21 on NK cell expression of this receptor, other studies did find either positive or negative effects of IL-21 on NKG2D expression (67, 69). Other tumor systems have allowed the delineation of IL-21-induced CD8+ T cell– mediated killing mechanisms. One study compared the antitumor activity of intraperitoneally delivered IL-2, IL-15, and IL-21 with syngeneic E.G7 thymomas. This study found that, although all three cytokines could induce greater survival than PBS, IL-21 was the most potent, and the administration of IL21 resulted in a doubling of the 50% survival time, with 20–30% of the mice surviving for more than four months after IL-21 was administered (76). When these long-term survivors were rechallenged with thymoma, all the mice survived for more than 100 days, and this survival was dependent on the presence of a persistent CD8+ T cell memory population that was less susceptible to apoptosis than were CD8+ T cells induced by treatment with IL-2 (76). In another study, mice with large, established melanomas were treated by adoptive transfer of in vitro expanded tumor-specific CD8+ T cells plus peptide vaccine, followed by intraperitoneal administration of either IL2, IL-15, or IL-21 or the combination of IL-15 plus IL-21 (55). Treatment with either IL-15 or IL-21 led to partial tumor regression, but consistent with the synergistic effects of these two cytokines on CD8+ T cell
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proliferation, the combination of IL-15 and IL-21 led to complete regression of a subset of these melanomas and long-term survival of the majority of the treated mice (55). Although treatment with IL-2 alone was less effective therapy than treatment with either IL-15 or IL-21, IL-21 acted synergistically with low-dose IL-2 after the adoptive transfer of naive tumor-specific CD8+ T cells into mice with preestablished melanomas (77). Nearly half of these treated mice survived for more than 150 days. When these long-term survivors were rechallenged with melanoma, all were protected, indicating the induction of long-term immunity as a result of the combination of IL-2 with IL-21. Although IL-21 has shown great potential as a cancer chemotherapeutic agent either alone or in combination with other cytokines, it also has potential for being used with other forms of therapy. The TRAIL/DR5 ligand/receptor pair controls apoptosis and has been the target for monoclonal antibody therapy in some tumors (78). AntiDR5 mAb can inhibit tumor growth in an FcR-dependent fashion mediated by NK cell antibody-dependent cellular cytotoxicity (79). IL-21 can enhance the ability of NK cells to lyse antibody-coated cancer cells (80). After anti-DR5 treatment of tumor-bearing mice, some tumor cells die, and these apoptotic tumor cells prime CTL to respond to tumorspecific antigens. When tumor-bearing mice were treated with anti-DR5, followed by IL21, there was enhanced suppression of metastasis of small, preestablished tumors as well as an enhanced CD8+ memory T cell response to secondary tumor challenge. In contrast, similar treatment did not eradicate large, established tumors (81). Another method for enhancing the innate immune response involves the use of the CD1d-reactive glycolipid α-GalCer. In vivo treatment of mice with α-GalCer potently activates NKT cells that then stimulate the activation and proliferation of other lymphoid populations (82). The combination of α-GalCer treatment and IL-21 administra-
tion resulted in synergistically enhanced prevention of tumor metastasis (83). Transfer of DCs pulsed with α-GalCer, followed by IL21, reduced already established metastatic tumors (83). Overall, these results suggest that the ability of IL-21 to enhance NK, NKT, and CD8+ T cell function can potentially be used in combination with numerous chemotherapeutic protocols to lead to further advances in the eradication of tumors. These preclinical studies have shown that IL-21 has significant antitumor activity against a variety of tumors that is mediated by multiple mechanisms involving both the innate and adaptive immune systems. IL-21 has entered human clinical trials, and phase I results in patients with metastatic melanoma have been reported (84). Consistent with the animal models, IL-21 was well tolerated, and there were few adverse effects, unlike the capillary leak syndrome or neurotoxicity resulting from IL-2 and IFN-α therapy. IL-21 potently upregulated perforin and granzyme B mRNA in patients, at all except the lowest dose tested. One patient in the phase I trial achieved complete remission, and 9 of 29 had stable disease at the end of the study.
Role of IL-21 in Autoimmune Disease In light of the pleiotropic effects of IL-21 on the function of different components of the innate and adaptive immune systems, it was difficult to predict the role that IL-21 would play in the various autoimmune diseases. The initial observation that suggested that IL-21 might play a role in the progression of B cell–mediated autoimmune disease was that, in the BXSB.B6-Yaa+ mouse model of systemic lupus erythematosus (SLE), the development of disease correlated with an increased serum expression of IL-21 (29). This was consistent with the increased serum Igs in these mice and the role for IL-21 in plasma cell differentiation. Another autoimmune mouse strain, the sanroque mutant, has a defect in the function www.annualreviews.org • Interleukin-21
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of a protein, Roquin, which is a negative regulator of the production of a unique population of follicular T helper (TFH) cells (85). These TFH cells produce high levels of IL-21, and sanroque mutant mice have increased levels of these TFH cells as well as increased production of IL-21 accompanied by augmented levels of antinuclear antibodies, glomerulonephritis, and peripheral lymphadenopathy (85). The hypothesis is that the increased levels of IL-21 lead to increased formation of high-affinity autoreactive antibodies by follicular B cells. That these autoimmune phenotypes were accompanied by high levels of IL-21 suggested that blocking the IL-21 signal might ameliorate autoimmune symptoms. Such a study was performed in the lupus-prone MRL-Fas/lpr mouse model through the use of IL-21R-Fc fusion proteins as blocking agents (86). Analogous to the Yaa mice results, lpr CD4+ T cells produced higher levels of IL-21. IL-17 IL-21
Th17
Th2 IFN-γ
Cytotoxicity, proliferation, antitumor activity
NKT
Th1
Cytotoxicity, proliferation, antitumor activity
IL-21 DC
NK
APC function
CD8
B Proliferation/apoptosis, plasma cell differentiation, Ig production
Cytotoxicity, proliferation/survival, antitumor activity
Figure 4 IL-21 has pleiotropic effects on multiple target cells. IL-21 is produced by multiple subpopulations of CD4+ T cells and by natural killer T (NKT) cells (indicated by the red arrows), although the amounts secreted by T helper (Th) 17 and NKT cells are significantly higher than those secreted by Th1 and Th2 cells. IL-21 can then function as an autocrine factor for these populations, with the indicated effects, or can then exert varied positive or negative effects on lineages that do not themselves produce IL-21. 72
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Treatment of these mice with the IL-21Rblocking agent led to a partial reduction of lymphadenopathy, morphological changes in kidney glomeruli, and slightly reduced levels of IgG1 and IgG2a. In a mouse model of collagen-induced arthritis, the IL-21Rblocking agent also slightly reduced inflammation (87), suggesting that interruption of the IL-21 signaling pathway may be beneficial in several autoimmune diseases. One of the genetic loci that are associated with the autoimmune diabetic phenotype in the nonobese diabetic mouse (NOD) is the insulin-dependent diabetes susceptibility 3 locus (Idd3). This locus contains the genes encoding both IL-21 and IL-2 (88). Because these cytokines are known to play roles in the proliferation and function of CD8+ T cells and Treg cells, attempts have been made to identify mutations within this region that associate with diabetes prevalence in the population. One study in the NOD mouse found increased levels of IL-21 mRNA in T cells and suggested that high levels of IL-21 protein may promote homeostatic proliferation of the autoreactive CD8+ T cells that mediate destruction of the pancreatic islet β cells (89). However, a recent study has ruled out the possibility that IL-21 is the genetic determinant of Idd3 that predisposes one to the development of diabetes (90). IL-21 also has disease-promoting effects in experimental allergic encephalitis (EAE) (91), an experimental model of human multiple sclerosis, which is induced by immunization of mice with myelin antigen in the presence of adjuvants. When IL-21 is administered to mice before induction of disease, there is increased severity of disease characterized by increased numbers of inflammatory cells in the central nervous system. However, if IL-21 is administered after disease has been initiated, there is no effect on the disease severity. The ability of IL-21 to exacerbate disease is totally dependent on the presence of NK cells because depletion of these cells before disease induction abrogates the effect of IL-21 (91). Although these effects were
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attributed to the ability of IL-21 to activate NK cell–mediated inflammatory responses, recent studies have pointed to the role that IL-21 plays in the induction and expansion of the Th17 population in this EAE model (40, 41). IL-21 or IL-21R KO mice have a tenfold reduction in the number of IL-17-producing cells and greatly reduced EAE disease progression (40, 41), as do mice deficient in IL17 (92). Interestingly, IL-21 KO mice have increased numbers of Treg cells (41). The enhanced autoimmune symptoms in the mice injected with IL-21 before the initiation of EAE may be the result of increased numbers of Th17 cells and reduced numbers of Treg cells (40).
CONCLUDING REMARKS Since the discovery of IL-21 and IL-21R in 2000, this γc family cytokine system has been demonstrated to have effects on an extremely broad set of target cells, including T cells, B cells, NK cells, NKT cells, and DCs (see Figure 4). The actions of IL-21 on each of these target cells can be either stimulatory
or suppressive, and the ultimate outcome depends on the manner by which the IL-21 signal is integrated with other signals received by a target cell. Although IL-21 was initially thought to be produced solely by antigenstimulated CD4+ T cells, the discovery that IL-21 is produced by NKT cells implies that it is a key player in early innate immune responses as well. The recent discovery that IL21 is produced by and plays a major role in the differentiation of the Th17 lineage has expanded our understanding of the ways that IL21 may contribute to inflammatory responses. Moreover, studies of cancer and autoimmune models suggest that administering IL-21 or blocking the action of IL-21 holds promise in a number of disease settings. IL-21 is thus an exciting cytokine with pleiotropic actions on multiple lineages whose modulation has clear therapeutic benefits in animal models. Understanding how and when it exerts various effects in vivo are some of the major basic science challenges, with the goal that future studies will both advance our scientific knowledge and contribute to moving IL-21 into the therapeutic setting.
FUTURE ISSUES 1. To be able to specifically amplify or neutralize the effects of IL-21 in pathological situations, investigators will require an understanding of the stage-specific and context-specific signaling events involved in the response to IL-21. 2. The in vivo sites where IL-21-producing cells are found are not yet defined. This awaits the construction of reporter mice, with the hope that mRNA expression will correlate with protein expression. The availability of these mice will allow an understanding of the physiological expression of IL-21 as well as mechanisms for controlling levels of IL-21. 3. An in-depth understanding of the molecular basis of IL-21 and IL-21R gene expression will be important to better understand and develop ways of controlling the expression of this cytokine and its receptor. Analogously, a more detailed understanding of IL-21-induced signaling pathways is also important. 4. A major clinical issue will be balancing the immunostimulatory effects of IL-21 on lymphoid lineages with the largely immunosuppressive actions on DCs and the apoptotic effects on inappropriately stimulated B cells.
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5. The effects of IL-21 on CD8+ T cell phenotype and function suggest that IL-21 will have an impact on immunological memory, with potential ramifications for vaccination strategies.
DISCLOSURE STATEMENT The authors have issued patents and/or patent applications related to IL-21.
ACKNOWLEDGMENT Annu. Rev. Immunol. 2008.26:57-79. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
This work was supported by the Intramural Research Program, National Heart, Lung, and Blood Institute, NIH.
LITERATURE CITED 1. Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, et al. 1993. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73:147–57 2. Leonard WJ. 2001. Cytokines and immunodeficiency diseases. Nat. Rev. Immunol. 1:200– 8 3. Leonard WJ, Spolski R. 2005. Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nat. Rev. Immunol. 5:688–98 4. Ozaki K, Kikly K, Michalovich D, Young PR, Leonard WJ. 2000. Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain. Proc. Natl. Acad. Sci. USA 97:11439–44 5. Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, et al. 2000. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408:57–63 6. Habib T, Senadheera S, Weinberg K, Kaushansky K. 2002. The common γ chain (γc) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK3. Biochemistry 41:8725–31 7. Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, et al. 2001. Cutting edge: the common γ-chain is an indispensable subunit of the IL-21 receptor complex. J. Immunol. 167:1–5 8. Jin H, Carrio R, Yu A, Malek TR. 2004. Distinct activation signals determine whether IL21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis. J. Immunol. 173:657–65 9. Bondensgaard K, Breinholt J, Madsen D, Omkvist DH, Kang L, et al. 2007. The existence of multiple conformers of interleukin-21 directs engineering of a superpotent analogue. J. Biol. Chem. 282:23326–36 10. Konforte D, Paige CJ. 2006. Identification of cellular intermediates and molecular pathways induced by IL-21 in human B cells. J. Immunol. 177:8381–92 11. Zeng R, Spolski R, Casas E, Zhu W, Levy DE, Leonard WJ. 2007. The molecular basis of IL-21-mediated proliferation. Blood 109:4135–42 12. Deleted in proof 74
Spolski
·
Leonard
Annu. Rev. Immunol. 2008.26:57-79. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-03
ARI
16 February 2008
11:18
13. Coquet JM, Kyparissoudis K, Pellicci DG, Besra G, Berzins SP, et al. 2007. IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production. J. Immunol. 178:2827–34 14. Kim HP, Korn LL, Gamero AM, Leonard WJ. 2005. Calcium-dependent activation of interleukin-21 gene expression in T cells. J. Biol. Chem. 280:25291–97 15. Mehta DS, Wurster AL, Weinmann AS, Grusby MJ. 2005. NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proc. Natl. Acad. Sci. USA 102:2016–21 16. Harada M, Magara-Koyanagi K, Watarai H, Nagata Y, Ishii Y, et al. 2006. IL-21-induced Bε cell apoptosis mediated by natural killer T cells suppresses IgE responses. J. Exp. Med. 203:2929–37 17. Brandt K, Bulfone-Paus S, Foster DC, Ruckert R. 2003. Interleukin-21 inhibits dendritic cell activation and maturation. Blood 102:4090–98 18. Distler JH, Jungel A, Kowal-Bielecka O, Michel BA, Gay RE, et al. 2005. Expression of interleukin-21 receptor in epidermis from patients with systemic sclerosis. Arthritis Rheum. 52:856–64 19. Caruso R, Fina D, Peluso I, Fantini MC, Tosti C, et al. 2007. IL-21 is highly produced in Helicobacter pylori-infected gastric mucosa and promotes gelatinases synthesis. J. Immunol. 178:5957–65 20. Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, et al. 2002. A critical role for IL-21 in regulating immunoglobulin production. Science 298:1630–34 20a. Ozaki K, Hishiya A, Hatanaka K, Nakajima H, Wang G, et al. 2006. Overexpression of interleukin 21 induces expansion of hematopoietic progenitor cells. Int. J. Hematol. 84:224–30 21. Wu Z, Kim HP, Xue HH, Liu H, Zhao K, Leonard WJ. 2005. Interleukin-21 receptor gene induction in human T cells is mediated by T-cell receptor-induced Sp1 activity. Mol. Cell Biol. 25:9741–52 22. Jin H, Malek TR. 2006. Redundant and unique regulation of activated mouse B lymphocytes by IL-4 and IL-21. J. Leukoc. Biol. 80:1416–23 23. Good KL, Bryant VL, Tangye SG. 2006. Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21. J. Immunol. 177:5236–47 24. Brenne AT, Baa de Ro T, Waage A, Sundan A, Borset M, Hjorth-Hansen H. 2002. Interleukin-21 is a growth and survival factor for human myeloma cells. Blood 99:3756– 62 25. Suto A, Nakajima H, Hirose K, Suzuki K, Kagami S, et al. 2002. Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line Cε transcription of IL-4stimulated B cells. Blood 100:4565–73 26. Wood N, Bourque K, Donaldson DD, Collins M, Vercelli D, et al. 2004. IL-21 effects on human IgE production in response to IL-4 or IL-13. Cell Immunol. 231:133–45 27. Puel A, Ziegler SF, Buckley RH, Leonard WJ. 1998. Defective IL7R expression in T− B+ NK+ severe combined immunodeficiency. Nat. Genet. 20:394–97 28. Mehta DS, Wurster AL, Whitters MJ, Young DA, Collins M, Grusby MJ. 2003. IL-21 induces the apoptosis of resting and activated primary B cells. J. Immunol. 170:4111– 18 29. Ozaki K, Spolski R, Ettinger R, Kim HP, Wang G, et al. 2004. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J. Immunol. 173:5361–71 www.annualreviews.org • Interleukin-21
75
ARI
16 February 2008
11:18
30. Tsuruoka N, Arima M, Arguni E, Saito T, Kitayama D, et al. 2007. Bcl6 is required for the IL-4-mediated rescue of the B cells from apoptosis induced by IL-21. Immunol. Lett. 110:145–51 31. Calame KL, Lin KI, Tunyaplin C. 2003. Regulatory mechanisms that determine the development and function of plasma cells. Annu. Rev. Immunol. 21:205–30 32. Shaffer AL, Lin KI, Kuo TC, Yu X, Hurt EM, et al. 2002. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17:51–62 33. Ettinger R, Sims GP, Fairhurst AM, Robbins R, da Silva YS, et al. 2005. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. J. Immunol. 175:7867–79 34. Pene J, Gauchat JF, Lecart S, Drouet E, Guglielmi P, et al. 2004. Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells. J. Immunol. 172:5154–57 35. Ettinger R, Sims GP, Robbins R, Withers D, Fischer RT, et al. 2007. IL-21 and BAFF/BLyS synergize in stimulating plasma cell differentiation from a unique population of human splenic memory B cells. J. Immunol. 178:2872–82 36. Ng LG, Mackay CR, Mackay F. 2005. The BAFF/APRIL system: life beyond B lymphocytes. Mol. Immunol. 42:763–72 37. Weaver CT, Hatton RD, Mangan PR, Harrington LE. 2007. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25:821–52 38. Wurster AL, Rodgers VL, Satoskar AR, Whitters MJ, Young DA, et al. 2002. Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon γ-producing Th1 cells. J. Exp. Med. 196:969–77 39. Chtanova T, Tangye SG, Newton R, Frank N, Hodge MR, et al. 2004. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J. Immunol. 173:68–78 40. Korn T, Bettelli E, Gao W, Awasthi A, J¨ager A, et al. 2007. IL-21 initiates an alternative pathway to induce proinflammatory TH 17 cells. Nature 448:484–87 41. Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, et al. 2007. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448:480– 83 42. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, et al. 2007. IL-6 programs TH -17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8:967–74 43. Suto A, Wurster AL, Reiner SL, Grusby MJ. 2006. IL-21 inhibits IFN-γ production in developing Th1 cells through the repression of Eomesodermin expression. J. Immunol. 177:3721–27 44. Strengell M, Sareneva T, Foster D, Julkunen I, Matikainen S. 2002. IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response. J. Immunol. 169:3600–5 45. Pesce J, Kaviratne M, Ramalingam TR, Thompson RW, Urban JF Jr, et al. 2006. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J. Clin. Invest. 116:2044–55 46. Frohlich A, Marsland BJ, Sonderegger I, Kurrer M, Hodge MR, et al. 2007. IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo. Blood 109:2023–31
Annu. Rev. Immunol. 2008.26:57-79. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-03
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·
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ANRV338-IY26-03
ARI
16 February 2008
11:18
47. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, et al. 2005. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6:1123–32 48. Park H, Li Z, Yang XO, Chang SH, Nurieva R, et al. 2005. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6:1133– 41 49. Li MO, Sanjabi S, Flavell RA. 2006. Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25:455–71 50. Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, et al. 2006. Transforming growth factor-β induces development of the TH 17 lineage. Nature 441:231–34 51. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, et al. 2006. Reciprocal developmental pathways for the generation of pathogenic effector TH 17 and regulatory T cells. Nature 441:235–38 52. Kastelein RA, Hunter CA, Cua DJ. 2007. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 25:221– 42 53. Bettelli E, Oukka M, Kuchroo VK. 2007. TH -17 cells in the circle of immunity and autoimmunity. Nat. Immunol. 8:345–50 54. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, et al. 2006. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–33 55. Zeng R, Spolski R, Finkelstein SE, Oh S, Kovanen PE, et al. 2005. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J. Exp. Med. 201:139–48 56. Schluns KS, Kieper WC, Jameson SC, Lefrancois L. 2000. Interleukin-7 mediates the homeostasis of na¨ıve and memory CD8 T cells in vivo. Nat. Immunol. 1:426–32 57. Zhang X, Sun S, Hwang I, Tough DF, Sprent J. 1998. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity 8:591–99 58. Alves NL, Arosa FA, van Lier RA. 2005. IL-21 sustains CD28 expression on IL-15activated human naive CD8+ T cells. J. Immunol. 175:755–62 59. Li Y, Bleakley M, Yee C. 2005. IL-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8 T cell response. J. Immunol. 175:2261–69 60. White L, Krishnan S, Strbo N, Liu H, Kolber MA, et al. 2007. Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation, and proliferation in CD8 T cells of patients with human immunodeficiency virus-1 (HIV). Blood 109:3873–80 61. Cao X, Shores EW, Hu-Li J, Anver MR, Kelsall BL, et al. 1995. Defective lymphoid development in mice lacking expression of the common cytokine receptor γ chain. Immunity 2:223–38 62. DiSanto JP, Muller W, Guy-Grand D, Fischer A, Rajewsky K. 1995. Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor γ chain. Proc. Natl. Acad. Sci. USA 92:377–81 63. Kasaian MT, Whitters MJ, Carter LL, Lowe LD, Jussif JM, et al. 2002. IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity 16:559–69 64. Vosshenrich CA, Ranson T, Samson SI, Corcuff E, Colucci F, et al. 2005. Roles for common cytokine receptor γ-chain-dependent cytokines in the generation, differentiation, and maturation of NK cell precursors and peripheral NK cells in vivo. J. Immunol. 174:1213–21 www.annualreviews.org • Interleukin-21
77
ARI
16 February 2008
11:18
65. Sivori S, Cantoni C, Parolini S, Marcenaro E, Conte R, et al. 2003. IL-21 induces both rapid maturation of human CD34+ cell precursors towards NK cells and acquisition of surface killer Ig-like receptors. Eur. J. Immunol. 33:3439–47 66. Toomey JA, Gays F, Foster D, Brooks CG. 2003. Cytokine requirements for the growth and development of mouse NK cells in vitro. J. Leukoc. Biol. 74:233–42 67. Brady J, Hayakawa Y, Smyth MJ, Nutt SL. 2004. IL-21 induces the functional maturation of murine NK cells. J. Immunol. 172:2048–58 68. Gays F, Martin K, Kenefeck R, Aust JG, Brooks CG. 2005. Multiple cytokines regulate the NK gene complex-encoded receptor repertoire of mature NK cells and T cells. J. Immunol. 175:2938–47 69. Burgess SJ, Marusina AI, Pathmanathan I, Borrego F, Coligan JE. 2006. IL-21 downregulates NKG2D/DAP10 expression on human NK and CD8+ T cells. J. Immunol. 176:1490–97 70. Godfrey DI, Kronenberg M. 2004. Going both ways: immune regulation via CD1ddependent NKT cells. J. Clin. Invest. 114:1379–88 71. Wang G, Tschoi M, Spolski R, Lou Y, Ozaki K, et al. 2003. In vivo antitumor activity of interleukin 21 mediated by natural killer cells. Cancer Res. 63:9016–22 72. Pelletier M, Bouchard A, Girard D. 2004. In vivo and in vitro roles of IL-21 in inflammation. J. Immunol. 173:7521–30 73. Ugai S, Shimozato O, Yu L, Wang YQ, Kawamura K, et al. 2003. Transduction of the IL-21 and IL-23 genes in human pancreatic carcinoma cells produces natural killer celldependent and -independent antitumor effects. Cancer Gene Ther. 10:771–78 74. Di Carlo E, Comes A, Orengo AM, Rosso O, Meazza R, et al. 2004. IL-21 induces tumor rejection by specific CTL and IFN-γ-dependent CXC chemokines in syngeneic mice. J. Immunol. 172:1540–47 75. Takaki R, Hayakawa Y, Nelson A, Sivakumar PV, Hughes S, et al. 2005. IL-21 enhances tumor rejection through a NKG2D-dependent mechanism. J. Immunol. 175:2167–73 76. Moroz A, Eppolito C, Li Q, Tao J, Clegg CH, Shrikant PA. 2004. IL-21 enhances and sustains CD8+ T cell responses to achieve durable tumor immunity: comparative evaluation of IL-2, IL-15, and IL-21. J. Immunol. 173:900–9 77. He H, Wisner P, Yang G, Hu HM, Haley D, et al. 2006. Combined IL-21 and low-dose IL-2 therapy induces antitumor immunity and long-term curative effects in a murine melanoma tumor model. J. Transl. Med. 4:24 78. Takeda K, Stagg J, Yagita H, Okumura K, Smyth MJ. 2007. Targeting death-inducing receptors in cancer therapy. Oncogene 26:3745–57 79. Takeda K, Yamaguchi N, Akiba H, Kojima Y, Hayakawa Y, et al. 2004. Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy. J. Exp. Med. 199:437– 48 80. Roda JM, Parihar R, Lehman A, Mani A, Tridandapani S, Carson WE 3rd. 2006. Interleukin-21 enhances NK cell activation in response to antibody-coated targets. J. Immunol. 177:120–29 81. Smyth MJ, Hayakawa Y, Cretney E, Zerafa N, Sivakumar P, et al. 2006. IL-21 enhances tumor-specific CTL induction by anti-DR5 antibody therapy. J. Immunol. 176:6347–55 82. Smyth MJ, Crowe NY, Pellicci DG, Kyparissoudis K, Kelly JM, et al. 2002. Sequential production of interferon-γ by NK1.1+ T cells and natural killer cells is essential for the antimetastatic effect of α-galactosylceramide. Blood 99:1259–66 83. Smyth MJ, Wallace ME, Nutt SL, Yagita H, Godfrey DI, Hayakawa Y. 2005. Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer. J. Exp. Med. 201:1973–85
Annu. Rev. Immunol. 2008.26:57-79. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-03
78
Spolski
·
Leonard
Annu. Rev. Immunol. 2008.26:57-79. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-03
ARI
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11:18
84. Davis ID, Skrumsager BK, Cebon J, Nicholaou T, Barlow JW, et al. 2007. An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma. Clin. Cancer Res. 13:3630–36 85. Vinuesa CG, Cook MC, Angelucci C, Athanasopoulos V, Rui L, et al. 2005. A RINGtype ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435:452–58 86. Herber D, Brown TP, Liang S, Young DA, Collins M, Dunussi-Joannopoulos K. 2007. IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL21R.Fc reduces disease progression. J. Immunol. 178:3822–30 87. Young DA, Hegen M, Ma HL, Whitters MJ, Albert LM, et al. 2007. Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum. 56:1152–63 88. Denny P, Lord CJ, Hill NJ, Goy JV, Levy ER, et al. 1997. Mapping of the IDDM locus Idd3 to a 0. 35-cM interval containing the interleukin-2 gene. Diabetes 46:695–700 89. King C, Ilic A, Koelsch K, Sarvetnick N. 2004. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell 117:265–77 90. Yamanouchi J, Rainbow D, Serra P, Howlett S, Hunter K, et al. 2007. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat. Genet. 39:329–37 91. Vollmer TL, Liu R, Price M, Rhodes S, La Cava A, Shi FD. 2005. Differential effects of IL-21 during initiation and progression of autoimmunity against neuroantigen. J. Immunol. 174:2696–701 92. Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, et al. 2006. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177:566–73
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Annual Review of Immunology
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:57-79. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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Contents
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Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal,1,∗ D. Malo,2,∗ J.-F. Marquis,3 and P. Gros3,∗ 1
Department of Microbiology and Immunology, 2 Research Institute of the McGill University Health Center and Department of Human Genetics, and 3 Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6; email:
[email protected] Annu. Rev. Immunol. 2008. 26:81–132
Key Words
First published online as a Review in Advance on October 22, 2007
forward genetics, positional cloning, macrophage, NK cell, innate immunity
The Annual Review of Immunology is online at immunol.annualreviews.org This article’s doi: 10.1146/annurev.immunol.26.021607.090304 c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0081$20.00 ∗
Authors contributed equally to this review.
Abstract Forward genetics is an experimental approach in which gene mapping and positional cloning are used to elucidate the molecular mechanisms underlying phenotypic differences between two individuals for a given trait. This strategy has been highly successful for the study of inbred mouse strains that show differences in innate susceptibility to bacterial, parasitic, fungal, and viral infections. Over the past 20 years, these studies have led to the identification of a number of cell populations and critical biochemical pathways and proteins that are essential for the early detection of and response to invading pathogens. Strikingly, the macrophage is the point of convergence for many of these genetic studies. This has led to the identification of diverse pathways involved in extracellular and intracellular pathogen recognition, modification of the properties and content of phagosomes, transcriptional response, and signal transduction for activation of adaptive immune mechanisms. In models of viral infections, elegant genetic studies highlighted the pivotal role of natural killer cells in the detection and destruction of infected cells.
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INTRODUCTION
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Infectious diseases continue to be a major determinant of global health, exacerbated by recent factors, such as global population growth, an increase in the number and size of vulnerable populations, limited access to medical care in areas of endemic disease, and the human immunodeficiency virus (HIV) pandemic. Increased worldwide travel has further facilitated the export of several diseases to nonendemic areas. The impact of infectious diseases has been most severe in the developing world owing to the degradation of socioeconomic conditions, movement to new habitats, and, importantly, emergence of drug resistance and the lack of efficacious vaccines leading to the remarkable resurgence of old foes, such as malaria and tuberculosis (TB) (1) (http://www.who.int). In addition to environmental factors, the health status of the host, and virulence determinants of the pathogen, clinical epidemiology and population studies as well as studies in twins have shown that host genetic factors play an important role, particularly in the onset but also in the progression of infection, the type of disease developed, and the ultimate outcome of infection with many pathogens (2, 3). In fact, infectious agents may have exerted the single most powerful evolutionary pressure on the human genome. Spectacular examples of the effect of infectious agents on the human genome include the protective effects of CCR5 mutations against HIV/AIDS (4) and the malaria-protective effect of heterozygosity at otherwise diseasecausing hemoglobinopathies, such as sickle cell anemia and thalassemias (5). Researchers have identified additional single-gene effects in humans that cause either selective or generalized immunodeficiencies, phenotypically expressed as an innate susceptibility to certain types of bacterial and viral infections (6). The study of these infrequent single-gene effects in humans is useful for better understanding the molecular pathogenesis of infection, but it also reveals normal host defense mechanisms that can potentially be used as novel targets for 82
Vidal et al.
drug discovery and therapeutic intervention in these diseases (7). However, linkage and association studies show that the genetic component of susceptibility to infection is usually complex and multigenic, which reflects the plurality of cell types and physiological and biochemical pathways involved in both the initial sensing of and the dynamic response to a pathogen (2). This complex host:microbe interaction interface gives rise to apparent genetic heterogeneity, incomplete penetrance, and variable expressivity that together reduce the power of standard genetic association or linkage studies. The laboratory mouse has proven to be extremely useful in the dissection of the genetic architecture of host defenses against many infectious diseases (8–11). Indeed, there exist excellent mouse models of experimental infection with many human pathogens, in which several aspects of the human disease are accurately reproduced: These include pathogenesis (tissues and cells involved, types and progression of lesions developed) and physiological responses (inflammation, immunity, etc.). These physiological responses can be studied in an environment in which pathogenassociated variables such as strain, virulence, dose, and route of infection can be carefully controlled. In addition, excellent immunological and biochemical reagents in the form of assays, markers, and antibodies are available to characterize innate and adaptive immune responses in these infection models. From a genetic standpoint, a number of inbred, recombinant, and naturally occurring or experimentally induced mutants [such as N-ethyl-N-nitrosourea (ENU)-induced mutants] exist that can be used to search for polymorphic alleles and major gene effects that affect onset, progression, host response, and ultimate outcome of infection. Additional mapping stocks such as recombinant inbred, recombinant congenic, and large multistrain intercross can sometimes be used to deconvolute multigenic effects into monogenic traits. With the sequencing and annotation of the mouse genome, good mapping tools are now
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available in the form of haplotype maps and informative markers, such as single nucleotide polymorphisms (SNPs) and simple sequence length polymorphisms (SSLPs). In addition, mRNA expression data are available for most genes, which facilitates the prioritization of candidate genes for positional cloning. Finally, germ line modification in transgenic mice can be used to generate gain- or lossof-function alleles for validation of the role of individual genes. Generally, two major genetic approaches in the mouse have been used to identify host proteins and biochemical pathways that affect host response to infection with viral, parasitic, fungal, and bacterial pathogens. The first is the reverse genetics approach in which the role of an individual gene is tested by directly infecting mice carrying a loss-of-function mutation (usually a deletion) at the corresponding locus. Usually, a possible role for a gene of interest is based on prior direct or indirect evidence that links the gene to pathogenesis or response to infection; researchers then examine the mutant for evidence supporting such a role. The second approach, which is the focus of this review, is the study of differential susceptibility of inbred mouse strains to infection with bacterial, parasitic, and viral pathogens. The major advantage of this socalled forward genetics approach is that the effect of the gene(s) on susceptibility is already validated in vivo. An obvious disadvantage of this approach is that the genetic effect may be complex, with individual monogenic contributions possibly difficult to delineate. Nevertheless, this approach has been extremely successful in the study of infectious diseases and has revealed a treasure trove of genes, proteins, and signaling pathways that play critical roles in the immune response to a large number of infectious agents. We describe some of the most informative examples of such discoveries (summarized in Table 1 and Figure 1), with an emphasis on the implications of the discovered genes and proteins for our evolving understanding of innate or acquired immune defenses.
THE Ity-Lsh-Bcg LOCUS: REGULATION OF MACROPHAGE INTRACELLULAR IRON BY Nramp1/Slc11a1 Specific groups of pathogens penetrate host cells and proliferate, sheltered in the intracellular milieu. Certain microbes enter different cell types via an active microbe-driven invasion process, whereas others can survive and replicate after engulfment by professional phagocytes (macrophages, monocytes, and neutrophils). The intracellular environment provides a replicative niche rich in nutrients and sheltered from attacks by the host immune system. In the case of engulfment by professional phagocytes, intracellular pathogens have evolved mechanisms to escape or resist the microbicidal arsenal of these cells: These mechanisms include escape from the phagosome (Listeria), modulation of phagosome maturation (Mycobacterium, Legionella, Salmonella), and survival in fully mature phagolysosomes (Leishmania) (12–15). Understanding the genetic basis of differential susceptibility to infection with intracellular pathogens in inbred mouse strains has proven extremely informative for understanding the interface of host:pathogen interaction and identifying normal defense mechanisms of phagocytes that may fail in permissive hosts. The Ity-Lsh-Bcg locus constitutes one of the oldest and best studied examples of a single mutation in mouse with pleiotropic consequences on host defenses against unrelated intracellular pathogens (for historical reviews, please see References 16 and 17). Thirty years ago, several groups independently noted interstrain differences in susceptibility to infection with Salmonella enterica serovar Typhimurium (S. Typhimurium), Leishmania donovani, and Mycobacterium bovis (BCG). Segregation analyses showed that differences in susceptibility were controlled by a single gene, which was given the appellation Ity, Lsh, and Bcg. Concordance in differential www.annualreviews.org • Immunity to Infection in the Mouse
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Table 1
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Host resistance loci revealed by forward genetics approachesa
Pathogen(s)
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Locus (Gene)
Main cell type(s)
Protein function or biological process/mechanism of action
Reference(s)
Salmonella Typhimurium Leishmania donovani Mycobacterium bovis (BCG)
Ity-Lsh-Bcg (Nramp1)
M
Iron transporter/regulation of intraphagosomal iron
16, 17, 20
Salmonella Typhimurium
Lps (Tlr4)
M
Surface receptor for bacterial LPS/cellular recognition of LPS
63, 64, 70, 75
Salmonella Typhimurium
xid (btk)
B
Tyrosine kinase/tegulation of B cell development
60, 65, 66
Legionella pneumophila
Lgn1 (Birc1e)
M
NLR protein/intracellular antigen recognition
113, 114
Bacillus anthracis
Ltsx1 (Nalp1b)
M
NLR protein/sensing of anthrax toxin
125, 126, 128
Mycobacterium bovis (BCG) Salmonella Typhimurium Plasmodium chabaudi AS Mycobacterium tuberculosis
Myls (Icsbp/IRF8)
M
Transcriptional regulator/regulation of the IL-12 and IFN-γ pathway
130, 134, 135
Mycobacterium tuberculosis Listeria monocytogenes
sst1 (Ipr1)
M
Transcriptional regulator/transcriptional activation in response to intracellular pathogens
139, 144–146
Candida albicans Listeria monocytogenes
C5 (C5a)
unknown
Component of complement cascade/proinflammatory activity
156–158, 161, 162
Plasmodium chabaudi AS
Char4 (Pklr)
E
Pyruvate kinase/glycolysis in erythrocytes (role for ATP production)
167–170
Plasmodium chabaudi AS
Char9 (Vnn1/Vnn3)
E
Pantetheinases/production of the antioxidant cysteamine
167, 171
Toxoplasma gondii
Tyk2 (Tyk2)
M
Jak kinase/cellular signaling by cytokine receptors
180, 181
Orientia tsutsugamushi
Ric (Spp1)
M, T, NK
Phosphoprotein/recruitment of leukocytes and T cell polarization
187, 189, 190, 192, 193
Chlamydia trachomatis
Ctrq3 (Irgb10)
M and others
p47GTPase/mediator of the inhibitory effect of IFN-γ
197, 199
Orthomyxovirus (influenza)
Mx (Mx1)
M
GTPase/inhibition of viral genome transcription
206–209
Coronavirus (MHV)
Hv2 (Ceacam1)
EP
Transmembrane glycoprotein (with Ig domains)/adhesion molecule, signal regulatory protein
236–239
West Nile Virus (WNV)
Flv (Oas1b)
M
Oligoadenylate synthetase/part of the OAS/RNase L system of RNA decay pathway stimulated by type I IFN
257–259
Cytomegalovirus (MCMV)
Cmv1 (Ly49h)
NK
MHC class I receptor/recognition of infected cells by NK cell receptors
272, 274–276, 277–280
Staphylococcus aureus
Obl (Cd36 )
M
Scavenger receptor type B/regulation of the Tlr2/6-dependent signaling pathway
299
Vesicular stomatitis virus (VSV) Vaccinia virus
Lps2 (Trif )
M
Toll-receptor–associated activator of IFN/regulation of the Tlr3- and Tlr4-dependent signaling pathway
300, 305–308
Cytomegalovirus (MCMV)
Cpg1 (Tlr9)
M
Transmembrane receptor/recognition of pathogen-derived molecules
301, 309
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(Continued )
Pathogen(s)
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Locus (Gene)
Main cell type(s)
Protein function or biological process/mechanism of action
Reference(s)
Cytomegalovirus (MCMV) Staphylococcus aureus Listeria monocytogenes
3d (Unc93b)
M
Molecular mechanism unknown/regulation of the Tlr3, Tlr7 and Tlr9-dependent signaling pathway
295, 302, 310
Cytomegalovirus (MCMV) Listeria monocytogenes Vesicular stomatitis virus (VSV)
Domino (Stat1)
M
Transcription factor/activated by IFN
313, 315
Cytomegalovirus (MCMV)
Jinx (Unc13d)
NK, CTL
Membrane trafficking/priming (fusion) of cytoplasmic vesicles
314, 316
a M, macrophages; E, erythrocytes; NK, natural killer cells; CTL, cytotoxic T lymphocytes; T, T cells; EP, epithelial cells; LPS, lipopolysaccharide; NLR, nucleotide-binding oligomerization domain (NOD)-like receptor; IL-12, interleukin-12; IFN-γ, interferon-γ; Jak, Janus kinase; p47GTPase, p47 family of IFN-γ-inducible GTPases; OAS, oligoadenylate synthetase; MHC, major histocompatibility complex; TLR, Toll-like receptor.
susceptibility to the three pathogens among inbred strains and in recombinant inbred strains (RIS) (bred from resistant and susceptible parents), together with cosegregation in progeny-testing experiments and colocalization of the three loci to the same proximal chromosome 1 domain, strongly suggested that Ity, Lsh, and Bcg were in fact the same locus (18, 19). In the three infection models, phenotypic expression of the locus is characterized by differential growth of the three pathogens in the spleen and liver, a phenomenon that can be reproduced in explanted macrophage populations ex vivo, which identified macrophages as responsible for the gene effect (17). The gene responsible for the ItyLsh-Bcg effect was one of the earliest genes to be isolated by positional cloning, which was in those days a laborious approach based on high-resolution linkage mapping, physical mapping by restriction enzyme analysis using pulsed-field gel electrophoresis, and the creation of a transcript map of the minimal physical interval via delineation of CpG islands and isolation of splicing-competent exons (20). Based on its tissue specific expression in liver, spleen, and macrophages, a positional candidate, Nramp1 [natural resistance–associated macrophage protein 1, now annotated as so-
lute carrier family 11 member 1 (Slc11a1)] was selected from five candidates for further study. Nramp1 encodes a membrane phosphoglycoprotein with 12 putative transmembrane domains. Studies in inbred strains of mice showed that susceptibility to infections was associated with a single Gly169Asp (G169D) mutation in predicted TM4 of the protein (20). The G169D mutation impairs protein folding and processing, which results in the absence of mature Nramp1 polypeptide in the membrane compartment of susceptible cells (21). Researchers validated Nramp1 as the gene underlying Ity-Lsh-Bcg by creating a null mutation (knockout) and demonstrating that this otherwise resistant 129Sv mouse stock becomes susceptible to S. Typhimurium, L. donovani, and M. bovis (BCG) infections when Nramp1 is deleted (22). Also, transfer of the Nramp1G169 allele onto the C57BL/6J (Nramp1D169 ) background restores resistance to infection (23). Finally, the human gene, NRAMP1, was cloned and studied for a possible role in resistance and susceptibility to mycobacterial infections in humans (24). Briefly, NRAMP1 maps on human chromosome 2q35, and researchers used numerous polymorphic variants within or outside the gene, including functional promotor www.annualreviews.org • Immunity to Infection in the Mouse
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during a TB outbreak in a Canadian Aboriginal family (26) and in pediatric TB cases from South Africa (27). Additional studies have shown that NRAMP1 is involved in susceptibility to two other common mycobacterial diseases, leprosy (28, 29) and Buruli ulcer (30).
polymorphisms, in case-control and familybased studies. NRAMP1 variants were consistently found to be associated with susceptibility to pulmonary TB in African and Asian populations but not in populations of European descent (25). In addition, direct genetic linkage data were obtained for NRAMP1
Chr. 1
A3
A5
B
C1
C2 C3
Stat1
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Chr. 2
A2 A3
A1
C5
E1 E2
D
Nramp1 B
C1
C3
E2
F
H1 H2 H3 H4
H6
H1 H2
H4
Ipr1 E1
D
E2 E3
E5 F2 F3
H3
C5a Chr. 3
A1 A2
A3
B
C
E1
D
E3
F1
F2
G1 G2 G3 H1
F3
H2
H3
H4
Pklr Chr. 4
A1 A2
A3
B2 B3
A5
C1 C2
C3
C5 C6
C7
D1
E1 E2
D3
Tlr4 Chr. 5
A1 A2
B1 B2 B3 C1
A3
D
Chr. 6
A2
A1
A3
B1
E2 E3 E4 E5
E1
Cd36
F
B3
B2
C1
Oas1b
D1 D2 D3 E1 E2 E3 F1 F2 F3
C3
Ly49p Chr. 7
A1
A2
C
A3 B1 B2 B3 B4 B5
D2
G2 G3
G1
Spp1
E1
E3 F1
F2
G3
G1
Ly49h F3
F4
F5
Ceacam1 Chr. 8
A2
A3
Chr. 9
A1 A2 A3
A4
B2 B3.1 B3.2 B3.3 C1 C2
C3 C4 C5
D1
D3
E1
E2
Icsbp/IRF8 B
C
D
E4
E1
F2 F3 F4
F1
Tyk2 Chr. 10
A1
A2
A3 A4
Tlr9
B1
B3
B2
B4
C1
C2
C3
D1
D2
D3
Vnn1/Vnn3 Chr. 11
A1 A2
A4
A5
B1.1 B1.2 B1.3 B2
Irgb10 Chr. 13
A2 A3.1
A1
A5
A3.3 A4
B1
B3
B4
C
B5
Nalp1b B2
B3
D
E1
E2
Unc13d
C1
C3
D1
Birc1e Chr. 16
A2 A3
B1
B2
B3
B4
B5
C1.1 C1.2 C1.3 C2 C3.1
C3.2
C3.3
C4
Mx1 Chr. 17
A2
A1
B1
B2
B3
C
D
E1.1 E1.2 E1.3 E2
A
B
E4
E5
Trif
H2-D Chr. 19
E3
C1
C2
C3
D1
D2
D3
Unc93b Chr. X
A2
A4
A5
A6
B
C1 C2 C3
D
E1 E2 E3 F1
F2 F3 F4 F5
Btk 86
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The Slc11a1 protein is present in the membrane of (a) Lamp-1+ lysosomes of macrophages and monocytes and (b) gelatinase+ tertiary granules of neutrophils (31, 32). Upon phagocytosis of inert particles or live microbes, Slc11a1 is rapidly recruited to the membrane of the maturing phagosome (31, 32). Clues about the function of Slc11a1 at the phagosomal membrane came from the discovery that the close mammalian relative Slc11a2 (Nramp2, DCT1, DMT1; ∼75% similarity to Slc11a1) functions as a pH-dependent iron (Fe2+ ) transport system (33, 34). Slc11a2 is required for the acquisition of nutritional iron at the duodenum brush border and acts as a transporter of transferrin-associated iron across the membrane of recycling endosomes in many cell types. Mutations in mouse and human (35) Slc11a2/Nramp2 cause a severe form of microcytic anemia (35, 36). Subsequently, microfluorescence imaging studies in live macrophages using inert particles labeled with metal-sensitive fluorophores, together with studies in transfected CHO cells, showed that Slc11a1 (Nramp1) similarly functions as a metal efflux pump for Mn2+ and Fe2+ ions at the phagosomal membrane (37, 38). Transport occurs down a pro-
ton gradient generated by the concanamycinsensitive vacuolar H+ /ATPase. Therefore, Nramp1 and Nramp2 transport metal ions by the same mechanism but individually perform this activity in a cell type– and subcellular compartment–specific fashion. Consequently, the antimicrobial effect of Nramp1/Slc11a1 against different infectious agents can be explained by its capacity to restrict metal ions from the phagosomal space. The mechanism by which Nramp1mediated iron restriction negatively affects intracellular microbial survival/growth was investigated using phagosomes containing Mycobacterium, Salmonella, and Leishmania. Using M. bovis (BCG) and Mycobacterium avium as test pathogens, investigators showed that Nramp1 recruitment to the phagosomal membrane abrogates the ability of mycobacteria to block phagosome maturation, which causes increased acidification, enhanced fusion to lysosomes, augmented mycobacterial cell damage, and reduced intracellular replication (39, 40). In the case of Salmonellacontaining vacuoles (SCV), recruitment of Nramp1 similarly antagonizes the ability of Salmonella to modulate phagosome maturation, which causes enhanced association
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Figure 1 Chromosomal location of mouse genes affecting susceptibility to infections and identified by forward genetics. The chromosomal position of host resistance-associated genes affecting susceptibility to infection with bacterial, viral, and parasitic pathogens is identified with respect to relevant mouse chromosomes. Map positions have been determined using the Mouse Ensembl annotation (www.ensembl.org/Mus musculus/index.html). The position of cytogenetically identifiable chromosomal bands is indicated. The chromosomes are not drawn to scale, and the exact position for each gene may differ slightly depending on the source of information. See text for details. [Abbreviations: Stat1, signal transducer and activator of transcription 1; Nramp1, natural-resistance-associated macrophage protein 1; Ipr1, intracellular pathogen resistance 1; C5a, complement component 5a; Pklr, pyruvate kinase liver and red blood cell; TLR, Toll-like receptor; Cd36, Cd36 antigen; Spp1, secreted phosphoprotein 1; Oas1b, 2 -5 oligoadenylate synthetase 1B; Ly49p, killer cell lectin-like receptor, subfamily A, member 16; Ly49h, killer cell lectin-like receptor, subfamily A, member 8; Ceacam1, CEA-related cell adhesion molecule 1; Icsbp, interferon (IFN) consensus sequence-binding protein; IRF8, IFN regulatory factor 8; Tyk2, tyrosine kinase 2; Vnn1/Vnn3, vanin 1 and 3; Irgb10, iron-regulated virulence protein 10; Nalp1b, NACHT, LRR, and Pyrin domain–containing 1b; Unc13d, unc-13 homolog D; Birc1e, baculoviral IAP repeat-containing 1e; Mx1, myxovirus resistance 1; H2-D, histocompatibility 2, D region; Trif, Toll receptor–associated activator of IFN; Unc93b, unc-93 homolog B; Btk, Bruton agammaglobulinemia tyrosine kinase.] www.annualreviews.org • Immunity to Infection in the Mouse
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of early endosomal proteins (e.g., EEA1, a fluid phase marker) and the late endosomal protein, the mannose-6-phosphate receptor (M6PR) (41). Furthermore, the addition of membrane-permeant iron chelators to Nramp1-negative macrophages can recapitulate the Nramp1 effect and stimulate recruitment of M6PR and EEA1 to SCVs (42). Salmonella responds to Nramp1-mediated iron depletion by activating transcription of several virulence genes that map within the Salmonella pathogenicity island 2 (SPI2) region, including ssrA and sseJ (43). An adequate supply of iron is essential for intracellular survival of Salmonella, and iron stimulates intracellular growth of this bacterium (44). The Salmonella genome encodes several high- and low-affinity transporters for ferric and ferrous iron ( fepBCDG, sitA-D, FeoABC, CorAD, and the Nramp homolog MntH ), and several of these transporters are essential for Salmonella virulence in vivo and for replication in Nramp1-negative macrophages (45, 46). Conversely, the presence of intracellular Salmonella is sensed by macrophages, which respond by activating an iron-restriction/extrusion pathway with enhanced expression of ferroportin (iron exporter), lipocalin 2, and heme oxygenase mRNAs (44). On a related note, Huynh and coworkers (47) recently identified the LIT1 protein as the major Fe2+ import system of Leishmania; LIT1 is uniquely expressed at the plasma membrane of the intracellular form of the parasite (amastigote), and it is essential for virulence in vivo and in macrophages ex vivo. LIT1 expression is induced in response to low iron levels, and LIT1 is differentially expressed in Nramp1positive (higher expression) and Nramp1negative (lower expression) macrophages (47). These studies highlight the critical role that iron plays at the interface of host:pathogen interaction, where metal transporters such as Nramp1 and ferroportin act as major defenses to restrict intracellular access to this essential nutrient.
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THE Lps LOCUS: CELLULAR RECOGNITION OF BACTERIAL LIPOPOLYSACCHARIDE BY TOLL-LIKE RECEPTOR 4 AND INNATE IMMUNITY TO SALMONELLA INFECTION Salmonella is a ubiquitous, facultative intracellular, Gram-negative bacterium that causes two major diseases in developed and developing countries: typhoid fever and salmonellosis. Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever and affects 17 million people annually, with 200,000 associated deaths. Salmonellosis is one of the most common and widely distributed food-borne diseases (http://www.cdc.gov). The frequency of multidrug-resistant nontyphoidal Salmonella (NTS) is increasing in developing countries; the disease presents as bacteremia (invasive NTS) often without diarrhea (48). Several specific human populations are at increased risk of Salmonella infection, including patients with sickle cell anemia (49), chronic granulomatous disease (50), and Plasmodium falciparum infection (51). In addition, humans who harbor mutations in genes that regulate the activation of phagocytes (IFNGR1, IFNGR2, IL12B, IL12RB1, and STAT1) are highly susceptible to recurrent Salmonella infections (reviewed in 52). Increased incidence of Salmonella infections also occurs in individuals with immunodeficiencies such as common variable immunodeficieny (CVID), X-linked agammaglobulinemia (XLA), major histocompatibility complex (MHC) class II deficiency, HIV infection, and ectodermal dysplasia with immunodeficiency (reviewed in 53). Several mouse models of Salmonella infection have been used for the study of host:pathogen interactions (54–57). The most widely used model is intravenous infection with S. Typhimurium, which causes systemic disease resembling typhoid fever. Response to this infection involves the activation of both the innate and adaptive immune responses of the host; genetic analysis in the
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Salmonella model has successfully identified key host genes and proteins participating in these two pathways. Sublethal systemic infection with S. Typhimurium is characterized by four distinct phases of infection: rapid clearance of the bacteria from the bloodstream (phase 1), which requires complement and the production of reactive oxygen species (ROS); sheltering of some bacteria in macrophages and polymorphonuclear leukocytes from the spleen and the liver where the bacteria initiate a replicative phase (phase 2); stimulation of the innate immune response pathways by Salmonella products, such as lipopolysaccharide (LPS), and priming of the adaptive innate immune response [by tumor necrosis factor α (TNF-α), IFN-γ, interleukin (IL)-12, IL-18, and Toll-like receptor 4 (Tlr4)], resulting in dampening of the infection (phase 3); and activation of antigen-specific immunity and clearance of the infection (phase 4) (53). Inbred strains of mice show differential susceptibility to infection with Salmonella (reviewed in 58). Strains such as C57BL/6J, C57BL/10J, BALB/cJ, FVB, and DBA/1J are extremely susceptible and succumb within 5– 6 days post infection owing to their inability to suppress bacterial growth during the early innate immune response phase (phase 2) (22; D. Malo, unpublished data). C3H/HeJ mice show a similar degree of susceptibility, although they are able to survive the second phase of infection. However, C3H/HeJ mice present with high bacterial load in spleen and liver later during infection because of an inadequate adaptive innate immune response. Strains A/J, DBA/2J, and C3H/HeN present an intermediate susceptibility phenotype and show increased survival time (most noticeable with lower infectious inoculum) but cannot survive beyond the transition of innate to acquired immune defenses (phase 3). CBA/J mice show increased survival times and are able to survive the first three phases of infection but ultimately succumb to infection because of their inability to mount an appropriate antigen-specific immunity. Finally, substrains of 129 inbred mice are ex-
tremely resistant, although they are unable to clear the infection, and they develop a chronic carrier state (56, 58). Investigators studying the natural variation of the host response to Salmonella infection in spontaneous mouse mutants (Ity, xid, Lps, and Ity4) (59–62) identified major novel host response pathways (Nramp1Ity , btkxid , Tlr4Lps , and PklrIty4 ) (20, 62– 66). The classical inbred strains, C57BL/6J, C57BL/10J, BALB/cJ, FVB, and DBA/1J, are all extremely susceptible to infection because of a loss-of-function mutation in the Nramp1/Slc11a1 gene (see the section on ItyLsh-Bcg), a major regulator of Salmonella susceptibility in mice. Mice carrying a mutant allele at Nramp1 all die early independently of their genetic background; the Nramp1 effect can be worsened in some cases by the presence of other Salmonella susceptibility alleles such as Tlr4Lps or PklrIty4 (see below) (62, 67, 68). The C3H/HeJ strain is exquisitely susceptible to infection with S. Typhimurium and other Gram-negative bacteria (59, 69, 70). This susceptibility is independent of Nramp1 alleles (C3H/HeJ has a resistance Nramp1G169 allele) but is linked to an aberrant response to the immunostimulatory properties of LPS. Sultzer (71) first described the Lps (lipopolysaccharide response) locus in C3H/HeJ mice in 1968, and observed that C3H/HeJ mice are 20 to 38 times more resistant than A/HeJ mice to the toxic effects of systemic administration of LPS. A defective LPS response in C3H/HeJ mice affects several cell types, including B cells, T cells, macrophages, and fibroblasts. Two allelic forms were recognized for Lps: a normal allele, Lpsn , and a defective allele, Lpsd (72). Other strains of mice (C57BL/10ScNCr and C57BL/6J.KB2mnd ) present LPS hyporesponsiveness as well (73, 74). F1 progeny from crosses between C3H/HeJ and C57BL/10ScNCr or between C3H/HeJ and C57BL/6J.KB2-mnd were also LPS hyporesponsive, which indicates that the three parental strains harbor a genetic defect in the same gene or in the same pathway. www.annualreviews.org • Immunity to Infection in the Mouse
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LPS hyporesponsiveness of C3H/HeJ mice is inherited as an autosomal codominant trait, whereas the LPS-hyporesponsive phenotype of C57BL/10ScCr mice is fully recessive (reviewed in 75). The response to Salmonella infection was inherited as a single dominant trait in all crosses performed between Lpsd and Lpsn mice. Using a variety of RIS, segregating backcrosses and congenic mice, the Lps locus was mapped to mouse chromosome 4 (reviewed in 75). A positional cloning approach was used by two research groups to identify the gene underlying the Lps phenotype (63, 64). Different subphenotypes were used to clone the Lps locus: the LPS-mitogenic response of splenocytes (63, 64), the response to Salmonella infection (64), and TNF production by macrophages (63). High-resolution linkage and physical mapping narrowed the Lps interval to 1.8 Mb (70; Ensembl mouse m36) that harbored an excellent positional candidate, Tlr4, an important component of the signal transduction initiated by LPS in humans in vitro (76). Support for Tlr4 underlying Lps came from the identification of independent mutant alleles at Tlr4 in mouse strains defective in LPS response: C3H/HeJ mice present a single missense mutation resulting in a proline to histidine substitution at codon 712 within the signaling domain of Tlr4 (63, 64); C57BL/10ScCr mice have no Tlr4 transcripts (63, 64), as a consequence of a 75-kb chromosomal deletion encompassing the whole Tlr4 gene (77); and the mutation identified in C57BL/6.KB2-mnd Tlr4 mice consists of a complete deletion of exon II owing to a splicing defect, which results in a mutant variant consisting of only the first 31 N-terminal residues of the protein (wildtype Tlr4 contains 835 residues) (74). Confirmation of the role of Tlr4 in LPS hyporesponsiveness and Salmonella susceptibility was obtained through the creation and study of Tlr4-deficient mice and Tlr4 transgenic mice (67, 68, 78, 79). TLR family members are evolutionarily conserved, type 1 transmembrane receptors
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characterized by an extracellular leucine-rich repeat (LRR) domain and an intracellular domain similar to the intracellular domain of the IL-1 receptor, the TIR (Toll/IL-1 receptor) domain. The first identified member of this family, Drosophila Toll, is involved with innate immunity to fungal infection through the induction of an antifungal peptide. In mammals, 12 TLRs have been identified and classified by their ability to sense specific pathogen-associated molecular patterns (PAMPs) in vitro (reviewed in 80). Several TLRs are essential for defense against different pathogens, as shown by studies in TLR-deficient mice. Tlr4 recognizes LPS with the cooperation of LPS-binding protein and coreceptors CD14 and MD2 (now annotated Ly96, lymphocyte antigen 96). Tlr4 triggers innate immunity through the activation of two signaling pathways: (a) nuclear factor-κB (NF-κB) signaling via the TIR domain–containing adapter protein (TIRAP) and myeloid differentiation primary response gene 88 (MyD88), which results in the activation of IL-1 receptor–associated kinases (IRAKs) and further recruitment of TNF receptor–associated factor 6 (TRAF6), and (b) a MyD88-independent pathway involving adapter proteins TRIF (Toll receptor– associated activator of IFN) and TRAM (TRIF-related adapter molecule), which results in the activation of IFN regulatory factor 3 (IRF3), the induction of type I IFNs, and a delayed NF-κB response (80). Recognition of LPS by TLR4 leads to the induction by macrophages of several proinflammatory cytokines, including IL-1, IL-6, IL-8, IL-12, chemokines, costimulatory molecules (CD80 and CD86), MHC class II, and nitric oxide synthase 2 (NOS2). Induction of CD80/CD86 and IL-12 by TLRs contributes to the initiation of adaptive immunity and the induction of T helper 1 (Th1) effector responses (81). TLR4 gene polymorphisms are associated with susceptibility to various infectious and noninfectious diseases (reviewed in 82, 83). Two polymorphisms, Asp299Gly and Thr399Ile, were originally associated with
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the lung response to inhaled LPS in healthy human volunteers (84). The Asp299Gly and Thr399Ile TLR4 alleles are associated with an increased risk of Gram-negative infection (85), sepsis (86, 87), severe inflammatory response syndrome (88), severe malaria (89), brucellosis (90), and respiratory syncytial virus disease (91). The same TLR4 alleles are protective against Legionnaire’s disease (92). Studies in mice bearing inactivating mutations for individual members of the TLR family have shown that other members of the TLR family likewise play a critical role in the host response to a broad range of bacterial, viral, fungal, and parasitic infections in TLRdeficient mice (reviewed in 80, 93) and in specific human populations (reviewed in 82, 83). In humans, genetic variants in TLR2 are associated with susceptibility to TB (94) and the clinical manifestations (paucibacillary versus multibacillary) of leprosy (95, 96). A common mutation within TLR5 is associated with an increased susceptibility to Legionella pneumophila, the causative agent of Legionnaire’s disease (97). Heritable defects of the human TLR signaling pathway have been identified in patients suffering from recurrent infection and carrying mutations within the genes NEMO (now annotated IκBkγ, inhibitor of kappaB kinase gamma), IKBA (now annotated NFκBiα, nuclear factor of kappa light chain gene enhancer in B-cells inhibitor, alpha), and IRAK4 (6).
THE X-LINKED IMMUNODEFICIENCY LOCUS: B CELL DEVELOPMENT AND HOST RESPONSE TO SALMONELLA INFECTION CBA/N mice do not survive the late phase of Salmonella infection because they are defective in the humoral immune response against bacterial antigens (60). CBA/N mice carry the xid mutation (x-linked immunodeficiency), which is phenotypically expressed as a reduced number of B cells (50% of the normal B cell num-
ber), decreased serum IgM and IgG3 levels, normal levels of IgG1, IgG2a, and IgG2b, and a compromised T cell–independent immune response (98). The susceptibility of xid mice is recessive and maps to the X-chromosome; hemizygous males and homozygous females (for the xid locus) are susceptible to Salmonella infection whereas heterozygous females are fully resistant (60). The transfer of specific anti-Salmonella antibodies restores resistance to infection in affected xid males, which shows the importance of circulating antibodies in resistance to S. Typhimurium during the late phase of infection (99). The xid mutation of CBA/N mice was cloned via a positional candidate approach several years after it was first described (65, 66). The xid mutation maps to a region of mouse chromosome X that is homologous to the human chromosomal region carrying the gene involved in XLA or Bruton’s agammaglobulinemia. Patients with XLA suffer from recurrent and persistent bacterial infections caused by Pseudomonas spp., Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae early in life. Lessfrequent intestinal infections with Salmonella spp. also occur in XLA patients. Male patients with XLA present a more severe immunodeficiency compared with the xid mouse, have less than 1% of the normal number of B cells, present panhypogammaglobulinemia [absence of immunoglobulins (Igs) of all classes], and fail to make antibody to all antigens (reviewed in 100). The gene responsible for the human disease, Bruton’s tyrosine kinase (BTK), was identified by positional cloning as a tyrosine kinase expressed during B cell development (101, 102). In humans, mutations within BTK occur in XLA families (101, 102). Soon after the human discovery, a mutation within the gene encoding btk was shown to be responsible for the xid phenotype in CBA/N mice (65, 66). The role of btk in xid was validated in vivo through the creation of a deletion allele; this allele causes a phenotype similar to xid and less severe than XLA in humans, possibly owing to www.annualreviews.org • Immunity to Infection in the Mouse
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the presence in the mouse of a btk-related kinase, Tec, that may compensate for the loss of btk function (103). Btk is a member of the Tec family of nonreceptor cytoplasmic tyrosine kinases that are highly expressed in most cells of the hematopoietic lineage (104). btk is expressed at all stages of B cell differentiation from pro to mature B cells, with the exception of plasma cells. Btk is also expressed in erythroid precursors, myeloid cells, mast cells, and megakaryocytes, but not in T or natural killer (NK) cells (101, 102). btk encodes a tyrosine kinase that possesses five different domains; these include the pleckstrinhomology (PH), the Tec-homology (TH), the Src homology 1 (SH1, known as the kinase domain), SH2, and SH3 domains (105). The expression of btk is critical for the proliferation, differentiation, survival, and apoptosis of B-lineage cells and is a major component of the B cell receptor (BCR) signalosome (105, 106). All domains of the btk protein bind a variety of interacting partners, which suggests its involvement in multiple signaling pathways (reviewed in 105). Notably, btk is involved in the activation of the transcription factor NFκB through the phosphorylation of the p65 subunit of the NF-κB complex in response to BCR engagement and to LPS (107, 108). Btk is also involved in the negative regulation of TLR signaling and, more specifically, in the phosphorylation of the adapter protein TIRAP after TLR2 and TLR4 stimulation (109, 110), which allows the interaction of TIRAP with SOCS-1 (suppressor of cytokine signaling 1). The interaction of TIRAP with SOCS-1 results in TIRAP polyubiquitination and subsequent degradation (110). Lindvall and colleagues (105) reported 554 different mutations in XLA patients that involve all domains of the BTK gene as well as noncoding sequences (http:// bioinf.uta.fi/BTKbase). In xid mice, a missense mutation at a conserved arginine residue (R28C) within the PH domain of btk prevents its ability to translocate to the plasma membrane and trigger signaling that regulates B cell survival and growth (111).
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THE LGN1 LOCUS: INTRACELLULAR RECOGNITION OF LEGIONELLA BY BIRC1E, A MEMBER OF THE NOD-LIKE RECEPTOR FAMILY Legionella pneumophila is a Gram-negative bacterium that causes a severe form of pneumonia called Legionnaire’s disease. L. pneumophila is a strict intracellular pathogen that survives and replicates in human macrophages, residing in a replicative phagosome that does not mature into a phagolysosome but rather acquires functional and biochemical characteristics of the endoplasmic reticulum (ER). These characteristics include the presence of ribosomes at the phagosomal membrane, retention of the ER markers calnexin and glucose-6-phosphatase, and the absence of lysosomal markers (e.g., Lamp1) (112). Macrophages from most inbred strains of mouse are resistant to infection with L. pneumophila (Philadelphia 1), with the exception of thioglycolate-elicited A/J macrophages that are permissive to the replication of L. pneumophila ex vivo (reviewed in 113). Studies in informative crosses between A/J and other inbred strains showed that susceptibility in A/J is controlled by a single locus on mouse chromosome 13, designated Lgn1. The minimal genetic interval (0.32 cM) is a highly complex and duplicated region containing several intact and rearranged copies of the Birc1 gene (113). Birc1 proteins are expressed in macrophages and are upregulated following macrophage phagocytosis of inert particles or live Legionella or Salmonella. Two intact gene copies, Birc1b and Birc1e, are contained within the minimal physical interval of Lgn1 (113). Functional complementation studies in transgenic mice, using large overlapping cloned segments from the region [bacterial artificial chromosome (BAC) clones], showed that Birc1e gene transfer to otherwise permissive A/J mice and overexpression of the Birc1e gene was sufficient to restore resistance and restrict L. pneumophila replication in macrophages derived from the transgenic mice. Parallel
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studies showed that morpholino-based antisense inhibition of Birc1e can partially reverse the nonpermissiveness of macrophages from mouse strains containing a transgenic copy of Birc1e (114, 115). Together, these results strongly suggested that Birc1e is the gene underlying the Lgn1 defect. The complexity of the genomic region overlapping Lgn1 has so far precluded the creation and testing of a lossof-function mutant at Birc1e or at other Birc1 family members. The Birc1 gene family was initially annotated as neuronal apoptosis inhibitory protein (Naip) on the basis of (a) a possible implication of Naip in spinal muscular atrophy as a regulator of neuronal apoptosis and (b) the presence of baculovirus inhibitor of apoptosis protein (IAP) repeat (BIR) domains in the predicted Naip polypeptide, which interact with cellular caspases (116). The role of Naip5 in macrophage function remained unknown for many years. The recent reclassification of Naip/Birc proteins as part of the nucleotidebinding oligomerization domain (NOD)-like receptor (NLR) family provided important clues to the possible function of Birc1e in macrophage defenses against infections. NLRs are a group of 23 structurally related cytosolic proteins (117, 118) that have several features in common: (a) a nucleotide binding domain (for oligomerization), (b) LRRs that act as recognition motifs for PAMPs in other proteins such as TLRs, and (c) a protein:protein interaction module that is specific for each member or subgroup of this family (e.g., BIR domains in Birc1). The NLR family [also known as the nucleotide binding site (NBS)-LRR or CATERPILLAR family] includes NOD1/NOD2 [also known as CARD (caspase recruitment domain)4/CARD15], which sense bacterial peptidoglycan; IL-1βconverting enzyme (ICE)-protease-activating factor (Ipaf ) (also known as CARD12), which interacts with intracellular flagellin from certain Gram-negative bacteria; cryopyrin [also known as NALP3 (nacht, LRR, and Pyrin domain–containing 3), which binds bacterial RNA; and others that function as intracellu-
lar sensors of bacterial products (117, 118). Mutations in NLR family members are associated with dysregulated inflammation in certain chronic conditions such as Crohn’s disease (NOD2), Blau syndrome (NOD2), atopic eczema and asthma (NOD1), familial cold inflammatory syndrome [cold autoinflammatory syndrome 1 (CIAS1)], and bare lymphocyte syndrome [MHC class II transactivator (CIITA)] (117, 118). Recent studies have shed considerable light on the mechanism of action (the ligand and cellular signaling pathways) of Birc1e in macrophage defenses against Legionella. Infection of macrophages with Legionella pneumophila induces caspase-1-dependent cell death, a protective mechanism that restricts intracellular replication and requires a functional copy of Birc1e (Birc1e is seemingly impaired in A/J cells) (119). Additional studies by Nunez and colleagues (120) pointed to further complexity in the activation of caspase-1 in macrophages following infection with L. pneumophila (in addition to Birc1e). Activation of caspase-1 is dependent on the transfer of Legionella products to the cytosol via a functional type IV secretion system, and macrophages deficient in caspase-1 (Casp1−/− ) or deficient in Ipaf (Card12−/− ) are more permissive to L. pneumophila infection than control C57BL/6J (B6) macrophages (119). These observations support a model in which recognition of Legionella products by the LRR domain of Birc1e causes activation of the Ipaf-containing inflammasome, which results in bacteriostatic activity and ultimately cell death. Recent genetic analyses of L. pneumophila mutants strongly suggest that flagellin may be the bacterial protein recognized by Birc1e: Bacterial flagellin mutants grow in otherwise nonpermissive B6 macrophages and do not induce cell death (121, 122). Finally, results from studies of L. pneumophila– containing phagosomes formed in wild-type and Birc1e-deficient macrophages suggest even more complexity in the mechanism of action of Birc1e. Indeed, the presence of Birc1e is associated with a reduced acquisition of ER www.annualreviews.org • Immunity to Infection in the Mouse
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markers (calnexin) and an enhanced acquisition of lysosomal markers (Lamp1, Cathepsin D) in primary macrophages (123). The Birc1e effect on phagosome maturation is very rapid, occurring within the first hour of infection, which raises the possibility that, in addition to caspase-1, the sensing of bacterial products by Birc1e may affect other early protein targets important in antagonizing the intracellular survival strategy of L. pneumophila. The identity of such targets is unknown but of great interest.
LTXS1: SENSING OF ANTHRAX TOXIN BY THE NOD-LIKE RECEPTOR PROTEIN NALP1B Bacillus anthracis is a Gram-positive bacterium that causes anthrax. Pathogenesis of B. anthracis infection involves the production of several soluble factors by the bacterium; these include the protective antigen (PA), the edema factor (EF), and the lethal factor (LF), which assemble to form the edema toxin (ET) (PA + EF) and the lethal toxin (LeTx) (PA + LF). LeTx causes necrosis, is highly toxic for macrophages, and induces rapid death in systemic anthrax infection (124). Inbred mouse strains differ in their degree of susceptibility to LeTx-induced macrophage necrosis: Strains such as AKR/J, C57BL/6J, A/J, P/J, NOD/LtJ, and SJL/J are resistant, and strains such as BALB/cJ, C3H/HeJ, CBA/J, FVB/NJ, SWR/J, and NON/LtJ are susceptible (125). Typically, C3H macrophages are lysed by LeTx concentrations 100,000 times lower than those required to lyse A/J macrophages, and it was therefore suggested that A/J cells lack the LeTx target (124). Initial mapping studies in informative BXH and AKXL RIS and in [B6 × C3H] F1 × B6 backcross mice showed that the differential response to LeTx is controlled by a single gene, designated Ltxs1, that was regionally assigned to the central portion of mouse chromosome 11 (HSA17) (126). Additional high-resolution linkage and physical mapping 94
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studies delineated the Ltxs1 interval to a 0.51 cM segment that contained 14 known genes and 5 unannotated sequences (125). Dietrich and coworkers (127) initially identified the kinesin-like motor protein Kif1C as responsible for the Ltxs1 gene effect on the basis that (a) Kif1C was the only gene in the minimal interval that showed polymorphic differences between responsive and unresponsive mouse strains, (b) alteration of the subcellular distribution of the Kif1C protein by brefeldin A increased susceptibility to LeTx, and (c) ectopic expression of the resistance allele of Kif1C in susceptible macrophages increased survival following LeTx exposure. Additional recent studies by Dietrich and coworkers (128) excluded Kif1C as a candidate and provided convincing evidence that an adjacent positional candidate, the NLR protein–encoding gene Nalp1b, is in fact responsible for the Ltxs1 effect. Nalp1b is part of a cluster of three adjacent paralogs (with Nalp1a and Nalp1c), and studies in macrophages from the susceptible strain 129S1 showed that of the three only Nalp1b was transcribed in that strain. Sequencing the Nalp1b gene in 18 mouse strains revealed a complex pattern of coding polymorphisms in the Nalp1b protein that can be grouped into four major alleles (128). LeTx-susceptible strains uniformly harbored the same allele (allele 1), whereas resistant strains carried either alleles 2, 3, or 4. Validation of the Nalp1b gene as responsible for Ltxs1 came from (a) the demonstration that transgenic mice from a B6 background (resistant) carrying a BAC clone containing the susceptible allele from 129S1 became susceptible to LeTx, whereas (b) treatment of 129S1 macrophages with antisense morpholino oligonucleotides against Nalp1b increased resistance to LeTx (128). Generating a death signal through Nalp1b in response to LeTx appears to involve caspase-1. Indeed, treatment of macrophages from susceptible strains but not resistant strains activates caspase-1, and macrophages from 129S1 (susceptible) mice carrying a null mutation at caspase-1 (Casp1−/− ) become resistant to
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cell lysis by LeTx. These results suggest a model for the cytoxicity of LeTx in susceptible strains in which the intracellular toxin interacts with Nalp1b, which results in the activation of caspase-1 and the induction of cell death. Although the mechanism by which LeTx activates Nalp1b remains unknown (PAMP emulation, direct proteolytic processing by the toxin, etc.), these studies provide another clear illustration of the role of NLR proteins as cytoplasmic sensors of bacterial products.
MYLS: PLEIOTROPIC EFFECTS OF ICSBP/IRF8 MUTATION ON MYELOPROLIFERATION AND SUSCEPTIBILITY TO INTRACELLULAR INFECTIONS As described above, susceptibility to infection with low doses of M. bovis (BCG) is determined in inbred mouse strains by alleles at the Nramp1 (Slc11a1) locus; Nramp1G169 is associated with resistance and Nramp1D169 with susceptibility (16). Notable exceptions include (a) the wild-derived strain Mus spretus, whose intermediate level of resistance (despite a Nramp1G169 haplotype) is caused by a complex set of modifiers (129), and (b) the BXH2 strain (130). BXH-2 is a RIS derived from C3H/HeJ and C57BL/6J parents, known to develop a chronic myelogenous leukemia by a two-step mutagenesis process (131). The first hit is an inherited, predisposing mutation specific to BXH-2 that causes myeloproliferation, whereas the second hit results from retroviral-mediated insertional mutagenesis that causes the expansion of clonal tumors (132). The second hit has been well characterized, including the nature of the replicationcompetent B-ecotropic virus, the multiple sites of integration, the study of which has unveiled a number of novel tumor suppressors and oncogenes altered by the virus (133). By monitoring splenomegaly and the infiltration of GR1+ /Mac1+ neutrophil precursors in spleen, liver, and lymph nodes as phenotypic markers, investigators showed that the BXH-
2-specific myeloproliferation trait is inherited as a single recessive trait (designated Myls) that maps to the distal portion of chromosome 8 (130). Additional genetic and physical mapping experiments identified IFN consensus sequence-binding protein 1 (Icsbp1), also known as IRF8, as a strong positional candidate. Icsbp1 is a transcriptional regulator that heterodimerizes with other members of the IRF family and plays an important role in activation of IFN-γ-responsive genes that bear internal ribosome entry site (IRES) regulatory sequence elements. BXH-2 mice carry a R294C mutation within the predicted IRFassociation domain of the protein. On the basis of previous reverse genetics studies showing that Icsbp1 acts as a negative regulator of the granulocyte lineage, investigators proposed that the R294C mutation is pathogenic. Subsequently, Turcotte and coworkers found the R294C allele to be associated with a failure of BXH-2 splenocytes to produce IL-12 and IFN-γ in response to activating stimuli (134). Despite a C3H/HeJ-derived Nramp1G169 allele, BXH-2 mice are susceptible to M. bovis (BCG) infection, and experiments in informative F2 crosses derived from BXH-2 showed that homozygosity for the mutant Irf8C294 allele is associated with increased BCG replication early in infection (130, 134). Strikingly, BXH-2 cannot resolve M. bovis (BCG) infection in spleen and liver late in infection. The associated uncontrolled replication of the otherwise avirulent M. bovis (BCG) is associated with the complete absence of granuloma formation in infected BXH-2 tissues (135). Additional preliminary data also indicate that BXH-2 mice are extremely susceptible to pulmonary TB following an intravenous challenge with highly virulent Mycobacterium tuberculosis H37Rv (J.F. Marquis and P. Gros, unpublished data). The effect of the Irf8C294 mutation is pleiotropic because BXH-2 mice show collateral susceptibility to infection with the unrelated pathogens S. Typhimurium and Plasmodium chabaudi (135). In the case of P. chabaudi, although BXH-2 mice can clear www.annualreviews.org • Immunity to Infection in the Mouse
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the initial burst of parasitemia, they fail to mount a long-term protective immune response as the animals develop multiple waves of recurring parasitemia late in the infection. These findings together suggest that Icsbp1 plays a critical role in both innate and acquired immune responses to intracellular pathogens.
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SUSCEPTIBILITY TO PULMONARY TUBERCULOSIS (SST1): ROLE OF THE IPR1 GENE IN MACROPHAGE RESPONSE TO MYCOBACTERIUM TUBERCULOSIS TB is caused by pulmonary infection with the bacterial pathogen Mycobacterium tuberculosis. TB remains a major global health issue, with an estimated 32% of the world’s population currently or previously infected (136), 8 million new cases per year (137), and 1–1.5 million deaths annually. Despite high infection rates, only 5%–10% of infected individuals have a lifetime risk of developing active disease, which suggests a possible role for genetic factors in human susceptibility to TB. Direct evidence for a genetic component includes the following: (a) epidemiological data indicating sex and racial differences in susceptibility, (b) geographical distribution and familial aggregation of disease, (c) population studies in endemic areas of disease and during first contact epidemics, and (d ) concordance rates in mono- and dizygotic twins (for a comprehensive review, see 138). Numerous case control studies pointed to several gene variants that contribute to the risk of TB, and whole-genome scans identified suggestive linkages on several chromosomes, including 8, 11, 15, 20, and X (138). The complex genetic component of susceptibility to TB has been extensively studied in mouse models of infection for the past 60 years. Briefly, the efficacy of the host response to pulmonary TB is under complex genetic control in the mouse, with a broad spectrum of disease severity observed among different strains (138). Genetic 96
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studies by whole-genome scanning have located a number of TB susceptibility loci, but so far only a single locus (Ipr1) has been identified (139) and is reviewed herein. There is an additional enormous body of published work on the effect of individual gene knockouts on the susceptibility to pulmonary infection with M. tuberculosis, using a reverse genetics approach (140–142); this work is not discussed here. Surveys of inbred strains for susceptibility to M. tuberculosis (H37Rv), as measured by the extent of pulmonary replication and overall survival following intravenous or aerosol infections, classified the CBA, DBA/2, C3H, and 129/Sv strains as susceptible and the C57BL/10, C57BL/6, and BALB/c strains as more resistant (143). In a number of F1 hybrids tested (B6D2, CD2, CB6, and B6129), resistance is inherited in a dominant fashion. Susceptibility is generally associated with a failure to contain bacterial growth in the lungs, an inflammatory reaction causing consolidation of the lungs, and ultimately death. Resistant strains limit bacterial growth and can prevent massive tissue injury (142). Kramnik and colleagues (144) recently characterized the unique supersusceptibility of the C3HeB/FeJ strains to infection with M. tuberculosis Erdman (106 bacilli, i.v.). Studies in informative C3HeB/FeJ × C57BL/6J F1 and F2 mice led to the localization of a major gene effect on central chromosome 1 [(LOD) = 10.4], designated sst1. Studies in congenic C3HeB/FeJ mice with B6 sst1r alleles (C3H.B6-sst1) showed that sst1 exerts pleiotropic effects on other intracellular pathogens and also confers increased protection in vivo against Listeria monocytogenes, and explanted sst1 congenic macrophages show increased IFN-γ-dependent listericidal activity in vitro (145). Resistance is associated with an increased capacity of macrophages to restrict replication of M. tuberculosis in vitro, linked to an induction of apoptosis in M. tuberculosis– infected resistant macrophages. Scrutiny of the sst1 genetic interval for positional candidates expressed in macrophages identified a
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transcript, designated intracellular pathogen resistance 1 (Ipr1), which is present in resistant macrophages and whose expression is induced upon M. tuberculosis infection but is absent from susceptible cells (139). The sst1 genetic interval includes part of a large unstable repeat of amplified DNA that contains several rearranged copies of Ipr1-related sequences. In C3HeB/FeJ, this amplification may have caused rearrangement(s) of the Ipr1 gene, leading to the absence of mRNA expression. The Ipr1 candidacy for sst1 was validated by showing that expression of the full-length Ipr1 transcript in transgenic C3HeB/FeJ mice can partially suppress M. tuberculosis replication in the lungs in vivo, and in macrophages in vitro (139). Ipr1 codes for IFN-induced protein 75 (Ifi75), a protein with several sequence motifs that indicate a nuclear localization and transcriptional regulatory activity. Ifi75 is a relative of the human protein SP110, a transcription factor regulated by IFN that interacts with certain viral proteins, including proteins from hepatitis C virus (HCV) and Epstein-Barr virus (146). These findings suggest that Ifi75 participates in transcriptional activation in macrophages in response to intracellular pathogens. In humans, loss-of-function mutations in SP110 cause veno-occlusive disease with immunodeficiency (VODI), an autosomal recessive disorder characterized by severe hypogammaglobulinemia, combined B cell and T cell immunodeficiency, absent lymph node germinal centers, absent tissue plasma cells, and hepatic vascular occlusion and fibrosis (147). Evidence for an association of SP110 alleles with susceptibility to TB has been obtained from studies of families from different areas of Western Africa, including Gambia, Guinea-Bissau, and the Republic of Guinea (148). Additional case-control studies with populations from West Africa (149), Russia (150), and South Africa (151) have failed to provide evidence for an association of Sp110 variants with susceptibility to TB.
DEFICIENCY IN THE C5 COMPONENT OF COMPLEMENT AND SUSCEPTIBILITY TO SYSTEMIC INFECTION WITH CANDIDA ALBICANS In humans, Candida albicans exists as a harmless commensal organism in the gastrointestinal and genitourinary tracts. However, C. albicans can also cause infections in immunocompromised individuals. Such infections can be superficial and limited to mucocutaneous candidiasis or can take the form of severe acute invasive candidiasis after bloodstream dissemination of the organism (152, 153). Researchers have described mouse models of mucocutaneous and acute infections and conducted genetic studies in inbred mouse strains in each model. The LD50 (lethal dose, 50%) for most C. albicans isolates introduced intravenously in immunocompetent mice is between 104 and 106 blastospores, depending on the strain of C. albicans, the growth conditions used to prepare the inoculum, and the genetic makeup of the murine host (154, 155). Candida albicans introduced by the intravenous route replicates in the spleen, liver, kidneys, and brain; inbred mouse strains are either resistant (C57BL/6J, BALB/cJ, CBA/J, and DBA/1) or susceptible (A/J, DBA/2J, NZB/J, and AKR/J) to infection, as measured by the extent of fungal replication, type and extent of tissue damage, and overall survival time (156). These studies further identified a partial correlation between the complement competence status (C5a) and susceptibility to infection (156). Recent genetic studies in A/J and C57BL/6J mice showed that extreme susceptibility in A/J mice is associated with the absence of an inflammatory response in infected tissues and very early death. Interestingly, A/J mice succumb to the acute infection within 48 h but display fungal loads in infected tissues that are considerably lower than those detected in moribund, resistant B6 mice three weeks after infection. In informative (A/J × B6) F2 mice, susceptibility is www.annualreviews.org • Immunity to Infection in the Mouse
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recessive and inherited as a monogenic trait that was mapped by whole-genome scan to the proximal part of chromosome 2 (157) in the vicinity of the structural gene for the C5 component of complement. Up to 40% of inbred strains carry an ancestral mutation consisting of a 2-bp deletion near the 5 end of the mRNA, which introduces a premature stop codon 4 bp downstream of the deletion (158). This mutation leads to the production of a truncated and nonfunctional 216 amino acid translation product. This truncated protein is not secreted. Thus, C5 deficiency in mice is associated with severe susceptibility to acute C. albicans infection. C5 is proteolytically processed to C5a, b, and c, which react with opsonized microbes to form a membrane attack complex that creates pores in the membrane of invading microbes following the binding of antibodies. In addition, C5a acts as a major chemoattractant to recruit neutrophils and macrophages to the site of infection, a response that is impaired in C5-deficient mice (157, 159). Analysis of the profile of cytokines during infection of A/J and B6 mice shows a pattern of extreme inflammatory and allergic response, which suggests unregulated production of proinflammatory molecules including TNF-α, IL-6, monocyte chemotactic protein 1 (MCP1), macrophage inflammatory protein 2 (MIP2), tissue inhibitor of metalloproteinase 1 (TIMP1), and KC. Transcript-profiling studies showed that this dysregulated inflammatory response is associated with severe cardiomyopathy (elevated creatine kinase and cardiac troponin I), hypoglycemia, and rapid death (160). In addition, C5 deficiency is associated with susceptibility to other types of infections, including infection by the intracellular pathogen L. monocytogenes. Indeed, the Lr1 locus previously shown to control interstrain difference in susceptibility to L. monocytogenes in A/J, C57BL/6J, and AXB/BXA recombinant inbred mice (161) was attributed to C5 deficiency (162). Finally, we observed that C5 deficiency in A/J mice and related strains has a positive effect on susceptibility to cerebral
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malaria caused by Plasmodium berghei (K. Kain and P. Gros, unpublished data), highlighting the detrimental impact of the host inflammatory response on the pathogenesis of cerebral malaria.
BLOOD-STAGE REPLICATION OF THE MALARIA PARASITE PLASMODIUM CHABAUDI: POSITIONAL CLONING OF THE CHAR4 AND CHAR9 RESISTANCE LOCI Malaria is caused by infection with members of the protozoan parasite family Plasmodium. Close to half a billion cases of malaria are believed to occur each year, with one million reported fatalities, mostly in young children from countries in sub-Saharan Africa. Severe anemia and cerebral malaria are major disease manifestations of blood-stage malaria, especially in Africa, where transmission rates are high. There is no effective vaccine against malaria, a problem exacerbated by the appearance of drug resistance in the Plasmodium parasite and insecticide resistance in the insect vector (163). Malaria is one of the clearest manifestations of host genetic factors influencing disease pathogenesis, with important threeway interactions between host genes, the environment, and the malaria parasite. Wellknown normal or disease-associated alterations in certain erythrocyte proteins can protect against malaria in humans, and positive selection by the parasite for heterozygosity at these variants occurs in endemic areas (coevolution). Celebrated examples include disease-causing alleles of thalassemias, sickle cell anemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and a few others. For a more comprehensive description of the genetic component of susceptibility to malaria in humans, the reader is referred to recent comprehensive reviews on this subject (5, 164). The genetic control of susceptibility to malaria has been studied in mouse via the use of two infection models: P. chabaudi
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AS and P. berghei, which respectively mimic the blood-stage and cerebral phases of the disease. Although linkage mapping studies have detected multiple loci that affect susceptibility to either type of infection (165), the genes underlying these effects have been identified in only two cases, which are reviewed below. Infection of mice with P. chabaudi– parasitized erythrocytes mimics several pathophysiological aspects of the blood-stage infection in humans, including host response, genetic control of parasitemia, and ultimate outcome of infection. Using levels of parasitemia at the peak of infection, investigators have classified inbred strains of mice as either resistant (C57BL/6J) or susceptible (A/J, C3H/HeJ, SJL) to blood-stage replication of P. chabaudi (165). Susceptibility is associated with muted inflammatory and erythropoietic responses and a decreased survival time. Whole-genome scans conducted in backcross and F2 mice bred from resistant and susceptible parents, using peak parasitemia and mortality as quantitative phenotypes, showed that the genetic control of interstrain differences is extremely complex, with as many as nine detected Chabaudi resistance loci (Char), including major contributions from distal chromosome 9 (Char1), central chromosome 8 (Char2), and chromosome 17 (Char3, H-2 locus) (165). This complex genetic trait has been studied in a set of AcB/BcA reciprocal recombinant congenic strains (derived from A/J and B6 mice by systematic inbreeding of a second backcross) (166). By virtue of the breeding scheme used in their derivation, individual AcB/BcA strains carry a small portion (12.5%) of one parental genome fixed as a set of congenic segments on the genetic background (87.5%) of the other parental strain. Of a subset of 18 AcB/BcA strains tested for susceptibility to infection with P. chabaudi AS, AcB55 and AcB61 mice showed a discordant phenotype; these mice were very resistant to P. chabaudi infection despite carrying A/J-derived susceptibility alleles at Char1 and Char2 (165). Linkage studies in informative
[AcB55 X A/J] F2 mice localized a strong gene effect (Char4) on chromosome 3 (LOD = 6.57) that regulates peak parasitemia following infection (167). Phenotypic characterization of AcB55 and AcB61 strains showed that resistance to malaria in these strains is associated with splenomegaly, elevated reticulocyte numbers in peripheral blood, and an elevated number of Ter119+ cells in the bone marrow, which suggests enhanced constitutive erythropoietic activity in both strains (168). Combined analysis of the level of blood stage parasitemia at the peak of infection and reticulocyte numbers showed that both traits are regulated by the same locus (Char4), which suggests that the two traits are physiologically related. The transcript map on the chromosomal region contained a strong positional candidate, liver- and red cell–specific pyruvate kinase (Pklr), on the basis of both its essential role for ATP production in erythrocytes and the fact that mutations in PKLR cause hemolytic anemia in humans. Sequencing revealed the presence of an isoleucine to asparagine substitution at residue 90 (I90N) of the Pklr protein in malaria-resistant AcB55 and AcB61 strains; this is a mutation that was previously described in a human case of pyruvate kinase (PK) deficiency (169). Recently, a second mutant allele was identified at the pklr locus in a CBA/N mouse genetic background (CBA/N-Pkslc ), G338D. Similar to the I90N allele, the G338D allele not only abrogates PK enzymatic activity and causes severe hemolytic anemia, but also confers dramatic protection against P. chabaudi infection (170). These findings show that deficiency in the erythrocyte PK protects against malaria. The mechanistic basis of the protective effect is related to (a) a reduced half-life of PK-deficient erythrocytes in vivo and (b) increased phagocytosis of uninfected and Plasmodium-infected erythrocytes in an Fc receptor–independent fashion (170). Therefore, the protective effect of PK deficiency is mechanistically related to the effect previously proposed for G6PD deficiency and β-thalassemias. Interestingly, the malaria-protective effect of the www.annualreviews.org • Immunity to Infection in the Mouse
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PK deficiency–induced hemolytic anemia has the opposite effect on susceptibility to acute infection with S. Typhimurium (170a). In this case, perturbations in either homeostasis of iron stores or hemopoietic cell composition (constitutive erythropoiesis) or both contribute to reduce host defenses or enhance replication of this unrelated pathogen. During the positional cloning of the Char4 locus, linkage analysis in [AcB55 × A/J] F2 mice revealed a second, albeit more modest, genetic contribution of chromosome 10 (D10Mit189) that is localized to a 14-Mb C57BL/6J-derived congenic segment fixed in the AcB55 strain (167). C57BL/6J alleles at this locus are protective (reduced peak parasitemia), are inherited in a codominant fashion, and show an additive effect with Char4. This locus was given the designation Char9 and was recently identified by positional cloning (171). The B6-derived 14-Mb Char9 congenic segment contains 77 predicted genes that were characterized with respect to (a) tissue-specific expression, (b) the presence of strain-specific alterations in the level of gene expression, and (c) strain-specific polymorphic variants in coding and regulatory regions of positional candidates. Vanin 1 (Vnn1) and Vnn3 were identified as the likely candidates responsible for Char9. Vnn1/Vnn3 map within a conserved haplotype block, and their expression is strictly cis-regulated by this haplotype. The absence of Vnn messenger RNA expression and the lack of pantetheinase protein activity in tissues are associated with susceptibility to malaria and are linked to a complex rearrangement in the Vnn3 promoter region (171). Vanin genes code for pantetheinases, a group of enzymes involved in the production of cysteamine, a key regulator of host responses to inflammatory stimuli. Passive administration of cysteamine in vivo partially corrects susceptibility to malaria in A/J mice, as measured by reduced blood parasitemia and decreased mortality (171). These studies suggest that pantetheinase is critical for the host response to malaria. Indeed, pantetheinase activity and cystamine production
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may be required to mount an early and beneficial inflammatory response against the infectious agent, which includes the production of protective type I cytokines such as IL-12. Conversely, elimination of pantetheinase activity in Vnn1−/− mice protects against the pathogenic inflammatory response in the gut caused by either chronic exposure to nonsteroid anti-inflammatory drugs or infection with Schistosoma mansoni (172). Finally, these results raise the possibility that cysteamine may be a valid, hostbased molecule for therapeutic intervention in malaria, either alone or in combination with current parasite-based antimalarial drugs such as mefloquine.
THE JANUS KINASE TYROSINE KINASE 2 AND ITS ROLE IN RESISTANCE TO TOXOPLASMA GONDII INFECTION Toxoplasma gondii is an obligate intracellular protozoan. Toxoplasmosis is an important opportunistic infection in pregnant women (causing abortion and fetal abnormalities) and immunocompromised individuals (causing ocular and brain necrosis during reactivation of toxoplasmosis). In immunocompetent hosts, toxoplasmosis is the most common cause of infection-associated eye disease worldwide (173). Domestic cats are the host and the main reservoir of the parasite, although most warm-blooded animals as well as fish and reptiles can be carriers of Toxoplasma. Human contaminations occur principally through ingestion of contaminated food and fecal contamination of hands or congenitally by transplacental transmission (reviewed in 174). During the acute phase of infection, Toxoplasma tachyzoites replicate in macrophages and dendritic cells (DCs). During this early phase of infection, the cytokine IL-12 is essential to trigger IFN-γ-dependent immune responses and for the development of a parasite-specific Th1 response (175–177). The mouse strain B10.Q-H2q/SgJ is extremely susceptible to infection with T. gondii,
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and these mice succumb within two weeks after systemic infection owing to an inability to control parasite replication in macrophages (178, 179). In B10.Q-H2q/SgJ, susceptibility is associated with a general defect in the production of IFN-γ early during infection in vivo and with the hyporesponsiveness of splenocytes to IL-12 in vitro with respect to IFN-γ production (178). An F1 cross between susceptible B10.Q-H2q/SgJ and the related but resistant substrain B10.QH2q/Ai demonstrated that the susceptible phenotype is recessive (179). Linkage mapping in (B10.Q-H2q/SgJ × C57BL/6J)F1 × B10.Q-H2q/SgJ backcrossed mice confirmed that susceptibility to infection with Toxoplasma is recessive and controlled by a single gene located on the centromeric part of chromosome 9 (HSA19) (180). Yap and colleagues (180) used a positional-candidate approach to identify tyrosine kinase 2 (Tyk2), a Janus kinase involved in cellular signaling by cytokine receptors as a strong candidate for the chromosome 9 locus (181). Sequencing of the Tyk2 gene led to the identification of a strain-specific missense mutation (E775K) in B10.Q-H2q/SgJ mice. The E775K mutation results in the complete loss of Tyk2 function, most likely owing to instability of the E775K Tyk2 protein variant. The mutation in Tyk2 was used for mapping in the segregating backcross panel with the mutation in Tyk2 and showed tight linkage to the disease phenotype (LOD score of 53.3). Tyk2-deficient mice were subsequently created and shown to be susceptible to infection with Toxoplasma; their response is characterized by impaired IFN-γ production and high parasite replication. More importantly, mice issued from a cross between B10.Q-H2q/SgJ and Tyk2-deficient mice remained susceptible to infection, which confirms that Tyk2 is the gene underlying the immune defect of B10.Q-H2q/SgJ mice (180). The family of Janus kinases consists of four members: Jak1, Jak2, Jak3, and Tyk2. Mutations in Jak3 cause severe combined immunodeficiency (SCID) in humans (182). Different Jak kinases associate constitutively with
the cytoplasmic domain of specific cytokine receptors (reviewed in 183). After activation of the receptor by ligand binding, Jak kinases phosphorylate the receptor and trigger the recruitment of signal transducer and activator of transcription proteins (STATs) and other adapter molecules. Activation of Tyk2 is involved in the signaling of several cytokines, including IL-12, IL-23, and type 1 IFNs (184). The critical role of TYK2 in humans was established by studies of a rare case of TYK2 deficiency in a patient presenting unusual susceptibility to various bacterial (S. aureus, atypic mycobacteria, nontyphi Salmonella), viral (herpes simplex infection), and fungal (oral candidasis) infections (185). The patient also suffered from atopic dermatitis with elevated levels of IgE. This patient displayed several cellular defects in cytokine signaling pathways, which explains his susceptibility to different classes of pathogens; the defects included alterations in signaling through type 1 IFN, IL-6, IL-10, IL-12, and IL-23. These studies in mouse and human demonstrated the pleiotropic role of Tyk2 in the innate and acquired immune responses to a variety of pathogens.
THE RIC LOCUS: RESISTANCE TO ORIENTIA TSUTSUGAMUSHI Orientia (formerly Rickettsia) tsutsugamushi is an obligate intracellular Gram-negative bacterium causing Scrub typhus, an acute, febrile, infectious disease zoonotic across southeast Asia and the western Pacific region (186). Approximately one million cases of Scrub typhus occur annually (http://www.cdc.gov). Humans acquire the disease when O. tsutsugamushi is transmitted by feeding trombiculid mites. The bacteria multiply at the inoculation site, causing local inflammation and eschars with regional lymphadenopathy, before progressing within a few days to cause a systemic disease involving the lungs, heart, liver, spleen, and CNS. Resistance to the lethal effects of acute systemic infection with O. tsutsugamushi was www.annualreviews.org • Immunity to Infection in the Mouse
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studied in inbred mouse strains. Groves & Osterman (187) classified mice as resistant (AKR/J, BALB/c, C57BL/6J, C57L/J, and SWR/J) or susceptible (A/HeJ, CBA/J, DBA/1J, DBA/2J, SJL/J, and several C3H substrains) to infection on the basis of LD50 after intraperitoneal infection. Susceptible mice develop local and systemic bacterial growth during the first week of O. tsutsugamushi infection and die within 10–12 days, whereas resistant mice show low microbial replication and complete survival after infection. Macrophage-mediated cellular immunity is essential for the resolution of infection in resistant strains (188). Genetic analyses in F1 and F2 crosses between resistant BALB/c and susceptible C3H/He progenitors showed that resistance to infection is determined by a single dominant gene, designated Ric (187, 189). Groves and colleagues mapped the Ric locus to a 45-Mb region of chromosome 5 using RIS of the BXH and CXS series (189). During the study of the molecular defect underlying Ric, a positional candidate, Eta1 (early T lymphocyte activation 1; also known as osteopontin and renamed Spp1 for secreted phosphoprotein 1), was identified. Eta1 expression is strongly induced during O. tsutsugamushi infection in vivo and is associated with inhibition of bacterial replication (190). Eta1 is a secreted, integrin-binding glycophosphoprotein with multiple functions that is expressed in several tissues during inflammation. Eta1 is produced by activated macrophages, T cells, and NK cells (191). More recent work using mice deficient in Eta1 indicated that Eta1 contributes to host resistance to virus (rotavirus and herpes simplex virus 1) and bacteria (L. monocytogenes) (192, 193) and correlates with the clinical outcome of mycobacterial infection in humans (194). The proinflammatory functions of Eta1 include recruitment of leukocytes to sites of inflammation and polarization of T cells (195). Although these studies clearly identified a critical role for Eta1 in the host response to certain intracellular pathogens, whether it is the primary molecular defect underlying the
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Ric mutation remains to be established. Additional high-resolution linkage studies, mutational analysis in O. tsutsugamushi permissive strains, and complementation testing with Eta1-deficient mice are required to clarify this point.
THE CTRQ3 LOCUS: ROLE OF THE P47GTPases IN SUSCEPTIBILITY TO CHLAMYDIA TRACHOMATIS Chlamydia trachomatis is an obligate intracellular pathogen that causes a variety of diseases in humans; different serotypes infect the ocular or genital mucosa. Chlamydia has a dual life cycle that involves an extracellular elementary body, a metabolically quiescent but infectious form, and a reticular body that replicates inside host cells. In host cells, Chlamydia replicates inside a specialized vacuole known as the inclusion (196). The variability in disease frequency and disease severity in people infected with Chlamydia suggested a possible contribution of genetic factors. Several infection models were developed in mice using either C. trachomatis (muco/cutaneous or systemic model) or C. pneumoniae (pulmonary model) (197, 198). In an intravenous infection with high doses of C. trachomatis, inbred mouse strains show different levels of susceptibility as determined by the extent of transient replication in the spleen (197). Typically, C57Bl/6J mice support 10-fold less replication than C3H mice, as measured by the amount of Chlamydia DNA (determined by PCR-based methods). The different degree of susceptibility to C. trachomatis infection in vivo can be partially reproduced ex vivo using mouse primary fibroblasts (MEFs), which suggests the involvement of a cell-autonomous mechanism of defense. Whole-genome scan experiments in F2 mice derived from C57BL/6J and C3H/HeJ, using spleen chlamydial load 29 h postinfection, suggested a multigenic control with three quantitative trait loci (QTLs). These QTL reach significance on chromosomes 2 (Ctrq1), 3 (Ctrq2), and 11 (Ctrq3) (197). A
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congenic mouse line carrying a 30 Mb chromosome 11 segment harboring Ctrq3 from C3H/HeJ (susceptible), transferred onto the resistant genetic background of C57BL/6J, was more permissive to C. trachomatis replication than were B6 controls. Therefore, the Ctrq3 locus can contribute to susceptibility independently of the Ctrq1 and Ctrq2 QTLs (197). Subsequent studies in subcongenic lines narrowed the Ctrq3 interval down to a 1.2 Mb segment (199). This segment contains 18 annotated genes, including two members of the p47 family of IFN-γinducible GTPases (p47GTPases), IFN-γinduced GTPase (Igtp), and iron-regulated virulence protein 10 (Irgb10). p47GTPases comprise a group of 23 related proteins that play an important role in the innate defense repertoire of macrophages and other cell types. p47GTPases are structurally defined by the presence of a nucleotidebinding domain (G domain) that confers GTP binding and hydrolysis properties on these proteins. The expression of p47GTPases is inducible (50- to 100-fold) by IFN-γ through STAT1-mediated transcriptional activation. P47GTPases bind to different endomembrane compartments and quickly relocalize to pathogen-containing vacuoles in macrophages and other cells upon infection (200). Recent reverse genetics studies showed that mice lacking members of this family become dramatically susceptible to infection with certain intracellular bacteria, including Mycobacterium, Salmonella, and Listeria, as well as protozoans such as T. gondii and Leishmania major, and viruses such as Coxsackie B3 and vesicular stomatostatis virus (VSV) (200). Expression studies showed that although constitutive and IFN-γ-inducible mRNA expression of Igtp is similar in both B6 and C3H mice, Igrb10 expression in response to IFN-γ was 20-fold higher in B6 than in C3H mice, which suggests that diminished expression of Igrb10 may be responsible for C. trachomatis susceptibility in C3H/HeJ mice (199). Addi-
tional experiments showed that overexpression of Irgb10 in MEFs from C3H/HeJ mice in the presence of IFN-γ caused increased resistance to C. trachomatis, whereas RNAimediated inhibition of Irgb10 in C57BL/6J cells rendered them more permissive to C. trachomatis replication (199). These results are supported by recent RNAi studies showing that another p47GTPase, IFN-inducible GTPase 1 (Iigp1), is a critical component of the inhibitory effect of IFN-γ on the growth of human C. trachomatis L2 in murine epithelial cells in vitro (201). Together, these results highlight the role of IFN-γ and p47GTPase signaling in effective host defenses against Chlamydia (see Figure 2).
THE MYXOVIRUS RESISTANCE (MX) LOCUS: IFN-INDUCIBLE GTPases OF THE DYNAMIN SUPERFAMILY AND RESISTANCE TO ORTHOMIXOVIRUS (INFLUENZA) INFECTION Influenza viruses (members of the orthomyxovirus family) cause upper respiratory tract infections in humans and various domestic animals; these include chickens (fowl plague), horses (equine influenza), and pigs (swine influenza). In nature, wildfowl and shorebirds may form the virus reservoir. According to the World Health Organization (WHO) (http://www.who.int/en/), in an influenza epidemic 5% to 15% of the population is affected, including 3–5 million cases of severe illness and between 250,000 to 500,000 deaths every year. The elderly, young children, and people with compromised health status are at high risk for serious complications. Highly pathogenic influenza of certain subtypes can cause global outbreaks. Three influenza pandemics have occurred in the twentieth century: the Spanish flu in 1918 resulted in approximately 50 million deaths worldwide, the Asian influenza in 1957 resulted in more than 1 million deaths, and the Hong Kong influenza in 1968 www.annualreviews.org • Immunity to Infection in the Mouse
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S. aureus?
LRR TLR4
MyD88 Tirap TIR Tram Trif
LRR TLR6 TIR
1 Early response (inflammatory cytokines) 2 Late response (lFN-β)
2
1
Pathogen
NK cells T cells
Irgb10 NF-κB
Igtp
IRF-3 Igtp Icsbp /IRF8
Irgb10
P47GTPases
IFN-γ
IL-12
IFN-γR
IFN-αβR
Ipr1/Ifi75 Jak1
STAT2
Cytokines
Tyk2
Ipaf
Anthrax toxin
pro-IL-1β
?
IL-1β
STAT1 STAT2
Legionellacontaining vacuole
Nalp1b Bacterial growth restriction Caspase 1
IFN-β STAT1
Flagellin
Birc1e
STAT1 STAT1
-β IFN
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Nr
am
p1
Fe2+
CD36 TLR2 LRR Phagosome
MyD88 Tirap TIR
Lysosome
LPS
IFN-β ?
NUCLEUS
Mtb MACROPHAGE
Figure 2 Central role of the macrophage in genetic studies of infection susceptibility loci. Schematic representation of several major biochemical, physiological, and signaling pathways relevant to macrophage defenses against infectious agents. Genes and proteins involved play a key role in these pathways; mutations identified by forward genetics as causing alterations in resistance to infections are shown in red. See text for details. [Abbreviations: Nramp1, natural-resistance-associated macrophage protein 1; LRR, leucine-rich repeat; MyD88, myeloid differentiation primary response gene 88; Tirap, Toll receptor-associated activator of interferon; Trif, Toll/IL-1 receptor (TIR) domain–containing adapter-inducing interferon-β; Tram, TRIF-related adapter molecule; Icsbp, IFN consensus sequence-binding protein; IRF, IFN regulatory factor; Mtb, Mycobacterium tuberculosis; Nalp1b, nacht, LRR, and Pyrin domain–containing 1b; Birc1e, baculoviral IAP repeat-containing 1e; Ipaf, IL-1 β-converting enzyme–protease-activating factor; JAK, Janus kinase; STAT, signal transducer and activator of transcription; Tyk, tyrosine kinase; CD36, CD36 antigen; Irgb10, iron-regulated virulence protein 10; Igtp, IFN-γ-induced GTPase; Ipr1, intracellular pathogen resistance 1; Ifi75, IFN-induced protein 75.]
was responsible for approximately 700,000 deaths (202). More recently, the emergence of the highly pathogenic avian H5N1 influenza virus, which is transmitted directly from birds 104
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to humans, highlights the threat of future influenza outbreaks and pandemics. Genetic studies in mouse models of influenza were used successfully to identify
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major host determinants of susceptibility and resistance to infection. Most laboratory mouse strains (C57BL/6J, C3H/HeJ, BALB/cJ CBA/J, CE/J, I/LnJ, and PERA/Ei) are extremely susceptible to intranasal infection with mouse-adapted strains of influenza virus, with the exception of the A2G strain and several wild-derived inbred strains (SL/NiA, T9, and CAST/Ei) (203–205). Resistance of A2G mice is specific for influenza and is controlled by a single dominant gene named Mx (myxovirus resistance locus); the protective effect of Mx is mediated by type 1 IFNs (206). The Mx locus has two phenotypic alleles: Mx+ (resistant, dominant) and Mx− (susceptible, recessive) (207). A candidate gene for Mx was identified as a protein that was differentially expressed (determined by 2D-gel electrophoresis) in Mx+ and Mx− cells in response to stimulation with type 1 IFN (208). A nuclear protein of 72 kDa, named Mx1, was inducible by type 1 IFN and present only in cells carrying the wild-type allele at Mx but not in cells of the Mx− phenotype. Staeheli and colleagues (207) further cloned the Mx1 gene, mapped it to mouse chromosome 16, and showed that it belongs to the superfamily of dynamin-like large GTPases. Linkage studies in informative backcross progeny issued from crosses between different laboratory strains carrying the Mx− allele established that susceptibility to influenza maps to the 8 Mb at the distal end of chromosome 16 where the Mx1 gene was previously localized (209). Mutational analyses revealed that the Mx− defect in BALB/cJ, C57BL/6J, and C3H/HeJ mice is caused by deletion of exons 9–11 and some flanking sequences, which results in a truncated, nonfunctional Mx1 protein. The Mx− phenotype of CBA/J, CE/J, I/LnJ, and PERA/Ei mice is caused by a nonsense mutation in exon 10 that converts codon 389 (Lys) to a termination codon, which prevents synthesis of functional Mxl (210). Mx1 is a nuclear protein whose expression is stimulated by IFN-α/β or by viral infection. Mx1 contributes to specific resistance against the influenza virus by acting at an early stage of the
viral infection cycle to inhibit primary transcription of the virus, probably through inhibition of the viral PB2 polymerase subunit (211, 212). Mx homologs are present in all eukaryotes examined, including humans, cattle, pigs, rats, horses, hamsters, chicken, fish, and yeast. In mice, a second Mx gene (Mx2), closely linked to Mx1 on chromosome 16, was identified and shown to be nonfunctional in classical inbred mouse strains (the Mx2 mRNA carries an insertion at position 1366, which causes a translational frameshift) (213). However, in wild-derived mice, Mx2 is expressed following exposure to type 1 IFN or viral infection and localizes to the cytoplasm, where it can inhibit VSV replication (214). In humans, two Mx proteins (MxA and MxB) were identified as GTPases and map to the region of chromosome 21 homologous to mouse chromosome 16. Only MxA has detectable antiviral activity and, in contrast to Mx1, inhibits replication of a spectrum of viruses, including members of the orthomyxoviruses (influenza and Thogoto virus), rhabdoviruses (VSV), paramyxoviruses (Measles virus), and picornaviruses (coxsackie virus), among others (reviewed in 215). The essential role of Mxl in influenza resistance has been demonstrated in vitro and in vivo. Transfection of the wild-type Mx1 allele into Mx− cells transforms them from a sensitive to a resistant phenotype (207). In addition, the resistant phenotype of Mx+ cells can be abolished by the use of an anti-Mxl antibody (216). In vivo, transgenic mice that express mouse Mx1 or human MxA are fully protected against influenza infection (217, 218).
THE HV2 LOCUS: CEACAM1B AND THE CONTROL OF CORONAVIRUS ENTRY INTO THE HOST CELL With a single-stranded positive-sense RNA genome of 30–32 kb (219), coronaviruses are the largest of all the RNA viruses. They have a broad host range and cause a variety of diseases. In humans, coronaviruses www.annualreviews.org • Immunity to Infection in the Mouse
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cause respiratory disease and, to a lesser extent, infections of the digestive tract and neurological syndromes. Human coronaviruses OC43 (HCoV-OC43) and HCoV-229E are the causative agents of the common cold (220); the more recently identified agents HCoV-HKU1 and HCoV-NL63 cause more severe, although rarely fatal, infections of the upper and lower respiratory tract (221–223). Severe acute respiratory syndrome (SARS)CoV causes a life-threatening pneumonia (224) and is the most pathogenic human coronavirus identified to date (225, 226). SARSCoV may reside in an animal reservoir (227, 228) and recently initiated an epidemic in humans through zoonotic transmission (228). Coronaviruses also cause economically important diseases of livestock, poultry, and laboratory animals (229). In mice, several strains of the prototype coronavirus, mouse hepatitis virus (MHV), with different degrees of pathogenicity and tissue tropism, have been used to study infection in vivo. For example, the A59 strain of MHV is hepatotropic (230), and the JMH strain induces encephalitis and sometimes demyelination (231). The MHV3 strain induces fatal hepatitis (232). More recently, researchers found that respiratory infection with the MHV1 strain produces severe pneumonia accompanied by tissue destruction, mainly in the lung (233). Several pathophysiological features are common between mice infected with MHV and patients infected with SARS-CoV and are consistent with immunopathological disease: These include the propensity of viruses to infect macrophages and DCs and an increased systemic concentration of chemokines and cytokines (234). In mice, activated macrophages are present at sites of inflammation and participate in tissue destruction (234). Inbred mouse strains are susceptible to experimental infection with MHV, although the SJ/L strain can sustain a 10,000-fold higher infectious dose (235). Examination and segregation analysis of several inbred strains showed that resistance is recessive and that expression of disease resistance is controlled by
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a single autosomal gene acting at the level of the infected cell (236). Following virus replication in macrophages, this resistance trait was mapped to mouse chromosome 7 at the Hv2 locus (237, 238), now designated carcinoembryonic antigen–related cell adhesion molecule 1 (Ceacam1). More recently, investigators showed that Ceacam1 controls survival differences between SJ/L and BALB/c mice (239). In the SJ/L strain, the inability of MHV to bind the host cell membrane suggested that resistance to infection is due to the absence of a functional receptor for the virus (240); the receptor was finally identified biochemically (241). CEACAM1 is a member of the carcinoembryonic antigen (CEA) family in the Ig superfamily (242). Mouse CEACAM1 isoforms are transmembrane glycoproteins with either two or four Ig domains that are produced by alternative splicing of the primary transcript (243). An immunoreceptor tyrosine-based inhibitory motif (ITIM) is present in the cytoplasmic domain of CEACAM1 and confers immunomodulatory function to this molecule (244). The expression of CEACAM1 glycoproteins is widespread not only on the apical membranes of epithelial cells in the gastrointestinal and respiratory tracts (245), which are the main targets of MHV replication, but also in small vascular endothelial cells, hematopoietic cells, and glial cells of the nervous system. In these tissues, CEACAM1 performs many important cellular functions. It may act as a cell adhesion molecule, an angiogenic factor, a tumor suppressor, and/or a signal regulatory protein (246). In inbred mice, there are two Ceacam1 alleles; susceptible strains carry the Ceacam1a allele. Expression of CEACAM1a in human and hamster cells is sufficient to overcome the species barrier to MHV infection, which supports the role of CEACAM1a as a functional MHV receptor. Resistant SJ/L mice carry the Ceacam1b allele, which encodes a protein with a 27 amino acid substitution in the first Ig domain of CEACAM1b. Extensive mutational and biochemical analysis showed that this region mediates CEACAM1
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binding to the spike protein of the MHV envelope. Three mouse lines with genetically engineered mutations in Ceacam1a were produced (247, 248). Mice with complete abrogation of the CEACAM1a protein exhibited resistance to MHV infection via the intranasal and intracerebral route with no clinical signs of disease even at high doses, which demonstrates the critical role of a virus receptor in resistance to infection. Human CEACAM1a proteins do not recognize mouse or human coronaviruses but instead bind Gram-negative bacteria in the vicinity of the MHV binding site. In addition to CEACAM1, CEACAM3, CEACAM5, and CEACAM6 proteins allow bacterial anchoring or invasion of the host cell (246). Infection with Neisseria gonorrhoeae promotes CEACAM1-mediated inhibition of CD4+ T cell activation, which indicates an immunoregulatory role for the cytoplasmic ITIM-containing tail of CEACAM1. In stark contrast, the neutrophil-restricted CEACAM3 receptor possesses an immunotyrosine activating motif (ITAM) in its intracellular domain, which promotes ITAMdependent internalization of the CEACAM3 bacterial complex and neutrophil bactericidal activity via a Syk kinase–dependent pathway (249–251). Thus, particular species of bacteria seem to exploit adhesion to CEACAM1 to promote immunosuppression.
THE FLV LOCUS: SPECIFIC INHIBITION OF WEST NILE VIRUS REPLICATION BY 2 ,5 -OLIGOADENYLATE SYNTHASE 1B West Nile virus (WNV) is a re-emerging pathogen that cycles primarily between mosquitoes and birds; humans represent one of several incidental hosts (252). The virus is widely distributed throughout Africa, the Middle East, and India but was not detected in the Western Hemisphere before 1999, when it caused an outbreak of viral encephalitis in New York (252). Since then, the virus
has propagated rapidly throughout all North America, resulting in considerable acute morbidity and mortality. Epidemiologic studies indicate that although 80% of infections remain subclinical, 20% progress to a febrile illness. Of these, more than 30% of cases in the U.S. progress to neuroinvasive disease, causing meningitis, encephalitis, and/or flaccid paralysis (253). WNV is a member of the genus Flavivirus (family Flaviviridae), which also contains the Yellow Fever, Dengue, and Japanese encephalitis viruses. Flaviviruses contain a positive-sense RNA genome of 10 kb. Viral replication in host cells generates negativestrand RNA intermediates that serve as templates for nascent positive-strand RNA synthesis. WNV replicates initially in Langerhans cells, a resident DC of the skin. Following peripheral replication, WNV spreads to the CNS, possibly through TNF-mediated changes in blood-brain barrier permeability. Neurons are the primary target of WNV in the brain and spinal cord. Although WNV can directly antagonize IFN-induced responses after infection, type I IFN is still required to restrict WNV replication and spread (254). The characterization of innate resistance to flavivirus-induced morbidity and mortality started as early as 1929 (255). Selective breeding in mice led to the development of resistant and susceptible lines, followed by the demonstration that a single autosomal dominant locus, designated Flv, is responsible for the differences in the host response against several types of flaviviruses (256). Following intracerebral infection, viral titers in the brain of resistant mice with the Flvr resistance allele are several orders of magnitude lower than in Flvs susceptible mice. Similarly, virus titer yields in cells cultured from resistant or susceptible animals are also dramatically different, which indicates that resistance to flavivirus acts intracellularly on flavivirus replication. Most common laboratory-inbred strains of mice are susceptible to experimental infection, whereas wild-derived strains (e.g., PR1, MBT/Pas, MAI/Pas) are not (257). The resistance www.annualreviews.org • Immunity to Infection in the Mouse
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allele from donor PR1 mice was introduced onto the susceptible C3H/He background to produce the congenic inbred C3H.PR1-Flvr . Using this strain in crosses with the susceptible C3H/He or BALB/c mouse strains, and following the load of Murray Valley encephalitis virus in brains of infected mice, Flv was mapped to chromosome 5 (258). Additional high-resolution linkage mapping experiments delineated a minimal interval for Flv of 0.45 cM (259). In a parallel study, an identical interval was defined for resistance in terms of survival to a low intraperitoneal inoculum of the recent WNV variant ISr98/NY99 (from New York) and of a different set of wildderived mouse strains (257). Physical mapping in BAC clones, exon trapping, and cDNA selection techniques were used to identify positional candidates. A cluster of genes encoding the 2 ,5 -oligoadenylate synthetases (2 ,5 OAS) contained excellent candidates on the basis of their known (IFN-inducible) antiviral activity in response to double-stranded RNA (dsRNA). Of the five functional Oas genes found in mice (Oas1g, Oas1b, Oas1a, Oas2, Oas3), only Oas1b is important for the host response to WNV and plays a key role in WNV pathogenesis. All susceptible mice tested so far have a T-to-C transition that replaces an arginine residue with a premature stop codon, which probably results in a defective enzyme without nucleotidyl transferase activity (257, 259). This assumption was reinforced by the observation that replication of WNV is less efficient in neuroblastoma cell clones that overexpress the normal copy of Oas1b than in those expressing the mutant variant (259). Moreover, upregulation of OAS1B (under the control of the Tet-Off expression system) in fibroblasts efficiently inhibited WNV replication at the early stages of the virus life cycle by dramatically reducing the levels of positivestranded viral RNA. It remains unclear what provides specificity to OAS1B in this system (259). OAS proteins are part of the OAS/RNase L system of RNA decay stimulated by the type I IFN antiviral response. Transcrip-
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tion of OAS genes is upregulated by type I IFN, and expressed OAS proteins are activated by dsRNA. Activated OAS catalyzes the synthesis of 2 ,5 -oligoadenylates, which in turn activate RNase L, a latent endoribonuclease that degrades viral and cellular RNAs. RNase L−/− murine embryonic fibroblasts and PKR−/− × RNase L−/− bone marrow–derived macrophages supported increased WNV replication in vitro (recently reviewed in 214). Moreover, mice deficient in both PKR and RNase L showed increased lethality following WNV infection, with greater viral loads in peripheral tissues at early time points after infection. However, the mechanisms by which Oas gene alleles affect flavivirus pathogenesis remain uncertain; recent reports suggest that Oas1b gene effects on WNV replication are independent of RNase L (253). A recent study of 33 WNV-infected patients showed a positive association between the nucleotide change T210C and susceptibility to WNV disease in humans (260). Their analysis predicted that the T210C nucleotide change creates a new OAS splice enhancer site that may result in production of a dominant-negative protein (260).
THE CMV1 LOCUS AND ITS RELATIVES: RECOGNITION OF THE CYTOMEGALOVIRUSINFECTED CELL BY NATURAL KILLER CELL RECEPTORS Most humans are infected by human cytomegalovirus (HCMV), a virus of the Herpesviridae family, characterized by a large double-stranded DNA genome (200 kb), wide tissue tropism, and the ability to establish latency in immunocompetent individuals. Primary infections are mostly subclinical or they may be associated with a selflimited mononucleosis-like syndrome. However, HCMV is the most common cause of virus-induced mental retardation and congenital deafness in the Western world. In addition, HCMV infections can cause serious
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morbidity and mortality among immunocompromised subjects (recently reviewed in 261). Patients with congenital defects in NK cells are also particularly vulnerable to infection by herpesvirus (262–265). A central aspect of the pathogenesis of CMV is that many genes serve to evade or subvert mechanisms of host defense (266– 268). Infection of mice with the closely related mouse CMV (MCMV) has proven exceptionally useful for the study of the complex host:pathogen interactions (recently reviewed in 269). In mice, genetically determined resistance against MCMV is under multigenic control, with contributions from both H2 and non-H2 genes (270, 271). Inbred strains carrying the H2k haplotype, such as CBA, C3H/HeJ, or congenic BALB.K, are up to 10 times more resistant (measured as survival time) to MCMV than strains with H2b or H2d haplotypes (271). However, in strains with a C57BL background and the H2b haplotype, non-H2-linked effects override H2determined susceptibility. The Cmv1 locus is one of the best characterized loci in the C57BL/6 mouse strain that is responsible for non-H2 host resistance against MCMV infection (272). Through genetic analysis of progeny from MCMVresistant and MCMV-susceptible parents, Scalzo and coworkers (272) identified a single locus, Cmv1, as the major determinant of MCMV-resistance in the C57BL/6 mouse strain. Cmv1 is an autosomal (chromosome 6) dominant trait that restricts viral replication at the level of the spleen and other target organs such as liver and lung (272). Cmv1 function is mediated by NK cells (273). Researchers cloned the Cmv1 locus using a combination of high-resolution mapping, physical mapping, and detailed immunological characterization of C57BL/6 mice. The cloning was complicated by the fact that Cmv1 resides within an interval that contains 14 highly related genes of the Ly49 family of MHC class I receptors (277). Ly49h, a gene that encodes an activating NK cell receptor, was identified as the gene underlying the Cmv1 locus
(274–276). Ly49h is present in the MCMVresistant strain C57BL/6 but is absent in susceptible strains such as BALB/c, DBA/2, and 129Sv/J (278). In fact, a clonal expansion of Ly49H+ NK cells occurs following MCMV infection of C57BL/6 mice (279). The crucial role of Ly49H-bearing NK cells in host defense against viral infection was validated by restoring MCMV-resistance in genetically susceptible mice through transgenic expression of Ly49h (280). Ly49 molecules constitute an extended family of activating and inhibitory C-lectintype receptors that recognize MHC class I (277, 281). Activating LY49H, contrary to inhibitory ITIM-bearing Ly49 receptors, associates with the ITAM-containing DNAXactivating protein of 12 kD (DAP12) adapter protein, also known as killer cell activating receptor–associated protein (KARAP). The importance of the Ly49H/DAP12 receptor complex in NK cell–mediated resistance to MCMV infection is supported by the observation that DAP12 mutant mice present a considerable increase in MCMV titers in the spleen and liver following infection (282). Ly49H specifically recognizes MCMVinfected cells via a direct interaction with the m157 MCMV protein, which has structural homology to MHC class I molecules (283, 284). Deletion of the m157 gene is associated with gain of virulence in Ly49H+ mouse strains but not in Ly49H− strains, which indicates that m157 is the only MCMV-encoded protein that activates Ly49H+ NK cells (285). Arase et al. (283) demonstrated that m157 also binds to an inhibitory receptor, Ly49I, expressed on NK cells in 129 mice, which suggests that m157 may have evolved as a mechanism to escape NK cell killing by targeting inhibitory receptors in certain susceptible mice. These observations predicted a dynamic interaction between Ly49 receptors and MCMV evasion genes, which was recently confirmed. In fact, several MCMV strains isolated from wild mice had variants of the m157 gene, many of which disrupted the open reading frame and inactivated the www.annualreviews.org • Immunity to Infection in the Mouse
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gene (286). In addition, sequential passage of the commonly used Smith strain of MCMV in Ly49H+ C57BL/6 mice (287) or in SCID mice (288) resulted in loss-of-function mutations in the m157 gene. This result demonstrates the ability of Ly49H+ NK cells to exert enough selective pressure to permit the specific outgrowth of MCMV escape mutants with alterations in m157. Further genetic analysis of MCMVresistant inbred strains demonstrated the presence of alternative NK cell–encoded resistance mechanisms, Cmv3 (289) and Cmv4 (290), which operate individually or in combination with specific H2 haplotypes. The Cmv4 locus is also tightly linked to the Ly49 cluster and presents a second example of a major locus effect in MCMV resistance present in a wild-derived inbred mouse strain, PWK/Pas. Although the Cmv4 effect is independent of Ly49H/m157, the most likely candidate remains another activating NK cell receptor that specifically recognizes MCMV-infected cells (290). Support for alternate activating Ly49 receptors determining MCMV resistance also comes from the study of the Cmv3 locus present in a resistant mouse strain, MA/My (289). This strain carries a Ly49 haplotype similar to that of the MCMV-susceptible 129 strain, which lacks Ly49h. MA/My mice also contain the protective H2k haplotype, whereas 129 (H2b ) present with susceptible haplotypes, which suggests a possible role of H2 in MA/My resistance. Linkage analyses suggested that MCMV resistance in MA/My is linked to the Ly49 gene cluster. However, only the specific combination of Ly49 (Ly49em ) with MHC (H2k ) alleles is associated with virus resistance. A model including contributions of Ly49 genes, H2-loci, and their interaction explained 40% of the phenotypic variance in this cross. A cell reporter assay, in which cells expressing the activating receptor Ly49P were responsive to challenge only with H2k target cells infected with MCMV, confirmed a physical interaction between the Ly49 and H2 gene products. Blocking anti-
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bodies to class I H2k gene product, H2-Dk , directly implicated this molecule in stimulation of Ly49P (289). Thus, Ly49P recognition of MCMV infection in the context of H2Dk points to a novel mechanism of NK cell function, in which an activating Ly49P receptor mediates host resistance against MCMV through specific recognition of a virally altered MHC class I molecule. The discovery of Ly49H- and Ly49P-mediated recognition of MCMV-infected cells supports the hypothesis that activating receptors have evolved under evolutionary pressures from pathogens and has revealed an exceptional specificity of this arm of the innate immune system for unique viral determinants (Figure 3). Human killer cell Ig-like receptors (KIR) are the functional counterparts of murine Ly49s (291). Rigorous epidemiological studies based on very large patient cohorts demonstrated that combinations of KIR and HLA are associated with protection against infections by several viruses, including HIV and HCV [recently reviewed by Carrington & Martin (292)]. Remarkably, the findings suggest that these genetic interactions may manifest different mechanisms of protection. During HIV infection, specific receptor-ligand pairs may convey protection by directly increasing NK cell activation (293). In the case of protection against low inoculums of HCV, specific weakly inhibitory KIR/HLA pairs may afford protection by lowering the threshold of NK cell activation (294). By analogy with mouse models of MCMV resistance, direct NK cell killing of infected cells may reduce the risk or severity of infection with human viruses.
THE OBLIVIOUS, CPG1, LPS2, AND TRIPLE D PHENOTYPES: TOLL-LIKE RECEPTOR PATHWAYS AND THE CONTROL OF VIRAL PROLIFERATION New models of host susceptibility to infection have recently been identified in largescale mouse mutagenesis projects via the use
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CD4
MHC I
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Endoplasmic reticulum Endosome Unc93b
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dsRNA ssRNA
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TLR7 CpG DNA NK
INNATE IMMUNE CELL
MyD88
Inflammatory cytokines Trif
IFN-αβ IFN-αβ STAT1
NF-κB
Mx 2'-5' OAS
STAT2
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NUCLEUS
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Viruscontaining vacuole CD8
IRF-7
R
IRF-3 STAT1
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TLR9
IFN-αβR IFN-αβ
Figure 3 Genetically identified molecular pathways activated in response to viral infections. Schematic representation of several major biochemical, physiological, and signaling pathways relevant to the response of cells of the immune system (CD4+ and CD8+ T cells, NK cells, and macrophages) against viral pathogens. Genes and proteins shown play a key role in these pathways; mutations identified by forward genetics as causing alterations in resistance to viruses are identified in red. (This figure is inspired by Reference 9.) See text for details. [Abbreviations: CpG DNA, DNA containing guanine–phosphate diester–cytosine dinucleotides; TRIF, Toll/IL-1 receptor (TIR) domain–containing adapter-inducing IFN-β; MyD88, myeloid differentiation primary response gene 88; STAT, signal transducer and activator of transcription; Mx, myxovirus resistance; 2 -5 OAS, 2 -5 -oligoadenylate synthetases; Ly49, killer cell lectin-like receptor; Jak1, Janus kinase 1; Tyk2, tyrosine kinase 2; Unc93b, unc-93 homolog B.]
of the chemical agent ENU (recently reviewed in 295). The technique can theoretically cause a mutation in any gene and is limited only by the ingenuity of the screening approach (recently reviewed in 296–298). In a typical whole-genome mutagenesis screen, inbred male mice are treated with ENU to
induce several hundred germ line mutations per mouse. The males are crossed to wildtype females of the same strain, and large cohorts of offspring are tested to identify the phenotypically distinct mice most likely to bear a large-effect mutation. ENU mutagenesis is a powerful tool to map novel www.annualreviews.org • Immunity to Infection in the Mouse
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biochemical and physiological pathways that play critical roles in host defenses against infections and aids in the establishment of new mouse models of human diseases. To explore TLR pathways, Beutler and coworkers (reviewed in 295) designed a genomewide screen for dominant and recessive ENUinduced mutations in C57BL/6 mice. In this experiment, thioglycolate-elicited peritoneal macrophages were collected from male mice, and researchers measured the TNF bioactivity of these cells in response to TLR agonists. Secondary screens of mice with unresponsive macrophages produced several new models of susceptibility to infection, including the Oblivious (299), Lps2 (300), CpG1 (301), and Triple D (3d ) (302) mutants that have been well characterized during in vivo infection. The Oblivious (Obl ) mutation causes a recessive immunodeficiency phenotype in which macrophages are insensitive to some [e.g., lipoteichoic acid, the diacylated bacterial macrophage-activating lipopeptide 2 (MALP2)] but not all (e.g., zymosan) TLR2/6-dependent microbial stimuli. Perhaps for this reason, Obl homozygous mutants are highly susceptible to Gram-positive S. aureus infections. Positional cloning of the Obl locus revealed a premature stop codon in the Cd36 gene (299). Macrophages from Obl mice have an identical phenotype to that of Cd36−/− mice, and macrophage function can be rescued by transfection of a wild-type version of Cd36, which provides convincing evidence that Cd36 is the gene responsible for the Obl phenotype (299). Unexpectedly, Obl mice permit MCMV to grow to high titers in vivo. CD36 is a member of the scavenger receptor type B family (303), previously implicated in the recognition of oxidized lowdensity lipoprotein (LDL) particles and the uptake of fatty acids (304), but unrelated to infection or TLR signaling. However, these experiments suggested that the TLR2/TLR6 complex uses CD36 as a coreceptor for some of its bacterial ligands and for a yet undefined molecule derived or elicited from MCMV.
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The Lps2 mutant phenotype causes macrophages to lose their responsiveness to TLR4 and TLR3 ligands, which indicates that Lps2 may be a common intermediary of the TLR4 and TLR3 intracellular pathways (300). Of particular importance to viral pathogenesis, Lps2 macrophages also cannot generate an LPS- or dsRNA-induced type I IFN response and are highly susceptible to infection with VSV or Vaccinia virus (300). In correlation, the Lps2 mutation abolishes the activation of the gene transcription factor IRF3. As a result, Lps2 homozygotes are markedly resistant to the lethal effect of challenge with LPS, and their immune response to MCMV is compromised, which allows high viral titers in the spleen (305). The enhanced pathogenicity to MCMV is associated with a failure to produce adequate amounts of type 1 IFN, as measured in the serum early after infection. Following positional cloning, the Lps2 mutation was found to correspond to a single base pair deletion in the Trif gene (306, 307). In vitro rescue experiments with Trif again compensated for the Lps2 phenotype, and the knockout of Trif yielded a phenotype similar to that of the Lps2 allele. The identification of Lps2 revealed the bipartite nature of LPS (which signals through MyD88 and Trif) and the role of this intracellular pathway in host resistance to virus infection (308). In parallel studies, the mouse phenotype CpG1 was first characterized by the unresponsiveness of mutant macrophages to stimulation with a synthetic analog of CpG-DNA. This PAMP is recognized by TLR9. Accordingly, sequencing of the Tlr9 coding region indicated that the genetic defect was a nucleotide substitution that resulted in a nonconservative amino acid replacement (L499P) in a well-conserved region of the protein (301). The CpG1 mutation is associated with severe susceptibility to MCMV (301), as is a targeted mutation in the TLR9 receptor (309). These and other data suggest that the signaling pathways of both TLR9, via the adapter MyD88, and TLR3, via the adapter TRIF, are activated by viral infection and
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contribute to innate defense in an additive and nonredundant manner by stimulating the production of type I IFN for activation of effector response by NK cells (295). Finally, the Triple D (3d ) mutant phenotype abrogates macrophage signaling via the RNA and DNA agonists of the intracellular receptors TLR3, TLR7, and TLR9 (302). 3d mice succumb early to a challenge with MCMV (most likely because nucleic acids are an important by-product of virus infection); however, these mice are also susceptible to other organisms such as S. aureus and L. monocytogenes (295). 3d mice are also deficient in APC activity despite normal levels of MHC class I and MHC class II antigen presenting molecules (302). Using positional cloning, researchers found that the 3d mutation introduces a single H412R substitution in the polytopic ER-resident membrane protein UNC93B. Transfection of the wild-type allele into 3d mutant mice rescues TNF production, which shows that the specific H412R mutation is responsible for the signaling defect in DCs from homozygous Unc93b mutant mice (302). The precise function of the UNC93B protein remains unknown. The mutation does not affect the stability or localization of the protein but rather abolishes the interaction between UNC93B and the transmembrane domain of TLR3 and TLR9 (310), which suggests that this physical association is crucial for TLR signaling. A notable human study by Casanova and colleagues (311) linked a mutation in UNC93B to the etiology of herpes simplex encephalitis (HSE). Cells isolated from an HSE patient presented a selective lack of response to TLR7, -8, and -9 agonists, similar to the response of cells obtained from 3d mutant mice. In addition, the production of type 1 IFNs was selectively impaired in the patient’s cells in response to stimulation with several viruses. Pedigree analysis and candidate gene sequencing associated the phenotype with a homozygous four-nucleotide deletion that introduces a premature stop codon in the UNC93B1 cDNA. Moreover, transfection
of wild-type cDNA into these cells complements cytokine secretion in the patient’s cells, which indicates that UNC93B deficiency is the predisposing factor to HSE in this family. Remarkably, the addition of recombinant IFN prior to viral infection fully complements the cellular phenotype of UNC93B mutant cells, which suggests that IFN could be a possible treatment in certain HSE patients. These studies provided the first description of the genetic etiology of HSE and validated the applicability of a chemical-mutagenesis approach to identify mechanisms of human susceptibility to infection.
DOMINO AND JINX: IN VIVO DISSECTION OF HOST RESISTANCE AGAINST MOUSE CYTOMEGALOVIRUS Beutler and colleagues (312) initiated a genome-wide screen of mice derived from ENU-progenitors for host susceptibility to infection against MCMV. In this experiment, mice were challenged with MCMV and observed for severe levels of morbidity or high viral counts in the spleen. Out of approximately 11,300 mutant mice derived from ENU-progenitors, they found 11 transmissible mutations (312), of which the Domino (313) and Jinx (314) mutant phenotypes were recently characterized. The Domino mutation manifests as a severe recessive phenotype that is associated with high MCMV load and mortality by day four postinfection (313). In addition, the in vivo response to L. monocytogenes and macrophage growth of VSV are also impaired (315). This latter phenotype is not corrected by administration of type I IFN. Candidate gene sequencing and in vivo crosses with Stat−/− mice demonstrated that Domino corresponds to a point mutation that alters the binding domain of STAT1, abolishing its activation (313). The study of the Jinx phenotype led to new insights into the pathogenesis of CMV infection (314). Despite high viral load in the spleen, Jinx mutants show robust cytokine www.annualreviews.org • Immunity to Infection in the Mouse
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production, which indicates adequate sensing of the infection. Detailed phenotypic characterization of Jinx mice showed defects in NK cell and cytotoxic T lymphocyte (CTL) granule exocytosis, which are specific to viral infection. Through mapping and sequencing, investigators attributed viral susceptibility to the creation of a novel donor splice site in Unc13d. This change is predicted to introduce a premature stop codon, thus eliminating one of the two Ca2+ binding domains of the 1085 amino acid protein (314). The precise function of the UNC13-D protein remains undefined, although it is required for the fusion competence of cytoplasmic vesicles only in certain immune cells (316). UNC13D is conserved throughout evolution from C. elegans to humans (317). Remarkably, mutations in the human ortholog MUNC13-4 cause type 3 familial hemophagocytic lymphohistiocytosis (FHL3), a severe disease characterized by hepatosplenomegaly, anemia, and thrombocytopenia (318). However, FHL3 may require either a virus or bacteria as an infectious trigger for expression of the phenotype (319). Likewise, Jinx mice do not present hepatosplenomegaly in the absence of infection. However, hemophagocytic lymphohistiocytosis (HLH) can be induced by at least one virus, the arenavirus lymphocytic choriomeningitis virus (LCMV), which confirms that UNC13-D is responsible for the Jinx phenotype (314). MUNC134/UNC13-D belongs to a large family of paralogous proteins, of which the closest relatives (MUNC13-1 to MUNC13-4) are expressed in the brain (320), where they serve partially redundant functions in the priming of synaptic vesicles (321, 322). This is clearly not the case for UNC13-D, whose role in NK function seems unique, and can now be explored in the Jinx model.
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CONCLUSIONS AND FUTURE PERSPECTIVES Over the past 75 years, the laboratory mouse has been the animal model of choice to study 114
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many aspects of host defenses against infections, which has led to numerous seminal discoveries. These discoveries include the major histocompatibility locus (and the concept of self-recognition), the presence of discrete cell populations such as macrophages, DCs, and lymphocytes responsible for early antigen recognition, the orchestration of the adaptive immune response, and the resulting long-term protection against reinfecting pathogens. With the advent of laboratoryinbred mouse strains some 50 years ago, scientists began readily to report reproducible differences in the responses of different mouse stocks to different types of infections, and the field of immunogenetics was born. Early segregation studies revealed that some of these strain-specific differences in susceptibility are inherited as monogenic traits, and scientists were prompt to realize that identification of the gene involved may yield important insight into the mechanisms by which the host recognizes, interacts with, and ultimately eliminates infectious agents. However, the absence of adequate mapping tools, including a paucity of genetic markers, the resulting frail genetic map, and the lack of DNA analysis methods rendered the task of going from a chromosomal localization to identification of the gene and protein involved largely impossible. The advent of interspecific mouse crosses, simple sequence length polymorphisms (dinucleotide repeats), fluorescence in situ hybridization, long-range physical mapping by pulsed-field gel electrophoresis, large insert libraries in artificial yeast and bacterial chromosomes, exon amplification, and efficient DNA sequencing technologies gave birth to the field of genomics 20 years ago. The years that followed saw the positional cloning of some of the oldest and best known so-called host-resistance loci, such as Mx (p47GTPase), Ity/Lsh/Bcg (Nramp1), Lps (Tlr4), Cmv1 (Ly49h) and several others covered in this review. Some of these discoveries had a dramatic impact on our understanding of host:pathogen interactions and shed considerable light on the critical early steps of
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this interaction. In particular, the discovery of LRRs as modular structures for the recognition of PAMPs and the critical role of LRRcontaining proteins (including the TLR and NLR families) uncovered a previously unknown pathway for extracellular and intracellular antigen recognition by macrophages and other cells. The next wave of innovation came in the form of a complete draft of the whole genome, an annotated transcript map together with powerful technologies such as high-throughput DNA sequencing and genotyping, and microarrays for whole-genome transcript profiling. These technologies have greatly facilitated the process of positional cloning, which has now become a fairly routine, albeit still laborious, endeavor, and have led to the discoveries of many other genes and
proteins important for the antimicrobial arsenal of the mammalian host. What is next? These new high-throughput technologies have opened the door to a more systematic sampling of the genetic diversity of inbred mouse stocks for differential response to infectious stimuli. Expanded genetic diversity may come not only from commercially available inbred mouse strains (Mouse Phenome Project), but also more importantly from ENU-mutagenized mouse stocks with the long-term potential to test the contribution of every gene in the genome to host response to infections. Although this is an enormous endeavor, several such large screens are currently underway. These screens will no doubt generate a wealth of additional information in this key area of immunology.
DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.
LITERATURE CITED 1. Corbett EL, Steketee RW, ter Kuile FO, Latif AS, Kamali A, Hayes RJ. 2002. HIV1/AIDS and the control of other infectious diseases in Africa. Lancet 359:2177–87 2. Hill AV. 2006. Aspects of genetic susceptibility to human infectious diseases. Annu. Rev. Genet. 40:469–86 3. Clementi M, Di Gianantonio E. 2006. Genetic susceptibility to infectious diseases. Reprod. Toxicol. 21:345–49 4. Lederman MM, Penn-Nicholson A, Cho M, Mosier D. 2006. Biology of CCR5 and its role in HIV infection and treatment. JAMA 296:815–26 5. Min-Oo G, Gros P. 2005. Erythrocyte variants and the nature of their malaria protective effect. Cell. Microbiol. 7:753–63 6. Casanova JL, Abel L. 2007. Human genetics of infectious diseases: a unified theory. EMBO J. 26:915–22 7. Casanova JL, Abel L. 2004. Human mannose-binding lectin in immunity: friend, foe, or both? J. Exp. Med. 199:1295–99 8. Buer J, Balling R. 2003. Mice, microbes and models of infection. Nat. Rev. Genet. 4:195– 205 9. Kielczewska A, Vidal SM. 2006. Enemy at the gates: forward genetics of the mouse antiviral response. Curr. Opin. Immunol. 18:617–26 10. Lipoldova M, Demant P. 2006. Genetic susceptibility to infectious disease: lessons from mouse models of leishmaniasis. Nat. Rev. Genet. 7:294–305 11. Tuite A, Gros P. 2006. The impact of genomics on the analysis of host resistance to infectious disease. Microbes Infect. 8:1647–53 www.annualreviews.org • Immunity to Infection in the Mouse
115
ARI
16 February 2008
11:22
12. Amer AO, Swanson MS. 2002. A phagosome of one’s own: a microbial guide to life in the macrophage. Curr. Opin. Microbiol. 5:56–61 13. Bogdan C, Rollinghoff M. 1999. How do protozoan parasites survive inside macrophages? Parasitol. Today 15:22–28 14. Rosenberger CM, Finlay BB. 2003. Phagocyte sabotage: disruption of macrophage signalling by bacterial pathogens. Nat. Rev. Mol. Cell Biol. 4:385–96 15. Russell DG. 2001. Mycobacterium tuberculosis: here today, and here tomorrow. Nat. Rev. Mol. Cell Biol. 2:569–77 16. Skamene E, Schurr E, Gros P. 1998. Infection genomics: Nramp1 as a major determinant of natural resistance to intracellular infections. Annu. Rev. Med. 49:275–87 17. Forbes JR, Gros P. 2001. Divalent-metal transport by NRAMP proteins at the interface of host-pathogen interactions. Trends Microbiol. 9:397–403 18. O’Brien AD, Rosenstreich DL, Taylor BA. 1980. Control of natural resistance to Salmonella typhimurium and Leishmania donovani in mice by closely linked but distinct genetic loci. Nature 287:440–42 19. Skamene E, Gros P, Forget A, Kongshavn PA, St Charles C, Taylor BA. 1982. Genetic regulation of resistance to intracellular pathogens. Nature 297:506–9 20. Vidal SM, Malo D, Vogan K, Skamene E, Gros P. 1993. Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell 73:469–85 21. Vidal SM, Pinner E, Lepage P, Gauthier S, Gros P. 1996. Natural resistance to intracellular infections: Nramp1 encodes a membrane phosphoglycoprotein absent in macrophages from susceptible (Nramp1 D169) mouse strains. J. Immunol. 157:3559–68 22. Vidal S, Tremblay ML, Govoni G, Gauthier S, Sebastiani G, et al. 1995. The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene. J. Exp. Med. 182:655–66 23. Govoni G, Vidal S, Gauthier S, Skamene E, Malo D, Gros P. 1996. The Bcg/Ity/Lsh locus: genetic transfer of resistance to infections in C57BL/6J mice transgenic for the Nramp1Gly169 allele. Infect. Immun. 64:2923–29 24. Poon A, Schurr E. 2004. The NRAMP genes and human susceptibility to common diseases. In The NRAMP Family, ed. M Cellier, P Gros, pp. 29–43. New York: Kluwer Acad./Plenum 25. Li HT, Zhang TT, Zhou YQ, Huang QH, Huang J. 2006. SLC11A1 (formerly NRAMP1) gene polymorphisms and tuberculosis susceptibility: a meta-analysis. Int. J. Tuberc. Lung Dis. 10:3–12 26. Greenwood CM, Fujiwara TM, Boothroyd LJ, Miller MA, Frappier D, et al. 2000. Linkage of tuberculosis to chromosome 2q35 loci, including NRAMP1, in a large aboriginal Canadian family. Am. J. Hum. Genet. 67:405–16 27. Malik S, Abel L, Tooker H, Poon A, Simkin L, et al. 2005. Alleles of the NRAMP1 gene are risk factors for pediatric tuberculosis disease. Proc. Natl. Acad. Sci. USA 102:12183–88 28. Abel L, Sanchez FO, Oberti J, Thuc NV, Hoa LV, et al. 1998. Susceptibility to leprosy is linked to the human NRAMP1 gene. J. Infect. Dis. 177:133–45 29. Alcais A, Sanchez FO, Thuc NV, Lap VD, Oberti J, et al. 2000. Granulomatous reaction to intradermal injection of lepromin (Mitsuda reaction) is linked to the human NRAMP1 gene in Vietnamese leprosy sibships. J. Infect. Dis. 181:302–8 30. Stienstra Y, van der Werf TS, Oosterom E, Nolte IM, van der Graaf WT, et al. 2006. Susceptibility to Buruli ulcer is associated with the SLC11A1 (NRAMP1) D543N polymorphism. Genes Immun. 7:185–89
Annu. Rev. Immunol. 2008.26:81-132. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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ANRV338-IY26-04
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11:22
31. Canonne-Hergaux F, Calafat J, Richer E, Cellier M, Grinstein S, et al. 2002. Expression and subcellular localization of NRAMP1 in human neutrophil granules. Blood 100:268– 75 32. Gruenheid S, Pinner E, Desjardins M, Gros P. 1997. Natural resistance to infection with intracellular pathogens: the Nramp1 protein is recruited to the membrane of the phagosome. J. Exp. Med. 185:717–30 33. Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, et al. 1997. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388:482–88 34. Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC. 1998. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc. Natl. Acad. Sci. USA 95:1148–53 35. Lam-Yuk-Tseung S, Camaschella C, Iolascon A, Gros P. 2006. A novel R416C mutation in human DMT1 (SLC11A2) displays pleiotropic effects on function and causes microcytic anemia and hepatic iron overload. Blood Cells Mol. Dis. 36:347–54 36. Fleming MD, Trenor CC 3rd, Su MA, Foernzler D, Beier DR, et al. 1997. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat. Genet. 16:383–86 37. Forbes JR, Gros P. 2003. Iron, manganese, and cobalt transport by Nramp1 (Slc11a1) and Nramp2 (Slc11a2) expressed at the plasma membrane. Blood 102:1884–92 38. Jabado N, Jankowski A, Dougaparsad S, Picard V, Grinstein S, Gros P. 2000. Natural resistance to intracellular infections: natural resistance-associated macrophage protein 1 (Nramp1) functions as a pH-dependent manganese transporter at the phagosomal membrane. J. Exp. Med. 192:1237–48 39. Hackam DJ, Rotstein OD, Zhang W, Gruenheid S, Gros P, Grinstein S. 1998. Host resistance to intracellular infection: mutation of natural resistance-associated macrophage protein 1 (Nramp1) impairs phagosomal acidification. J. Exp. Med. 188:351–64 40. Frehel C, Canonne-Hergaux F, Gros P, De Chastellier C. 2002. Effect of Nramp1 on bacterial replication and on maturation of Mycobacterium avium-containing phagosomes in bone marrow-derived mouse macrophages. Cell. Microbiol. 4:541–56 41. Cuellar-Mata P, Jabado N, Liu J, Furuya W, Finlay BB, et al. 2002. Nramp1 modifies the fusion of Salmonella typhimurium-containing vacuoles with cellular endomembranes in macrophages. J. Biol. Chem. 277:2258–65 42. Jabado N, Cuellar-Mata P, Grinstein S, Gros P. 2003. Iron chelators modulate the fusogenic properties of Salmonella-containing phagosomes. Proc. Natl. Acad. Sci. USA 100:6127–32 43. Zaharik ML, Vallance BA, Puente JL, Gros P, Finlay BB. 2002. Host-pathogen interactions: Host resistance factor Nramp1 up-regulates the expression of Salmonella pathogenicity island-2 virulence genes. Proc. Natl. Acad. Sci. USA 99:15705–10 44. Nairz M, Theurl I, Ludwiczek S, Theurl M, Mair SM, et al. 2007. The co-ordinated regulation of iron homeostasis in murine macrophages limits the availability of iron for intracellular Salmonella typhimurium. Cell. Microbiol. 9:2126–40 45. Boyer E, Bergevin I, Malo D, Gros P, Cellier MF. 2002. Acquisition of Mn(II) in addition to Fe(II) is required for full virulence of Salmonella enterica aerovar typhimurium. Infect. Immun. 70:6032–42 46. Kehres DG, Janakiraman A, Slauch JM, Maguire ME. 2002. SitABCD is the alkaline Mn2+ transporter of Salmonella enterica serovar Typhimurium. J. Bacteriol. 184:3159– 66 www.annualreviews.org • Immunity to Infection in the Mouse
117
ARI
16 February 2008
11:22
47. Huynh C, Sacks DL, Andrews NW. 2006. A Leishmania amazonensis ZIP family iron transporter is essential for parasite replication within macrophage phagolysosomes. J. Exp. Med. 203:2363–75 48. Kariuki S, Revathi G, Kariuki N, Muyodi J, Mwituria J, et al. 2005. Increasing prevalence of multidrug-resistant nontyphoidal salmonellae, Kenya, 1994–2003. Int. J. Antimicrob. Agents 25:38–43 49. Wong WY. 2001. Prevention and management of infection in children with sickle cell anaemia. Paediatr. Drugs 3:793–801 50. Mouy R, Fischer A, Vilmer E, Seger R, Griscelli C. 1989. Incidence, severity, and prevention of infections in chronic granulomatous disease. J. Pediatr. 114:555–60 51. Graham SM, Hart CA, Molyneux EM, Walsh AL, Molyneux ME. 2000. Malaria and Salmonella infections: cause or coincidence? Trans. R. Soc. Trop. Med. Hyg. 94:227 52. Casanova JL, Abel L. 2004. The human model: a genetic dissection of immunity to infection in natural conditions. Nat. Rev. Immunol. 4:55–66 53. Mastroeni P. 2006. Mechanisms of immunity to Salmonella infection. In Salmonella Infections: Clinical, Immunological and Molecular Aspects, ed. P Mastroeni, D Maskell, pp. 17–36. Cambridge, UK: Cambridge Univ. Press 54. Barthel M, Hapfelmeier S, Quintanilla-Martinez L, Kremer M, Rohde M, et al. 2003. Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host. Infect. Immun. 71:2839–58 55. Caron J, Loredo-Osti JC, Laroche L, Skamene E, Morgane K, Malo D. 2002. Identification of genetic loci controlling bacterial clearance in experimental Salmonella enteritidis infection: an unexpected role of Nramp 1 (Slc11a1) in the persistence of infection in mice. Genes Immun. 3:196–204 56. Monack DM, Bouley DM, Falkow S. 2004. Salmonella typhimurium persists within macrophages in the mesenteric lymph nodes of chronically infected Nramp1+/+ mice and can be reactivated by IFNγ neutralization. J. Exp. Med. 199:231–41 57. Sukupolvi S, Edelstein A, Rhen M, Normark SJ, Pfeifer JD. 1997. Development of a murine model of chronic Salmonella infection. Infect. Immun. 65:838–42 58. Roy MF, Malo D. 2002. Genetic regulation of host responses to Salmonella infection in mice. Genes Immun. 3:381–93 59. O’Brien AD, Rosenstreich DL, Scher I, Campbell GH, MacDermott RP, Formal SB. 1980. Genetic control of susceptibility to Salmonella typhimurium in mice: role of the LPS gene. J. Immunol. 124:20–24 60. O’Brien AD, Scher I, Campbell GH, MacDermott RP, Formal SB. 1979. Susceptibility of CBA/N mice to infection with Salmonella typhimurium: influence of the X-linked gene controlling B lymphocyte function. J. Immunol. 123:720–24 61. Plant J, Glynn AA. 1976. Genetics of resistance to infection with Salmonella typhimurium in mice. J. Infect. Dis. 133:72–78 62. Roy MF, Riendeau N, Loredo-Osti JC, Malo D. 2006. Complexity in the host response to Salmonella Typhimurium infection in AcB and BcA recombinant congenic strains. Genes Immun. 7:655–66 63. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, et al. 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–88 64. Qureshi ST, Lariviere L, Leveque G, Clermont S, Moore KJ, et al. 1999. Endotoxintolerant mice have mutations in Toll-like receptor 4 (Tlr4). J. Exp. Med. 189:615–25
Annu. Rev. Immunol. 2008.26:81-132. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-04
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Vidal et al.
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ANRV338-IY26-04
ARI
16 February 2008
11:22
65. Rawlings DJ, Saffran DC, Tsukada S, Largaespada DA, Grimaldi JC, et al. 1993. Mutation of unique region of Bruton’s tyrosine kinase in immunodeficient XID mice. Science 261:358–61 66. Thomas JD, Sideras P, Smith CI, Vorechovsky I, Chapman V, Paul WE. 1993. Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes. Science 261:355–58 67. Bihl F, Salez L, Beaubier M, Torres D, Lariviere L, et al. 2003. Overexpression of Tolllike receptor 4 amplifies the host response to lipopolysaccharide and provides a survival advantage in transgenic mice. J. Immunol. 170:6141–50 68. Roy MF, Lariviere L, Wilkinson R, Tam M, Stevenson MM, Malo D. 2006. Incremental expression of Tlr4 correlates with mouse resistance to Salmonella infection and fine regulation of relevant immune genes. Genes Immun. 7:372–83 69. Robson HG, Vas SI. 1972. Resistance of inbred mice to Salmonella typhimurium. J. Infect. Dis. 126:378–86 70. Qureshi ST, Lariviere L, Sebastiani G, Clermont S, Skamene E, et al. 1996. A highresolution map in the chromosomal region surrounding the Lps locus. Genomics 31:283– 94 71. Sultzer BM. 1968. Genetic control of leucocyte responses to endotoxin. Nature 219:1253–54 72. Watson J, Kelly K, Largen M, Taylor BA. 1978. The genetic mapping of a defective LPS response gene in C3H/HeJ mice. J. Immunol. 120:422–24 73. Coutinho A, Forni L, Melchers F, Watanabe T. 1977. Genetic defect in responsiveness to the B cell mitogen lipopolysaccharide. Eur. J. Immunol. 7:325–28 74. Bihl F, Lariviere L, Qureshi ST, Flaherty L, Malo D. 2001. LPS-hyporesponsiveness of mnd mice is associated with a mutation in Toll-like receptor 4. Genes Immun. 2:56–59 75. Qureshi ST, Gros P, Malo D. 1999. The Lps locus: genetic regulation of host responses to bacterial lipopolysaccharide. Inflamm. Res. 48:613–20 76. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. 1997. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–97 77. Poltorak A, Smirnova I, Clisch R, Beutler B. 2000. Limits of a deletion spanning Tlr4 in C57BL/10ScCr mice. J. Endotoxin Res. 6:51–56 78. Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, et al. 1999. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. 162:3749–52 79. Kalis C, Kanzler B, Lembo A, Poltorak A, Galanos C, Freudenberg MA. 2003. Toll-like receptor 4 expression levels determine the degree of LPS-susceptibility in mice. Eur. J. Immunol. 33:798–805 80. Akira S, Uematsu S, Takeuchi O. 2006. Pathogen recognition and innate immunity. Cell 124:783–801 81. Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R. 2001. Toll-like receptors control activation of adaptive immune responses. Nat. Immunol. 2:947–50 82. Miller SI, Ernst RK, Bader MW. 2005. LPS, TLR4 and infectious disease diversity. Nat. Rev. Microbiol. 3:36–46 83. Verstak B, Hertzog P, Mansell A. 2007. Toll-like receptor signalling and the clinical benefits that lie within. Inflamm. Res. 56:1–10 84. Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, et al. 2000. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat. Genet. 25:187–91 www.annualreviews.org • Immunity to Infection in the Mouse
119
ARI
16 February 2008
11:22
85. Agnese DM, Calvano JE, Hahm SJ, Coyle SM, Corbett SA, et al. 2002. Human Toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J. Infect. Dis. 186:1522–25 86. Lorenz E, Mira JP, Frees KL, Schwartz DA. 2002. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch. Intern. Med. 162:1028–32 87. Smirnova I, Mann N, Dols A, Derkx HH, Hibberd ML, et al. 2003. Assay of locusspecific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc. Natl. Acad. Sci. USA 100:6075–80 88. Child NJ, Yang IA, Pulletz MC, de Courcy-Golder K, Andrews AL, et al. 2003. Polymorphisms in Toll-like receptor 4 and the systemic inflammatory response syndrome. Biochem. Soc. Trans. 31:652–53 89. Mockenhaupt FP, Cramer JP, Hamann L, Stegemann MS, Eckert J, et al. 2006. Toll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria. J. Commun. Dis. 38:230–45 90. Rezazadeh M, Hajilooi M, Rafiei A, Haidari M, Nikoopour E, et al. 2006. TLR4 polymorphism in Iranian patients with brucellosis. J. Infect. 53:206–10 91. Tal G, Mandelberg A, Dalal I, Cesar K, Somekh E, et al. 2004. Association between common Toll-like receptor 4 mutations and severe respiratory syncytial virus disease. J. Infect. Dis. 189:2057–63 92. Hawn TR, Verbon A, Janer M, Zhao LP, Beutler B, Aderem A. 2005. Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires’ disease. Proc. Natl. Acad. Sci. USA 102:2487–89 93. Trinchieri G, Sher A. 2007. Cooperation of Toll-like receptor signals in innate immune defence. Nat. Rev. Immunol. 7:179–90 94. Ben-Ali M, Barbouche MR, Bousnina S, Chabbou A, Dellagi K. 2004. Toll-like receptor 2 Arg677Trp polymorphism is associated with susceptibility to tuberculosis in Tunisian patients. Clin. Diagn. Lab. Immunol. 11:625–26 95. Bochud PY, Hawn TR, Aderem A. 2003. Cutting edge: a Toll-like receptor 2 polymorphism that is associated with lepromatous leprosy is unable to mediate mycobacterial signaling. J. Immunol. 170:3451–54 96. Kang TJ, Chae GT. 2001. Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunol. Med. Microbiol. 31:53–58 97. Hawn TR, Verbon A, Lettinga KD, Zhao LP, Li SS, et al. 2003. A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to Legionnaires’ disease. J. Exp. Med. 198:1563–72 98. Wicker LS, Scher I. 1986. X-linked immune deficiency (xid) of CBA/N mice. Curr. Top. Microbiol. Immunol. 124:87–101 99. O’Brien AD, Scher I, Metcalf ES. 1981. Genetically conferred defect in anti-Salmonella antibody formation renders CBA/N mice innately susceptible to Salmonella typhimurium infection. J. Immunol. 126:1368–72 100. Conley ME, Broides A, Hernandez-Trujillo V, Howard V, Kanegane H, et al. 2005. Genetic analysis of patients with defects in early B-cell development. Immunol. Rev. 203:216–34 101. Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, et al. 1993. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 361:226–33 102. Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, et al. 1993. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 72:279–90
Annu. Rev. Immunol. 2008.26:81-132. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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120
Vidal et al.
Annu. Rev. Immunol. 2008.26:81-132. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-04
ARI
16 February 2008
11:22
103. Ellmeier W, Jung S, Sunshine MJ, Hatam F, Xu Y, et al. 2000. Severe B cell deficiency in mice lacking the tec kinase family members Tec and Btk. J. Exp. Med. 192:1611–24 104. Smith CI, Baskin B, Humire-Greiff P, Zhou JN, Olsson PG, et al. 1994. Expression of Bruton’s agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. J. Immunol. 152:557–65 105. Lindvall JM, Blomberg KE, Valiaho J, Vargas L, Heinonen JE, et al. 2005. Bruton’s tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling. Immunol. Rev. 203:200–15 106. Fruman DA, Satterthwaite AB, Witte ON. 2000. Xid-like phenotypes: a B cell signalosome takes shape. Immunity 13:1–3 107. Bajpai UD, Zhang K, Teutsch M, Sen R, Wortis HH. 2000. Bruton’s tyrosine kinase links the B cell receptor to nuclear factor κB activation. J. Exp. Med. 191:1735–44 108. Doyle SL, Jefferies CA, O’Neill LA. 2005. Bruton’s tyrosine kinase is involved in p65mediated transactivation and phosphorylation of p65 on serine 536 during NFκB activation by lipopolysaccharide. J. Biol. Chem. 280:23496–501 109. Gray P, Dunne A, Brikos C, Jefferies CA, Doyle SL, O’Neill LA. 2006. MyD88 adapterlike (Mal) is phosphorylated by Bruton’s tyrosine kinase during TLR2 and TLR4 signal transduction. J. Biol. Chem. 281:10489–95 110. Mansell A, Smith R, Doyle SL, Gray P, Fenner JE, et al. 2006. Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat. Immunol. 7:148–55 111. Kang SW, Wahl MI, Chu J, Kitaura J, Kawakami Y, et al. 2001. PKCβ modulates antigen receptor signaling via regulation of Btk membrane localization. EMBO J. 20:5692–702 112. Tilney LG, Harb OS, Connelly PS, Robinson CG, Roy CR. 2001. How the parasitic bacterium Legionella pneumophila modifies its phagosome and transforms it into rough ER: implications for conversion of plasma membrane to the ER membrane. J. Cell Sci. 114:4637–50 113. Fortier A, Diez E, Gros P. 2005. Naip5/Birc1e and susceptibility to Legionella pneumophila. Trends Microbiol. 13:328–35 114. Diez E, Lee SH, Gauthier S, Yaraghi Z, Tremblay M, et al. 2003. Birc1e is the gene within the Lgn1 locus associated with resistance to Legionella pneumophila. Nat. Genet. 33:55–60 115. Wright EK, Goodart SA, Growney JD, Hadinoto V, Endrizzi MG, et al. 2003. Naip5 affects host susceptibility to the intracellular pathogen Legionella pneumophila. Curr. Biol. 13:27–36 116. Maier JK, Lahoua Z, Gendron NH, Fetni R, Johnston A, et al. 2002. The neuronal apoptosis inhibitory protein is a direct inhibitor of caspases 3 and 7. J. Neurosci. 22:2035– 43 ˜ G. 2005. NOD-LRR proteins: role 117. Inohara N, Chamaillard M, McDonald C, Nunez in host-microbial interactions and inflammatory disease. Annu. Rev. Biochem. 74:355–83 118. Fritz JH, Ferrero RL, Philpott DJ, Girardin SE. 2006. Nod-like proteins in immunity, inflammation and disease. Nat. Immunol. 7:1250–57 119. Zamboni DS, Kobayashi KS, Kohlsdorf T, Ogura Y, Long EM, et al. 2006. The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat. Immunol. 7:318–25 ˜ 120. Lamkanfi M, Amer A, Kanneganti TD, Munoz-Planillo R, Chen G, et al. 2007. The Nod-like receptor family member Naip5/Birc1e restricts Legionella pneumophila growth independently of caspase-1 activation. J. Immunol. 178:8022–27 www.annualreviews.org • Immunity to Infection in the Mouse
121
ARI
16 February 2008
11:22
121. Molofsky AB, Byrne BG, Whitfield NN, Madigan CA, Fuse ET, et al. 2006. Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection. J. Exp. Med. 203:1093–104 122. Ren T, Zamboni DS, Roy CR, Dietrich WF, Vance RE. 2006. Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity. PLoS Pathog. 2:e18 123. Fortier A, de Chastellier C, Balor S, Gros P. 2007. Birc1e/Naip5 rapidly antagonizes modulation of phagosome maturation by Legionella pneumophila. Cell. Microbiol. 9:910– 23 124. Friedlander AM, Bhatnagar R, Leppla SH, Johnson L, Singh Y. 1993. Characterization of macrophage sensitivity and resistance to anthrax lethal toxin. Infect. Immun. 61:245–52 125. Watters JW, Dietrich WF. 2001. Genetic, physical, and transcript map of the Ltxs1 region of mouse chromosome 11. Genomics 73:223–31 126. Roberts JE, Watters JW, Ballard JD, Dietrich WF. 1998. Ltx1, a mouse locus that influences the susceptibility of macrophages to cytolysis caused by intoxication with Bacillus anthracis lethal factor, maps to chromosome 11. Mol. Microbiol. 29:581–91 127. Watters JW, Dewar K, Lehoczky J, Boyartchuk V, Dietrich WF. 2001. Kif1C, a kinesinlike motor protein, mediates mouse macrophage resistance to anthrax lethal factor. Curr. Biol. 11:1503–11 128. Boyden ED, Dietrich WF. 2006. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat. Genet. 38:240–44 129. Turcotte K, Loredo-Osti JC, Fortin P, Schurr E, Morgan K, Gros P. 2006. Complex genetic control of susceptibility to Mycobacterium bovis (Bacille Calmette-Guerin) infection in wild-derived Mus spretus mice. Genes. Immun. 7:684–87 130. Turcotte K, Gauthier S, Mitsos LM, Shustik C, Copeland NG, et al. 2004. Genetic control of myeloproliferation in BXH-2 mice. Blood 103:2343–50 131. Bedigian HG, Johnson DA, Jenkins NA, Copeland NG, Evans R. 1984. Spontaneous and induced leukemias of myeloid origin in recombinant inbred BXH mice. J. Virol. 51:586–94 132. Bedigian HG, Taylor BA, Meier H. 1981. Expression of murine leukemia viruses in the highly lymphomatous BXH-2 recombinant inbred mouse strain. J. Virol. 39:632–40 133. Li J, Shen H, Himmel KL, Dupuy AJ, Largaespada DA, et al. 1999. Leukaemia disease genes: large-scale cloning and pathway predictions. Nat. Genet. 23:348–53 134. Turcotte K, Gauthier S, Tuite A, Mullick A, Malo D, Gros P. 2005. A mutation in the Icsbp1 gene causes susceptibility to infection and a chronic myeloid leukemia-like syndrome in BXH-2 mice. J. Exp. Med. 201:881–90 135. Turcotte K, Gauthier S, Malo D, Tam M, Stevenson MM, Gros P. 2007. Icsbp1/IRF-8 is required for innate and adaptive immune responses against intracellular pathogens. J. Immunol. 179:2467–76 136. WHO. 2000. The World Health Report 2000: Health Systems Improving Performance. Geneva: WHO 137. WHO. 2002. The World Health Report 2002: Global Tuberculosis Control: Surveillance, Planning, Financing. Geneva: WHO 138. Fortin A, Abel L, Casanova JL, Gros P. 2007. Host genetics of Mycobacterial diseases in mice and men: Forward genetic studies of BCG-osis and tuberculosis. Annu. Rev. Genomics Hum. Genet. 8:163–92 139. Pan H, Yan BS, Rojas M, Shebzukhov YV, Zhou H, et al. 2005. Ipr1 gene mediates innate immunity to tuberculosis. Nature 434:767–72
Annu. Rev. Immunol. 2008.26:81-132. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-04
122
Vidal et al.
Annu. Rev. Immunol. 2008.26:81-132. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-04
ARI
16 February 2008
11:22
140. Kaufmann SH. 2003. Immune response to tuberculosis: experimental animal models. Tuberculosis 83:107–11 141. Kaufmann SH. 2001. How can immunology contribute to the control of tuberculosis? Nat. Rev. Immunol. 1:20–30 142. North RJ, Jung YJ. 2004. Immunity to tuberculosis. Annu. Rev. Immunol. 22:599–623 143. Medina E, North RJ. 1998. Resistance ranking of some common inbred mouse strains to Mycobacterium tuberculosis and relationship to major histocompatibility complex haplotype and Nramp1 genotype. Immunology 93:270–74 144. Kramnik I, Dietrich WF, Demant P, Bloom BR. 2000. Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA 97:8560–65 145. Boyartchuk V, Rojas M, Yan BS, Jobe O, Hurt N, et al. 2004. The host resistance locus sst1 controls innate immunity to Listeria monocytogenes infection in immunodeficient mice. J. Immunol. 173:5112–20 146. Nicewonger J, Suck G, Bloch D, Swaminathan S. 2004. Epstein-Barr virus (EBV) SM protein induces and recruits cellular Sp110b to stabilize mRNAs and enhance EBV lytic gene expression. J. Virol. 78:9412–22 147. Roscioli T, Cliffe ST, Bloch DB, Bell CG, Mullan G, et al. 2006. Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and hepatic veno-occlusive disease. Nat. Genet. 38:620–22 148. Tosh K, Campbell SJ, Fielding K, Sillah J, Bah B, et al. 2006. Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa. Proc. Natl. Acad. Sci. USA 103:10364–68 149. Thye T, Browne EN, Chinbuah MA, Gyapong J, Osei I, et al. 2006. No associations of human pulmonary tuberculosis with Sp110 variants. J. Med. Genet. 43:e32 150. Szeszko JS, Healy B, Stevens H, Balabanova Y, Drobniewski F, et al. 2007. Resequencing and association analysis of the SP110 gene in adult pulmonary tuberculosis. Hum. Genet. 121:155–60 151. Babb C, Keet EH, van Helden PD, Hoal EG. 2007. SP110 polymorphisms are not associated with pulmonary tuberculosis in a South African population. Hum. Genet. 121:521–22 152. Kullberg BJ, Filler SG. 2002. Candidemia. In Candida and Candidiasis, ed. RA Calderone, pp. 327–40. Washington, DC: ASM Press 153. Eggimann P, Garbino J, Pittet D. 2003. Epidemiology of Candida species infections in critically ill nonimmunosuppressed patients. Lancet Infect. Dis. 3:685–702 154. Ashman RB. 1998. Candida albicans: pathogenesis, immunity and host defence. Res. Immunol. 149:281–88 155. Ashman RB, Fulurija A, Papadimitriou JM. 1996. Strain-dependent differences in host response to Candida albicans infection in mice are related to organ susceptibility and infectious load. Infect. Immun. 64:1866–69 156. Tuite A, Mullick A, Gros P. 2004. Genetic analysis of innate immunity in resistance to Candida albicans. Genes Immun. 5:576–87 157. Tuite A, Elias M, Picard S, Mullick A, Gros P. 2005. Genetic control of susceptibility to Candida albicans in susceptible A/J and resistant C57BL/6J mice. Genes Immun. 6:672–82 158. Wetsel RA, Fleischer DT, Haviland DL. 1990. Deficiency of the murine fifth complement component (C5). A 2-base pair gene deletion in a 5 -exon. J. Biol. Chem. 265:2435– 40 www.annualreviews.org • Immunity to Infection in the Mouse
123
ARI
16 February 2008
11:22
159. Mullick A, Elias M, Picard S, Bourget L, Jovcevski O, et al. 2004. Dysregulated inflammatory response to Candida albicans in a C5-deficient mouse strain. Infect. Immun. 72:5868–76 160. Mullick A, Leon Z, Min-Oo G, Berghout J, Lo R, et al. 2006. Cardiac failure in C5deficient A/J mice after Candida albicans infection. Infect. Immun. 74:4439–51 161. Gervais F, Stevenson M, Skamene E. 1984. Genetic control of resistance to Listeria monocytogenes: regulation of leukocyte inflammatory responses by the Hc locus. J. Immunol. 132:2078–83 162. Gervais F, Desforges C, Skamene E. 1989. The C5-sufficient A/J congenic mouse strain. Inflammatory response and resistance to Listeria monocytogenes. J. Immunol. 142:2057– 60 163. Good MF. 2005. Vaccine-induced immunity to malaria parasites and the need for novel strategies. Trends Parasitol. 21:29–34 164. Kwiatkowski DP. 2005. How malaria has affected the human genome and what human genetics can teach us about malaria. Am. J. Hum. Genet. 77:171–92 165. Fortin A, Stevenson MM, Gros P. 2002. Complex genetic control of susceptibility to malaria in mice. Genes Immun. 3:177–86 166. Fortin A, Diez E, Rochefort D, Laroche L, Malo D, et al. 2001. Recombinant congenic strains derived from A/J and C57BL/6J: a tool for genetic dissection of complex traits. Genomics 74:21–35 167. Fortin A, Cardon LR, Tam M, Skamene E, Stevenson MM, Gros P. 2001. Identification of a new malaria susceptibility locus (Char4) in recombinant congenic strains of mice. Proc. Natl. Acad. Sci. USA 98:10793–98 168. Min-Oo G, Fortin A, Tam MF, Gros P, Stevenson MM. 2004. Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model. Genes Immun. 5:168–75 169. Min-Oo G, Fortin A, Tam MF, Nantel A, Stevenson MM, Gros P. 2003. Pyruvate kinase deficiency in mice protects against malaria. Nat. Genet. 35:357–62 170. Min-Oo G, Tam M, Stevenson MM, Gros P. 2007. Pyruvate kinase deficiency: Correlation between enzyme activity, extent of hemolytic anemia and protection against malaria in independent mouse mutants. Blood Cells Mol. Dis. 39:63–69 170a. Roy M-F, Riendeau N, B´edard C, H´elie P, Min-Oo G, et al. 2007. Pyruvate kinase deficiency confers susceptibility to Salmonella typhimurium infection in mice. J. Exp. Med. 204:2949–61 171. Min-Oo G, Fortin A, Pitari G, Tam M, Stevenson MM, Gros P. 2007. Complex genetic control of susceptibility to malaria: positional cloning of the Char9 locus. J. Exp. Med. 204:511–24 172. Martin F, Penet MF, Malergue F, Lepidi H, Dessein A, et al. 2004. Vanin-1−/− mice show decreased NSAID- and Schistosoma-induced intestinal inflammation associated with higher glutathione stores. J. Clin. Invest. 113:591–97 173. Pavesio CE, Lightman S. 1996. Toxoplasma gondii and ocular toxoplasmosis: pathogenesis. Br. J. Ophthalmol. 80:1099–107 174. Aliberti J. 2005. Host persistence: exploitation of anti-inflammatory pathways by Toxoplasma gondii. Nat. Rev. Immunol. 5:162–70 175. Gazzinelli RT, Wysocka M, Hayashi S, Denkers EY, Hieny S, et al. 1994. Parasiteinduced IL-12 stimulates early IFN-γ synthesis and resistance during acute infection with Toxoplasma gondii. J. Immunol. 153:2533–43
Annu. Rev. Immunol. 2008.26:81-132. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-04
124
Vidal et al.
Annu. Rev. Immunol. 2008.26:81-132. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-04
ARI
16 February 2008
11:22
176. Scanga CA, Aliberti J, Jankovic D, Tilloy F, Bennouna S, et al. 2002. Cutting edge: MyD88 is required for resistance to Toxoplasma gondii infection and regulates parasiteinduced IL-12 production by dendritic cells. J. Immunol. 168:5997–6001 177. Gaddi PJ, Yap GS. 2007. Cytokine regulation of immunopathology in toxoplasmosis. Immunol. Cell Biol. 85:155–59 178. Ortmann R, Smeltz R, Yap G, Sher A, Shevach EM. 2001. A heritable defect in IL-12 signaling in B10.Q/J mice. I. In vitro analysis. J. Immunol. 166:5712–19 179. Yap GS, Ortmann R, Shevach E, Sher A. 2001. A heritable defect in IL-12 signaling in B10.Q/J mice. II. Effect on acute resistance to Toxoplasma gondii and rescue by IL-18 treatment. J. Immunol. 166:5720–25 180. Shaw MH, Boyartchuk V, Wong S, Karaghiosoff M, Ragimbeau J, et al. 2003. A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity. Proc. Natl. Acad. Sci. USA 100:11594–99 181. Velazquez L, Fellous M, Stark GR, Pellegrini S. 1992. A protein tyrosine kinase in the interferon α/β signaling pathway. Cell 70:313–22 182. Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, et al. 1995. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 377:65–68 183. Watford WT, O’Shea JJ. 2006. Human tyk2 kinase deficiency: another primary immunodeficiency syndrome. Immunity 25:695–97 184. Yap GS, Shaw MH, Ling Y, Sher A. 2006. Genetic analysis of host resistance to intracellular pathogens: lessons from studies of Toxoplasma gondii infection. Microbes Infect. 8:1174–78 185. Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, et al. 2006. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25:745–55 186. Jeong YJ, Kim S, Wook YD, Lee JW, Kim KI, Lee SH. 2007. Scrub typhus: clinical, pathologic, and imaging findings. Radiographics 27:161–72 187. Groves MG, Osterman JV. 1978. Host defenses in experimental scrub typhus: genetics of natural resistance to infection. Infect. Immun. 19:583–88 188. Nacy CA, Groves MG. 1981. Macrophages in resistance to rickettsial infections: early host defense mechanisms in experimental scrub typhus. Infect. Immun. 31:1239–50 189. Groves MG, Rosenstreich DL, Taylor BA, Osterman JV. 1980. Host defenses in experimental scrub typhus: mapping the gene that controls natural resistance in mice. J. Immunol. 125:1395–99 190. Patarca R, Freeman GJ, Singh RP, Wei FY, Durfee T, et al. 1989. Structural and functional studies of the early T lymphocyte activation 1 (Eta-1) gene. Definition of a novel T cell-dependent response associated with genetic resistance to bacterial infection. J. Exp. Med. 170:145–61 191. O’Regan AW, Nau GJ, Chupp GL, Berman JS. 2000. Osteopontin (Eta-1) in cellmediated immunity: teaching an old dog new tricks. Immunol. Today 21:475–78 192. Ashkar S, Weber GF, Panoutsakopoulou V, Sanchirico ME, Jansson M, et al. 2000. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 287:860–64 193. Rollo EE, Hempson SJ, Bansal A, Tsao E, Habib I, et al. 2005. The cytokine osteopontin modulates the severity of rotavirus diarrhea. J. Virol. 79:3509–16 194. Nau GJ, Chupp GL, Emile JF, Jouanguy E, Berman JS, et al. 2000. Osteopontin expression correlates with clinical outcome in patients with mycobacterial infection. Am. J. Pathol. 157:37–42 www.annualreviews.org • Immunity to Infection in the Mouse
125
ARI
16 February 2008
11:22
195. Shinohara ML, Jansson M, Hwang ES, Werneck MB, Glimcher LH, Cantor H. 2005. T-bet-dependent expression of osteopontin contributes to T cell polarization. Proc. Natl. Acad. Sci. USA 102:17101–6 196. Gambhir M, Basanez MG, Turner F, Kumaresan J, Grassly NC. 2007. Trachoma: transmission, infection, and control. Lancet Infect. Dis. 7:420–27 197. Bernstein-Hanley I, Balsara ZR, Ulmer W, Coers J, Starnbach MN, Dietrich WF. 2006. Genetic analysis of susceptibility to Chlamydia trachomatis in mouse. Genes Immun. 7:122–29 198. Li D, Borovkov A, Vaglenov A, Wang C, Kim T, et al. 2006. Mouse model of respiratory Chlamydia pneumoniae infection for a genomic screen of subunit vaccine candidates. Vaccine 24:2917–27 199. Bernstein-Hanley I, Coers J, Balsara ZR, Taylor GA, Starnbach MN, Dietrich WF. 2006. The p47 GTPases Igtp and Irgb10 map to the Chlamydia trachomatis susceptibility locus Ctrq-3 and mediate cellular resistance in mice. Proc. Natl. Acad. Sci. USA 103:14092–97 200. Taylor GA, Feng CG, Sher A. 2004. p47 GTPases: regulators of immunity to intracellular pathogens. Nat. Rev. Immunol. 4:100–9 201. Nelson DE, Virok DP, Wood H, Roshick C, Johnson RM, et al. 2005. Chlamydial IFN-γ immune evasion is linked to host infection tropism. Proc. Natl. Acad. Sci. USA 102:10658–63 202. Rajagopal S, Treanor J. 2007. Pandemic (avian) influenza. Semin. Respir. Crit. Care Med. 28:159–70 203. Lindenmann J. 1962. Resistance of mice to mouse-adapted influenza A virus. Virology 16:203–4 204. Lindenmann J. 1964. Inheritance of resistance to influenza virus in mice. Proc. Soc. Exp. Biol. Med. 116:506–9 205. Lindenmann J, Lane CA, Hobson D. 1963. The resistance of A2g mice to myxoviruses. J. Immunol. 90:942–51 206. Haller O, Arnheiter H, Gresser I, Lindenmann J. 1979. Genetically determined, interferon-dependent resistance to influenza virus in mice. J. Exp. Med. 149:601–12 207. Staeheli P, Haller O, Boll W, Lindenmann J, Weissmann C. 1986. Mx protein: constitutive expression in 3T3 cells transformed with cloned Mx cDNA confers selective resistance to influenza virus. Cell 44:147–58 208. Horisberger MA, Staeheli P, Haller O. 1983. Interferon induces a unique protein in mouse cells bearing a gene for resistance to influenza virus. Proc. Natl. Acad. Sci. USA 80:1910–14 209. Reeves RH, O’Hara BF, Pavan WJ, Gearhart JD, Haller O. 1988. Genetic mapping of the Mx influenza virus resistance gene within the region of mouse chromosome 16 that is homologous to human chromosome 21. J. Virol. 62:4372–75 210. Staeheli P, Sutcliffe JG. 1988. Identification of a second interferon-regulated murine Mx gene. Mol. Cell. Biol. 8:4524–28 211. Pavlovic J, Haller O, Staeheli P. 1992. Human and mouse Mx proteins inhibit different steps of the influenza virus multiplication cycle. J. Virol. 66:2564–69 212. Stranden AM, Staeheli P, Pavlovic J. 1993. Function of the mouse Mx1 protein is inhibited by overexpression of the PB2 protein of influenza virus. Virology 197:642–51 213. Staeheli P, Grob R, Meier E, Sutcliffe JG, Haller O. 1988. Influenza virus-susceptible mice carry Mx genes with a large deletion or a nonsense mutation. Mol. Cell. Biol. 8:4518–23 214. Guenet JL. 2005. Assessing the genetic component of the susceptibility of mice to viral infections. Brief. Funct. Genomic Proteomics 4:225–40
Annu. Rev. Immunol. 2008.26:81-132. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-04
126
Vidal et al.
Annu. Rev. Immunol. 2008.26:81-132. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-04
ARI
16 February 2008
11:22
215. Haller O, Kochs G. 2002. Interferon-induced mx proteins: dynamin-like GTPases with antiviral activity. Traffic 3:710–17 216. Arnheiter H, Haller O. 1988. Antiviral state against influenza virus neutralized by microinjection of antibodies to interferon-induced Mx proteins. EMBO J. 7:1315–20 217. Arnheiter H, Skuntz S, Noteborn M, Chang S, Meier E. 1990. Transgenic mice with intracellular immunity to influenza virus. Cell 62:51–61 218. Pavlovic J, Arzet HA, Hefti HP, Frese M, Rost D, et al. 1995. Enhanced virus resistance of transgenic mice expressing the human MxA protein. J. Virol. 69:4506–10 219. Lai MM, Cavanagh D. 1997. The molecular biology of coronaviruses. Adv. Virus Res. 48:1–100 220. Riski H, Hovi T. 1980. Coronavirus infections of man associated with diseases other than the common cold. J. Med. Virol. 6:259–65 221. van der Hoek L, Pyrc K, Jebbink MF, Vermeulen-Oost W, Berkhout RJ, et al. 2004. Identification of a new human coronavirus. Nat. Med. 10:368–73 222. Fouchier RA, Schneeberger PM, Rozendaal FW, Broekman JM, Kemink SA, et al. 2004. Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc. Natl. Acad. Sci. USA 101:1356–61 223. Woo PC, Lau SK, Chu CM, Chan KH, Tsoi HW, et al. 2005. Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia. J. Virol. 79:884–95 224. Peiris JS, Lai ST, Poon LL, Guan Y, Yam LY, et al. 2003. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 361:1319–25 225. Marra MA, Jones SJ, Astell CR, Holt RA, Brooks-Wilson A, et al. 2003. The genome sequence of the SARS-associated coronavirus. Science 300:1399–404 226. Rota PA, Oberste MS, Monroe SS, Nix WA, Campagnoli R, et al. 2003. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science 300:1394–99 227. Li W, Shi Z, Yu M, Ren W, Smith C, et al. 2005. Bats are natural reservoirs of SARS-like coronaviruses. Science 310:676–79 228. Lau SK, Woo PC, Li KS, Huang Y, Tsoi HW, et al. 2005. Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats. Proc. Natl. Acad. Sci. USA 102:14040–45 229. Navas-Martin S, Weiss SR. 2003. SARS: lessons learned from other coronaviruses. Viral Immunol. 16:461–74 230. Navas S, Seo SH, Chua MM, Sarma JD, Lavi E, et al. 2001. Murine coronavirus spike protein determines the ability of the virus to replicate in the liver and cause hepatitis. J. Virol. 75:2452–57 231. Iacono KT, Kazi L, Weiss SR. 2006. Both spike and background genes contribute to murine coronavirus neurovirulence. J. Virol. 80:6834–43 232. Parr RL, Fung L, Reneker J, Myers-Mason N, Leibowitz JL, Levy G. 1995. Association of mouse fibrinogen-like protein with murine hepatitis virus-induced prothrombinase activity. J. Virol. 69:5033–38 233. De Albuquerque N, Baig E, Ma X, Zhang J, He W, et al. 2006. Murine hepatitis virus strain 1 produces a clinically relevant model of severe acute respiratory syndrome in A/J mice. J. Virol. 80:10382–94 234. Perlman S, Dandekar AA. 2005. Immunopathogenesis of coronavirus infections: implications for SARS. Nat. Rev. Immunol. 5:917–27 www.annualreviews.org • Immunity to Infection in the Mouse
127
ARI
16 February 2008
11:22
235. Stohlman SA, Frelinger JA, Weiner LP. 1980. Resistance to fatal central nervous system disease by mouse hepatitis virus, strain JHM. II. Adherent cell-mediated protection. J. Immunol. 124:1733–39 236. Knobler RL, Haspel MV, Oldstone MB. 1981. Mouse hepatitis virus type 4 (JHM strains) induced fatal central nervous system disease. I. genetic control and murine neuron as the susceptible site of disease. J. Exp. Med. 153:832–43 237. Smith MS, Click RE, Plagemann PG. 1984. Control of mouse hepatitis virus replication in macrophages by a recessive gene on chromosome 7. J. Immunol. 133:428–32 238. Knobler RL, Taylor BA, Wooddell MK, Beamer WG, Oldstone MB. 1984. Host genetic control of mouse hepatitis virus type-4 (JHM strain) replication. II. The gene locus for susceptibility is linked to the Svp-2 locus on mouse chromosome 7. Exp. Clin. Immunogenet. 1:217–22 239. Ohtsuka N, Taguchi F. 1997. Mouse susceptibility to mouse hepatitis virus infection is linked to viral receptor genotype. J. Virol. 71:8860–63 240. Boyle JF, Weismiller DG, Holmes KV. 1987. Genetic resistance to mouse hepatitis virus correlates with absence of virus-binding activity on target tissues. J. Virol. 61:185–89 241. Williams RK, Jiang GS, Holmes KV. 1991. Receptor for mouse hepatitis virus is a member of the carcinoembryonic antigen family of glycoproteins. Proc. Natl. Acad. Sci. USA 88:5533–36 242. Thompson JA, Grunert F, Zimmermann W. 1991. Carcinoembryonic antigen gene family: molecular biology and clinical perspectives. J. Clin. Lab. Anal. 5:344–66 243. McCuaig K, Rosenberg M, N´edellec P, Turbide C, Beauchemin N. 1993. Expression of the Bgp gene and characterization of mouse colon biliary glycoprotein isoforms. Gene 127:173–83 244. Chen T, Zimmermann W, Parker J, Chen I, Maeda A, Bolland S. 2001. Biliary glycoprotein (BGPa, CD66a, CEACAM1) mediates inhibitory signals. J. Leukoc. Biol. 70:335–40 245. Beauchemin N, Draber P, Dveksler G, Gold P, Gray-Owen S, et al. 1999. Redefined nomenclature for members of the carcinoembryonic antigen family. Exp. Cell Res. 252:243–49 246. Kuespert K, Pils S, Hauck CR. 2006. CEACAMs: their role in physiology and pathophysiology. Curr. Opin. Cell Biol. 18:565–71 247. Blau DM, Turbide C, Tremblay M, Olson M, Letourneau S, et al. 2001. Targeted disruption of the Ceacam1 (MHVR) gene leads to reduced susceptibility of mice to mouse hepatitis virus infection. J. Virol. 75:8173–86 248. Hemmila E, Turbide C, Olson M, Jothy S, Holmes KV, Beauchemin N. 2004. Ceacam1a−/− mice are completely resistant to infection by murine coronavirus mouse hepatitis virus A59. J. Virol. 78:10156–65 249. Schmitter T, Pils S, Sakk V, Frank R, Fischer KD, Hauck CR. 2007. The granulocyte receptor carcinoembryonic antigen-related cell adhesion molecule 3 (CEACAM3) directly associates with Vav to promote phagocytosis of human pathogens. J. Immunol. 178:3797–805 250. McCaw SE, Schneider J, Liao EH, Zimmermann W, Gray-Owen SD. 2003. Immunoreceptor tyrosine-based activation motif phosphorylation during engulfment of Neisseria gonorrhoeae by the neutrophil-restricted CEACAM3 (CD66d) receptor. Mol. Microbiol. 49:623–37 251. Schmitter T, Agerer F, Peterson L, Munzner P, Hauck CR. 2004. Granulocyte CEACAM3 is a phagocytic receptor of the innate immune system that mediates recognition and elimination of human-specific pathogens. J. Exp. Med. 199:35–46
Annu. Rev. Immunol. 2008.26:81-132. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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ANRV338-IY26-04
ARI
16 February 2008
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252. Mackenzie JS, Gubler DJ, Petersen LR. 2004. Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat. Med. 10:S98– 109 253. Samuel MA, Diamond MS. 2006. Pathogenesis of West Nile Virus infection: a balance between virulence, innate and adaptive immunity, and viral evasion. J. Virol. 80:9349–60 254. King NJ, Getts DR, Getts MT, Rana S, Shrestha B, Kesson AM. 2007. Immunopathology of flavivirus infections. Immunol. Cell Biol. 85:33–42 255. Webster L. 1936. Inheritance of resistance of mice to enteric bacterial and neurotropic virus infections. J. Exp. Med. 65:261–86 256. Sangster MY, Heliams DB, Mackenzie JS, Shellam GR. 1993. Genetic studies of flavivirus resistance in inbred strains derived from wild mice: evidence for a new resistance allele at the flavivirus resistance locus (Flv). J. Virol. 67:340–47 257. Mashimo T, Lucas M, Simon-Chazottes D, Frenkiel MP, Montagutelli X, et al. 2002. A nonsense mutation in the gene encoding 2 -5 -oligoadenylate synthetase/L1 isoform is associated with West Nile virus susceptibility in laboratory mice. Proc. Natl. Acad. Sci. USA 99:11311–16 258. Sangster MY, Urosevic N, Mansfield JP, Mackenzie JS, Shellam GR. 1994. Mapping the Flv locus controlling resistance to flaviviruses on mouse chromosome 5. J. Virol. 68:448–52 259. Perelygin AA, Scherbik SV, Zhulin IB, Stockman BM, Li Y, Brinton MA. 2002. Positional cloning of the murine flavivirus resistance gene. Proc. Natl. Acad. Sci. USA 99:9322– 27 260. Yakub I, Lillibridge KM, Moran A, Gonzalez OY, Belmont J, et al. 2005. Single nucleotide polymorphisms in genes for 2 -5 -oligoadenylate synthetase and RNase L inpatients hospitalized with West Nile virus infection. J. Infect. Dis. 192:1741–48 261. Soderberg-Naucler C. 2006. Human cytomegalovirus persists in its host and attacks and avoids elimination by the immune system. Crit. Rev. Immunol. 26:231–64 262. Biron CA, Byron KS, Sullivan JL. 1989. Severe herpesvirus infections in an adolescent without natural killer cells. N. Engl. J. Med. 320:1731–35 263. Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP. 1999. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17:189–220 264. Etzioni A, Eidenschenk C, Katz R, Beck R, Casanova JL, Pollack S. 2005. Fatal varicella associated with selective natural killer cell deficiency. J. Pediatr. 146:423–25 265. Bernard F, Picard C, Cormier-Daire V, Eidenschenk C, Pinto G, et al. 2004. A novel developmental and immunodeficiency syndrome associated with intrauterine growth retardation and a lack of natural killer cells. Pediatrics 113:136–41 266. Lilley BN, Ploegh HL. 2005. Viral modulation of antigen presentation: manipulation of cellular targets in the ER and beyond. Immunol. Rev. 207:126–44 267. Mocarski ES Jr. 2002. Immunomodulation by cytomegaloviruses: manipulative strategies beyond evasion. Trends Microbiol. 10:332–39 268. Reddehase MJ. 2002. Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance. Nat. Rev. Immunol. 2:831–44 269. Scalzo AA, Corbett AJ, Rawlinson WD, Scott GM, Degli-Esposti MA. 2007. The interplay between host and viral factors in shaping the outcome of cytomegalovirus infection. Immunol. Cell Biol. 85:46–54 270. Grundy JE, Mackenzie JS, Stanley NF. 1981. Influence of H-2 and non-H-2 genes on resistance to murine cytomegalovirus infection. Infect. Immun. 32:277–86 www.annualreviews.org • Immunity to Infection in the Mouse
129
ARI
16 February 2008
11:22
271. Chalmer JE, Mackenzie JS, Stanley NF. 1977. Resistance to murine cytomegalovirus linked to the major histocompatibility complex of the mouse. J. Gen. Virol. 37:107–14 272. Scalzo AA, Fitzgerald NA, Simmons A, La Vista AB, Shellam GR. 1990. Cmv-1, a genetic locus that controls murine cytomegalovirus replication in the spleen. J. Exp. Med. 171:1469–83 273. Scalzo AA, Fitzgerald NA, Wallace CR, Gibbons AE, Smart YC, et al. 1992. The effect of the Cmv-1 resistance gene, which is linked to the natural killer cell gene complex, is mediated by natural killer cells. J. Immunol. 149:581–89 274. Lee SH, Girard S, Macina D, Busa M, Zafer A, et al. 2001. Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily. Nat. Genet. 28:42–45 275. Daniels KA, Devora G, Lai WC, O’Donnell CL, Bennett M, Welsh RM. 2001. Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H. J. Exp. Med. 194:29–44 276. Brown MG, Dokun AO, Heusel JW, Smith HR, Beckman DL, et al. 2001. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292:934–37 277. Anderson SK, Ortaldo JR, McVicar DW. 2001. The ever-expanding Ly49 gene family: repertoire and signaling. Immunol. Rev. 181:79–89 278. Lee SH, Gitas J, Zafer A, Lepage P, Hudson TJ, et al. 2001. Haplotype mapping indicates two independent origins for the Cmv1s susceptibility allele to cytomegalovirus infection and refines its localization within the Ly49 cluster. Immunogenetics 53:501–5 279. Dokun AO, Kim S, Smith HR, Kang HS, Chu DT, Yokoyama WM. 2001. Specific and nonspecific NK cell activation during virus infection. Nat. Immunol. 2:951–56 280. Lee SH, Zafer A, de Repentigny Y, Kothary R, Tremblay ML, et al. 2003. Transgenic expression of the activating natural killer receptor Ly49H confers resistance to cytomegalovirus in genetically susceptible mice. J. Exp. Med. 197:515–26 281. Dimasi N, Biassoni R. 2005. Structural and functional aspects of the Ly49 natural killer cell receptors. Immunol. Cell Biol. 83:1–8 282. Sjolin H, Tomasello E, Mousavi-Jazi M, Bartolazzi A, Karre K, et al. 2002. Pivotal role of KARAP/DAP12 adaptor molecule in the natural killer cell-mediated resistance to murine cytomegalovirus infection. J. Exp. Med. 195:825–34 283. Arase H, Mocarski ES, Campbell AE, Hill AB, Lanier LL. 2002. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296:1323–26 284. Smith HR, Heusel JW, Mehta IK, Kim S, Dorner BG, et al. 2002. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc. Natl. Acad. Sci. USA 99:8826–31 285. Bubic I, Wagner M, Krmpotic A, Saulig T, Kim S, et al. 2004. Gain of virulence caused by loss of a gene in murine cytomegalovirus. J. Virol. 78:7536–44 286. Voigt V, Forbes CA, Tonkin JN, Degli-Esposti MA, Smith HR, et al. 2003. Murine cytomegalovirus m157 mutation and variation leads to immune evasion of natural killer cells. Proc. Natl. Acad. Sci. USA 100:13483–88 287. French AR, Pingel JT, Wagner M, Bubic I, Yang L, et al. 2004. Escape of mutant double-stranded DNA virus from innate immune control. Immunity 20:747–56 288. French AR, Pingel JT, Kim S, Yang L, Yokoyama WM. 2005. Rapid emergence of escape mutants following infection with murine cytomegalovirus in immunodeficient mice. Clin. Immunol. 115:61–69
Annu. Rev. Immunol. 2008.26:81-132. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-04
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Annu. Rev. Immunol. 2008.26:81-132. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-04
ARI
16 February 2008
11:22
289. Desrosiers MP, Kielczewska A, Loredo-Osti JC, Adam SG, Makrigiannis AP, et al. 2005. Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell-mediated innate resistance to cytomegalovirus infection. Nat. Genet. 37:593–99 290. Adam SG, Caraux A, Fodil-Cornu N, Loredo-Osti JC, Lesjean-Pottier S, et al. 2006. Cmv4, a new locus linked to the NK cell gene complex, controls innate resistance to cytomegalovirus in wild-derived mice. J. Immunol. 176:5478–85 291. Long EO, Burshtyn DN, Clark WP, Peruzzi M, Rajagopalan S, et al. 1997. Killer cell inhibitory receptors: diversity, specificity, and function. Immunol. Rev. 155:135–44 292. Carrington M, Martin MP. 2006. The impact of variation at the KIR gene cluster on human disease. Curr. Top. Microbiol. Immunol. 298:225–57 293. Martin MP, Nelson G, Lee JH, Pellett F, Gao X, et al. 2002. Cutting edge: susceptibility to psoriatic arthritis: influence of activating killer Ig-like receptor genes in the absence of specific HLA-C alleles. J. Immunol. 169:2818–22 294. Khakoo SI, Thio CL, Martin MP, Brooks CR, Gao X, et al. 2004. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 305:872–74 295. Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, et al. 2006. Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu. Rev. Immunol. 24:353–89 296. Papathanasiou P, Goodnow CC. 2005. Connecting mammalian genome with phenome by ENU mouse mutagenesis: gene combinations specifying the immune system. Annu. Rev. Genet. 39:241–62 297. Godinho SI, Nolan PM. 2006. The role of mutagenesis in defining genes in behaviour. Eur. J. Hum. Genet. 14:651–59 298. Clark AT, Goldowitz D, Takahashi JS, Vitaterna MH, Siepka SM, et al. 2004. Implementing large-scale ENU mutagenesis screens in North America. Genetica 122:51–64 299. Hoebe K, Georgel P, Rutschmann S, Du X, Mudd S, et al. 2005. CD36 is a sensor of diacylglycerides. Nature 433:523–27 300. Hoebe K, Du X, Georgel P, Janssen E, Tabeta K, et al. 2003. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424:743–48 301. Tabeta K, Georgel P, Janssen E, Du X, Hoebe K, et al. 2004. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc. Natl. Acad. Sci. USA 101:3516–21 302. Tabeta K, Hoebe K, Janssen EM, Du X, Georgel P, et al. 2006. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat. Immunol. 7:156–64 303. Calvo D, Dopazo J, Vega MA. 1995. The CD36, CLA-1 (CD36L1), and LIMPII (CD36L2) gene family: cellular distribution, chromosomal location, and genetic evolution. Genomics 25:100–6 304. Endemann G, Stanton LW, Madden KS, Bryant CM, White RT, Protter AA. 1993. CD36 is a receptor for oxidized low density lipoprotein. J. Biol. Chem. 268:11811–16 305. Hoebe K, Du X, Goode J, Mann N, Beutler B. 2003. Lps2: a new locus required for responses to lipopolysaccharide, revealed by germline mutagenesis and phenotypic screening. J. Endotoxin Res. 9:250–55 306. Oshiumi H, Matsumoto M, Funami K, Akazawa T, Seya T. 2003. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-β induction. Nat. Immunol. 4:161–67 www.annualreviews.org • Immunity to Infection in the Mouse
131
ARI
16 February 2008
11:22
307. Yamamoto M, Sato S, Mori K, Hoshino K, Takeuchi O, et al. 2002. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-β promoter in the Toll-like receptor signaling. J. Immunol. 169:6668–72 308. Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, et al. 2003. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301:640– 43 309. Krug A, French AR, Barchet W, Fischer JA, Dzionek A, et al. 2004. TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity 21:107–19 310. Brinkmann MM, Spooner E, Hoebe K, Beutler B, Ploegh HL, Kim YM. 2007. The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling. J. Cell Biol. 177:265–75 311. Casrouge A, Zhang SY, Eidenschenk C, Jouanguy E, Puel A, et al. 2006. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 314:308–12 312. Beutler B, Crozat K, Koziol JA, Georgel P. 2005. Genetic dissection of innate immunity to infection: the mouse cytomegalovirus model. Curr. Opin. Immunol. 17:36–43 313. Crozat K, Georgel P, Rutschmann S, Mann N, Du X, et al. 2006. Analysis of the MCMV resistome by ENU mutagenesis. Mamm. Genome 17:398–406 314. Crozat K, Hoebe K, Ugolini S, Hong NA, Janssen E, et al. 2007. Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis. J. Exp. Med. 204:853–63 315. Beutler B, Georgel P, Rutschmann S, Jiang Z, Croker B, Crozat K. 2005. Genetic analysis of innate resistance to mouse cytomegalovirus (MCMV). Brief. Funct. Genomic Proteomics 4:203–13 316. Neeft M, Wieffer M, de Jong AS, Negroiu G, Metz CH, et al. 2005. Munc13–4 is an effector of rab27a and controls secretion of lysosomes in hematopoietic cells. Mol. Biol. Cell 16:731–41 317. Brose N, Hofmann K, Hata Y, Sudhof TC. 1995. Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins. J. Biol. Chem. 270:25273–80 318. Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, et al. 2003. Munc13–4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 115:461–73 319. Fisman DN. 2000. Hemophagocytic syndromes and infection. Emerg. Infect. Dis. 6:601– 8 320. Brose N, Rosenmund C, Rettig J. 2000. Regulation of transmitter release by Unc-13 and its homologues. Curr. Opin. Neurobiol. 10:303–11 321. Verhage M, Maia AS, Plomp JJ, Brussaard AB, Heeroma JH, et al. 2000. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science 287:864–69 322. Varoqueaux F, Sons MS, Plomp JJ, Brose N. 2005. Aberrant morphology and residual transmitter release at the Munc13-deficient mouse neuromuscular synapse. Mol. Cell Biol. 25:5973–84
Annu. Rev. Immunol. 2008.26:81-132. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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Annual Review of Immunology
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:81-132. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislˆaine Martins and Kathryn Calame Department of Microbiology, Columbia University College of Physicians and Surgeons, New York, New York 10032; email:
[email protected],
[email protected] Annu. Rev. Immunol. 2008. 26:133–69
Key Words
The Annual Review of Immunology is online at immunol.annualreviews.org
transcription, repressor, terminal differentiation, cytokines
This article’s doi: 10.1146/annurev.immunol.26.021607.090241
Abstract
c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0133$20.00
B lymphocyte–induced maturation protein-1 (Blimp-1), discovered 16 years ago as a transcriptional repressor of the IFNβ promoter, plays fundamentally important roles in many cell lineages and in early development. This review focuses on Blimp-1 in lymphocytes. In the B cell lineage, Blimp-1 is required for development of immunoglobulin-secreting cells and for maintenance of long-lived plasma cells (LLPCs). Direct targets of Blimp-1 and the transcriptional cascades Blimp-1 initiates to trigger plasmacytic differentiation are described. Blimp-1 also affects the homeostasis and function of CD4+ , CD8+ , and regulatory CD4+ T cells, and Blimp-1 levels are highest in antigen-experienced T cells. Blimp-1 attenuates T cell proliferation and survival and modulates differentiation. Roles for Blimp-1 in Th1/Th2 specification, regulatory T cell function, and CD8 differentiation and function are under investigation. Signals that induce Blimp-1 in B cells include Toll-like receptor ligands and cytokines; in T cells, T cell receptors and cytokines induce Blimp-1. In spite of some commonalities, different targets and regulators of Blimp-1 in B and T cells suggest intriguing evolutionary divergence of this regulatory machinery.
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INTRODUCTION
Annu. Rev. Immunol. 2008.26:133-169. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Zinc finger: the structural domain of a protein, composed of ∼30 amino acids binding a zinc ion, that mediates sequence-specific binding to DNA
Although transcription factors containing zinc finger DNA-binding domains constitute the largest family of transcription factors (1), a single zinc finger–containing transcriptional repressor, B lymphocyte–induced maturation protein-1 (Blimp-1, also called PRDIBF1) plays critical and nonredundant roles in both B and T lymphocytes. In addition, Blimp-1 plays important roles in certain nonlymphoid lineages in adults and in various aspects of embryonic development in many organisms. In this article, we review the role of Blimp-1 in B and T lymphocytes in detail, with an emphasis on recent findings. Other reviews including this topic have appeared recently (2–7).
BLIMP-1 BASICS Although there is nothing unusual about its structure, an unusual role for Blimp-1 in B cells was indicated in early work.
Discovery Blimp-1 cDNA was first cloned by Maniatis and colleagues (8), who used expression cloning to identify a human cDNA encoding a zinc finger–containing protein that bound to the positive regulatory domain I (PRDI) of the human IFNβ promoter. They named the protein PRDIBF1 (positive regulatory domain I-binding factor 1) and, in addition to verifying its binding specificity, demonstrated that the protein was a transcriptional repressor, which was induced upon virus infection of the human osteosarcoma line U20S. Three years later, Davis and colleagues (9) isolated a murine cDNA from a subtractive screen of BCL1 lymphoma cells compared before and after induction of differentiation to Ig-secreting plasma cells by treatment with IL-2+IL-5. Because the message was induced following cytokine-dependent differentiation of the cells, they called it B lymphocyteinduced maturation protein-1, or Blimp-1 (9). Although they did not show directly that the zinc finger protein encoded by their cDNA 134
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was a transcription factor or define a binding site, they made the critical observation that ectopic expression of the protein was sufficient to drive the BCL1 cells to mature into Igsecreting plasmacytoid cells. Later that year, Huang (10) brought these two lines of study together by showing that Blimp-1 was the murine homolog of PRDIBF1, although the mouse protein had a slightly different N terminus from the human, containing 67 additional amino acids (10). Indeed, the human and mouse proteins are highly homologous and are interchangeable in functional assays. (For simplicity, we use the name Blimp-1 for both the human and mouse proteins in this review.) Huang’s recognition that PRDIBF1 and Blimp-1 were homologs identified this protein as a transcriptional repressor, with a defined binding specificity, that was capable of driving BCL1 lymphoma cells to differentiate into Ig-secreting plasma cells. Subsequently the gene structure of prdm1 (11), encoding Blimp-1, as well as its location on human chromosome 6q21, and the syntenic region of mouse chromosome 10 (12) were defined. The mouse gene extends over ∼23 kb and contains 8 exons. Exons 6, 7, and 8 encode the zinc finger domains (Figure 1a,b).
Protein Domains and Biochemical Mechanism of Action Murine Blimp-1 contains 856 amino acids and is predicted to be a 95,835-Da protein. Human Blimp-1 has 789 amino acids and a predicted molecular weight of 87,990 Da. The five C2 H2 zinc finger motifs in the C terminus of Blimp-1 were clearly implicated as the DNA-binding domain; however, further study showed that only the first two finger motifs are necessary for recognition of the PRDI region in the IFNβ promoter (13). The consensus-binding site for Blimp-1 was determined and, consistent with the Maniatis papers (8, 13), was very similar to that of IFN regulatory factor (IRF)1 and IRF2 (14). In fact, Blimp-1 and IRF1/2 compete for binding to the site in the IFNβ promoter (14).
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c prdm gfp
IRES
GFP pA
d
LoxP
LoxP
prdm flox Figure 1 Blimp-1 mRNA and the prdm1 gene. (a) Murine Blimp-1 mRNA showing which portions are encoded by each exon. 5 and 3 noncoding regions are white. Coding regions are colored, with acidic regions light blue, PR region orange, proline-rich region dark blue, and zinc fingers dark green (11). (b–d ) Murine prdm1 gene with exons shown as raised boxes. Coding regions are blue, and noncoding are white. The approximate location of clustered transcription start sites is indicated by an arrow. The gene covers about 23 kb; in the figure, the scale for introns is 2 times less than the scale for exons. (c) Alterations in prdm1 to make the prdm1gfp knockin allele. A region containing a splice acceptor site followed by stop codons in all three frames ( yellow hexagon), an internal ribosome entry site (IRES), and cDNA encoding e-GFP (green fluorescent protein) followed by a SV40 polyadenylation site (pA) was inserted into intron 6 (24). (d ) Structure of the prdm1flox allele. LoxP sites (red bolts) were inserted in intron 5 and 3 to exon 8. Upon Cre-dependent deletion, exons 6–8, encoding the zinc finger domains, are deleted (34).
Other domains of the protein (Figure 1a) include a proline-rich region N-terminal to the zinc fingers and a PR domain conserved between Blimp-1 and the Rb-binding protein RIZ1 (encoded by prdm2) (15, 16). The proline-rich region along with the zinc fingers is required for transcriptional repression and has been shown to mediate association of Blimp-1 with transcriptional corepressor hGroucho (17) and histone deacetylases 1 and 2 (18). Deacetylation of histone lysine residues is associated with a repressive chromatin structure. The PR domain was named for the first two proteins where it was discovered, PRDIBF1 and RIZ. PR domains in Blimp-1 and RIZ have similarity to SET domains found
in histone methyl transferases (HMT) (19), and the PR domain of RIZ1 does have HMT activity (20). Although the PR domain of Blimp-1 does not have demonstrable HMT activity, Blimp-1 recruits the G9a HMT to the IFNβ promoter (21). G9a methylates lysine 9 on histone 3, a repressive histone modification. H3K9 methylation occurs in the IFN-β promoter upon ectopic expression of Blimp-1 (21). Finally, in primordial germ cells, Blimp-1 complexes with prmt5, an arginine HMT that catalyzes symmetrical dimethylation of arginine 3 on H2A and H4 (22). Thus, Blimp-1 appears to repress transcription by recruiting proteins or corepressor complexes that modify histones (by deacetylation, H3K9 methylation, and www.annualreviews.org • Blimp-1 in T and B Lymphocytes
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GC: germinal center Cre and “floxed” alleles: bacteriophage P1’s Cre recombinase excises DNA between two similarly oriented 34 bp loxP recombination sites, leaving a single loxP site. DNA flanked by loxP sites is said to be “floxed” and is a target for Cre-dependent deletion
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arginine methylation) to create a more closed or repressive chromatin structure. However, further work is necessary to learn exactly how chromatin is modified at specific Blimp1 target genes when Blimp-1 represses them and to learn if chromatin modification is the only mechanism by which Blimp-1 represses transcription.
BLIMP-1 IN B CELL BIOLOGY Based on the demonstration by Davis and colleagues (9) that Blimp-1 was sufficient to drive plasmacytic differentiation, much work has focused on the role of Blimp-1 in the B cell lineage. This work provides a paradigm for exploring its roles in other cell lineages.
Expression Pattern of Blimp-1 Blimp-1 expression in the B cell lineage has been studied by immunohistochemistry (IHC) in mice and humans and using a green fluorescent protein (GFP) reporter gene knocked into one allele of the prdm1 locus in mice (Figure 1c). In mice, both IHC (23) and GFP (24) studies show that some plasmablasts and all plasma cells express Blimp-1. GFP analyses provide evidence that increasing levels of Blimp-1 correspond to stages of plasma cell differentiation from plasmablasts to long-lived plasma cells (LLPCs) in the bone marrow (24). Consistent with this idea, plasma cells resulting from a secondary response had higher levels of Blimp-1 compared with those formed in a primary response (25). No Blimp-1 expression has been observed in memory B cells in mouse (26) or human (27). Although peritoneal B-1 cells express low levels of Blimp-1 mRNA (28) and protein, indicated by the GFP reporter (29), Blimp1 mRNA is induced by lipopolysaccharide (LPS) upon Toll-like receptor (TLR) 4 signaling in B-1 cells (30), and the kinetics of induction, measured using the GFP reporter, are more rapid than that for B2 cells (29).
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Although IHC is not quantitative, it is probably more sensitive than the GFP reporter. Furthermore, half-lives of Blimp-1 and GFP mRNA and protein are probably not exactly the same, introducing some doubt into using GFP as an absolute indicator of endogenous Blimp-1 expression. IHC for endogenous Blimp-1 has revealed that a small fraction (∼5%–15%) of cells in germinal centers (GCs) also express Blimp-1. (Blimp-1 has not been detected in B cells at earlier stages.) Blimp-1+ cells in GCs do not express Bcl-6 but do contain cytoplasmic Ig and probably represent centrocytes that are fated to leave the GC as plasmablasts (23). Blimp-1 appears in these GC cells before Syndecan-1 (CD138) (31). Blimp-1 expression patterns in humans are similar to those in mice (32, 33). The GC B cells that express Blimp-1 are Pax5+ Bcl-6− ; outside the GC, human plasma cells do not express Pax5 (32, 33). In an in vitro system in which human centrocytes were induced to become Ig-secreting plasma cells, high levels of Blimp-1 mRNA were not achieved until levels of Bcl-6, Pax5, and Bach2 had fallen significantly (27).
Blimp-1 Is Required for Ig Secretion Mice with a conditional deletion of prdm1 in the B lineage were created by crossing mice with “floxed” prdm1 alleles to CD19Cre transgenic mice (34). In these mice, exons 6– 8, which encode all the zinc finger domains, are deleted in mature B cells in the presence of Cre recombinase (Figure 1d ). Consistent with Blimp-1’s expression pattern, these mice revealed that Blimp-1 is required for plasma cell formation and for normal Ig secretion in response to both T-independent (TI) and Tdependent (TD) antigens. In the B cell conditional knockout (CKO) mice, peripheral B cell subsets were normal, and GCs formed in response to the TD antigen. Class switch recombination (CSR) occurred normally, as evidenced by the appearance of switch circles (M. Shapiro-Shelef & K. Calame, unpublished),
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but secretion of all isotypes was severely reduced. In addition, GCs were enlarged in CKO mice, suggesting a developmental block at the late/post-GC stage. Subsequent studies on the CD19Cre CKO mice revealed that, although B1 B cells were present in normal numbers and were capable of self-renewal, they failed to secrete Ig normally (30). Thus, Blimp-1 is required for normal Ig secretion in all B cell subsets. A recent report (110) has investigated in more detail the low Ig secretion observed in mice lacking Blimp-1 in the B cell lineage (34). Using reconstitution of Rag−/− mice with fetal liver cells from prdm1gfp/gpf mice, these researchers showed that there is an early phase in plasmacytic differentiation, which they call a “preplasmablast,” during which Pax5 activity is inhibited and genes repressed by Pax5 and other plasma cell genes, but not Blimp-1, are expressed. These cells secrete low amounts of Ig and provide evidence for an early phase of plasmacytic differentiation that is independent of Blimp-1 but requires inhibition of Pax5. Thus, these authors conclude that, although Blimp-1 is required for full plasmacytic differentiation and normal levels of Ig secretion, B cells can enter an initial phase of plasmacytic differentiation without Blimp1. One caveat regarding this work, however, is the question of whether the prdm1gfp allele used in this study is a true null allele or a hypomorphic allele, owing to the potential, via differential splicing, to form Blimp-1 mRNA (Figure 1c ). Embryos homozygous for the prdm1gfp allele live until at least E13 or E14, allowing transfer of fetal liver cells for reconstitution studies (35). In contrast, embryos homozygous for either of two different deletion alleles, including one generated from the prdm1flox allele (Figure 1d ), die significantly earlier at E10.5 (36). Blimp-1 is not required for formation of memory B cells because in the CKO mice there is an exaggerated GC response upon a secondary challenge even though these cells are unable to differentiate into plasma cells (34). This is consistent with the finding that
Blimp-1 mRNA is not present in human memory B cells formed in in vitro cultures (27) or in ex vivo purified human memory cells (26). Preplasma memory cells in the bone marrow, however, were dramatically reduced in the CKO mice, suggesting a requirement for Blimp-1 to form this interesting but controversial (26, 37, 38) subset. Using an inducible gene deletion system, investigators showed that LLPCs (see the Long-Lived Plasma Cells sidebar) in the bone marrow, formed in the presence of Blimp-1, require continued expression of Blimp-1 for their maintenance (39). LLPCs in the bone marrow provide a second form of humoral memory by providing continuous immunity to pathogens that have been previously encountered. They survive in the bone marrow without proliferation or antigen stimulation for long periods of time (40). The continued requirement for Blimp-1 shows that the repressive changes in chromatin that Blimp-1 facilitates must be labile on at least an important subset of its target genes, requiring continued activity of Blimp-1 to maintain repression. These studies showed that when prdm1 was deleted, CD138+ , Ig-secreting cells, resident in the bone marrow disappeared; however, whether they died or dedifferentiated was not established and requires further study. Thus, Blimp-1 is uniquely required for formation and maintenance of all Ig-secreting B cells, and interfering with its activity might be a way to target LLPC in autoimmunity or other pathological conditions.
Plasmacytic differentiation: terminal differentiation of an activated B cell to become an Ig-secreting plasma cell
Targets of Blimp-1 Not only is Blimp-1 necessary for plasma cell formation and function, it is also sufficient. The striking ability of ectopically expressed Blimp-1 to drive plasmacytic development, originally demonstrated in 1994 by Davis and colleagues (9), was subsequently extended beyond BCL1 cells to normal splenic B cells (47, 48). Importantly, however, when Blimp-1 expression is forced in B cells at earlier developmental stages, it causes cell death (49). www.annualreviews.org • Blimp-1 in T and B Lymphocytes
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LONG-LIVED PLASMA CELLS In a primary response, most plasma cells formed after a T cell–dependent GC reaction secrete antibodies with high affinity and switched isotypes. Because of changes in chemokine receptors such as CXCR5, they exit the follicles, and some migrate to niches in the bone marrow. In the bone marrow niches, they receive survival signals that include IL-6, made by bone marrow stromal cells (41), and TNF family members BAFF (B cell-activating factor) or APRIL (a proliferation-inducing ligand) that signal through BCMA (B cell maturation antigen) (42). LLPCs have been shown to survive for months to years, sometimes for the lifetime of the organism (43) in the absence of an antigen (44) or cell division (45). Interestingly, when an organism mounts a new primary response, some previously formed LLPCs, resident in the bone marrow, are mobilized to leave the bone marrow survival niches, presumably providing space for newly formed plasma cells and ensuring a dynamic repertoire of LLPCs, reflecting the immunological experience of the organism (46). Because they provide constant immunological vigilance in the form of secreted antibodies, LLPCs are considered one form of humoral immunity. For more details on LLPCs, see a recent review (40).
XBP-1: X-box binding protein-1 Gene expression profile: the unique, global pattern of genes expressed as steady-state mRNA in a given cell type
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Ig-secreting plasma cells differ significantly, both morphologically and functionally, from activated B cells; they express neither BCR nor MHC class II on their surface, and they are postmitotic (6). The ability of a single transcription factor to trigger such a complex and dramatic developmental decision is unusual and was a driving force behind efforts to identify targets of Blimp-1-dependent repression in B cells. Gene expression analyses comparing Burkitt lymphoma lines with or without forced expression of Blimp-1 revealed more than 250 genes whose expression was altered by Blimp-1 (50). Obviously such experiments reveal both direct and indirect Blimp-1 targets (Figure 2). Three main programs of gene expression were altered by Blimp-1. (a) A proliferative program including cMYC, E2F1, and other genes required for entry into cycle and cell division was repressed. Myc had Martins
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previously been shown to be a direct target of Blimp-1-dependent repression (51, 52). (b) A program involved in Ig secretion, including J chain, X-box binding protein-1 (XBP-1), as well as Ig heavy and Ig light chain genes, was induced. (c) An extensive program of gene expression characteristic of activated or GC B cells was repressed, including genes encoding the critical transcription factors Pax5 and Bcl-6. Pax5 was previously shown to be a direct target of Blimp-1 (53), and recent studies show that bcl6 is also directly repressed by Blimp-1 (L. Cimmino & K. Calame, unpublished). The “B cell program” repressed by Blimp-1 includes repression of genes involved in response to signals from the BCR; genes, notably AICDA, involved in CSR and somatic hypermutation (SHM); genes encoding costimulatory molecules for T cells; and genes for chemokine receptors (Figure 2). Direct targets among this group also include class II transactivator (CIITA) via promoter III, required for MHC class II expression in B cells (48, 54), ID3 and SPIB (50) (Figure 3, Table 1). Another gene expression study identified genes regulated by Blimp-1 in BCL1 and M12 cells (55). This study confirmed much of the earlier work but also identified other interesting genes regulated by Blimp-1 in B cells, including induction of irf4 and repression of taci. Using mutant forms of Blimp-1, investigators also identified genes whose regulation depended on the PR domain of Blimp-1, including ell2 (55). XBP-1 is a transcriptional activator that is required for plasma cell development and function (56). When the gene expression profiles of splenic B cells lacking Blimp1 and XBP-1 were compared (57), it was clear that Blimp-1 expression is necessary for expression of XBP-1 and that XBP-1 is the proximate activator of multiple genes necessary for expanded endoplasmic reticulum and protein secretion as well as of genes causing increased cell size, lysosome content, mitochondrial mass and function, ribosome numbers, and total protein synthesis. In the
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Figure 2 Transcription factors that are targets of Blimp-1 in B cells. Panel (a) indicates genes shown to be directly repressed by Blimp-1, and panel (b) indicates genes Blimp-1 represses by a currently unknown mechanism. In both cases, target genes that are known to be regulated by the indicated transcription factors and that had their expression altered by Blimp-1 (50) are shown. Green indicates genes involved in cell proliferation, purple, genes involved in B cell phenotype and function, and blue, genes involved in Ig secretion. All genes are given murine designations for clarity and consistency.
absence of Blimp-1, neither XBP-1 nor its target genes are expressed normally (57). The mechanism responsible for Blimp-1dependent induction of XBP-1 may be via repression of pax5 since Pax5 has been reported to repress xbp1 (59). However, a detailed gene expression study in B cells lacking Pax5 did not show that XBP-1 was elevated (60), suggesting another, currently unknown, mechanism may be responsible for Blimp-1-dependent expression of XBP-1. In chicken DT40 cells lacking Pax5, both Blimp-1 and XBP-1 were elevated (61), providing evidence that Pax5 does repress xbp1 in this setting. Thus, although it is established that Blimp-1 is necessary for XBP1 induction in B cells, the exact mechanism
by which Blimp-1 regulates XBP-1 remains uncertain.
Regulation of Blimp-1 and Plasmacytic Differentiation Plasmacytic differentiation must be strictly regulated. Failure to mount a humoral response in a timely fashion would clearly jeopardize the organism. However, if plasmacytic differentiation occurred too soon during a TD response, before germinal center reactions were completed, affinity maturation and class switching would be compromised, and the strength and quality of both primary and secondary responses would be www.annualreviews.org • Blimp-1 in T and B Lymphocytes
Germinal center (GC) reaction: In response to T cell–dependent antigens and T cell help, B cells form GCs, where they undergo rapid proliferation, affinity maturation, and CSR. Memory cells and plasmablasts result from the GC reaction
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xbp1
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Figure 3 Inhibition of genes required for plasma cell differentiation in earlier naive follicular B cells and by germinal center (GC) B cells. Red bars indicate transcriptional repression, and the blue arrow indicates induction. Factors in naive B cells are shown in the yellow box; factors in GC B cells are shown in the blue box (59–61, 90, 95–97, 100, 103, 106).
diminished. In addition, peripheral tolerance requires B cells to selectively respond to signals from self-antigens by dying or becoming anergic rather than undergoing plasmacytic differentiation. Finally, it is important that memory B cells be poised to differentiate to Table 1
plasma cells rapidly in response to secondary antigenic challenge but also be regulated so that spontaneous differentiation does not occur in the absence of a stimulus. Expression of Blimp-1 sets plasmacytic differentiation into effect in what is normally an irreversible process. Thus, understanding the regulation of Blimp-1 expression is critical for understanding how appropriate primary humoral responses, peripheral B cell tolerance, and B cell memory are regulated. The data detailed below support a general model in which (a) the B cell developmental stage and (b) the nature, strength, and duration of signals that B cells receive from antigen, TLRs, and cytokines combine to determine Blimp-1 expression and plasmacytic development. In B cells, Blimp-1 expression is regulated primarily at the level of transcription initiation (11). Multiple, clustered transcription initiation sites have been mapped in the mouse gene that give rise to a full-length protein (11). An alternative transcription start site, located 5 of exon 4 in the human gene,
Direct targets of Blimp-1 repression in lymphocytes
Gene
Transcriptional regulator?
B cell target
T cell target
References
bcl6
Yes, repressor
Yes
Yes
L. Cimmino & K. Calame, unpublished
myc
Yes, activator and repressor
Yes
No
51; G. Martins, L. Cimmino & K. Calame, unpublished
ciita (promoter III)
Yes, coactivator
Yes
Not expressed
48, 54
fos
Yes, activator
n.d.
Yes
162a; E. Magnusdottis, G. Martins & K. Calame, unpublished
Id3
Yes, inhibitor of E proteins
Yes
n.d.
50
ifng
No
Not expressed
Yes
L. Cimmino & K. Calame, unpublished
il2
No
n.d.
Yes
62; G. Martins & K. Calame, unpublished
pax5
Yes, activator and repressor
Yes
Not expressed
53
spib
Yes, activator
Yes
n.d.
50
tbet
Yes, activator
n.d.
Yes
L. Cimmino & K. Calame, unpublished
n.d., not determined.
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gives rise to a shorter protein known as the beta form, which lacks 101 N-terminal amino acids, contains only a partial PR domain, and has reduced transcription repression activity (62). This form is usually present in submolar amounts relative to the full-length form. Blimp-1 mRNA and protein are labile, with half-lives of less than 2 h (C. Tunyaplin & K. Calame, unpublished). Although phosphorylation of the protein has been observed ( J. Noronha & K. Calame, unpublished), there is no evidence that levels of phosphorylation are regulated, and the effect of phosphorylation on function has not been assessed. IHC shows Blimp-1 is localized entirely in the nucleus in mouse (23) and human (32) B cells. Activators of prdm1 transcription. Pattern-recognition receptors (63), including TLRs, RIG-I-like receptors, and possibly NOD-like receptors, induce Blimp-1 in many settings. This was first demonstrated by induction of Blimp-1 by Sendai virus (double-stranded RNA) infection of U20S cells (8). In B cells treated in vitro, LPS, which activates TLR4, is a strong inducer of Blimp-1 mRNA for murine splenic B cells and for B-1 cells from the peritoneal cavity (30, 47). CpG, which activates TLR9, induces Blimp-1 in human tonsillar B cell cultures (T. Kuo & K. Calame, unpublished). Reishi polysaccharides, which activate TLR4/TLR2, also induce Blimp-1, apparently using different signaling pathways in human and murine B cells (64). These data are consistent with an analysis of TLR4−/− and MyD88−/− mice (65). [MyD88 is an obligate signal transducer for all TLRs except TLR3 and TLR4, which have both MyD88-dependent and MyD88independent pathways (63, 66).] B cells from these mice do not secrete IgM or IgG antibodies normally. Further analysis showed that for a TI-2 response to flagellin, which activates TLR5, MyD88−/− B cells had a defective IgM and IgG1, but not IgG3, response. In a TD GC reaction, both TLR4−/− and MyD88−/− B cells were defective in formation of GC
B cells. GC B cells lacking MyD88 had decreased Blimp-1 mRNA and increased Bcl-6 mRNA. These data are consistent with the idea that TLR signals induce Blimp-1 in both TI and TD responses. However, a more recent paper (67) calls into question the role of TLR signals for B cell responses as it showed that mice lacking all TLR-dependent signaling mounted normal responses to TD antigens delivered in various adjuvants. Thus, the role of TLRs in B cell responses is unclear at present, although their ability to induce Blimp-1 is unquestioned. Pattern recognition receptors activate NF-κB (63), and NF-κB appears to be a direct activator of prdm1 transcription (Table 3), as evidenced by the failure of p65−/− p50−/− 3T3 cells to induce Blimp-1 in response to Sendai virus infection, failure of splenic B cells to induce Blimp-1 in response to LPS in the presence of NF-κB inhibitors, and the binding of p65 in vivo to multiple κB sites in the region 5 to transcription initiation on prdm1 (T. Kuo, E. Magnusdottir & K. Calame, unpublished). TLR or RIG-I activation of Blimp-1 mRNA is sufficient to induce plasmacytic differentiation in activated B cells. However, activated NF-κB is apparently not sufficient to induce Blimp-1 in all stages of B cell development because it plays important roles earlier in B cell development (68), yet Blimp1 is not expressed in these earlier B cells. Furthermore, BCR, CD40 ligation, and B cell–activating factor (BAFF)-dependent signaling also activate NF-κB but do not induce Blimp-1 mRNA (69). In fact, BCR, CD40, and IL-4 signals block LPS-dependent induction of Blimp-1 in murine splenic B cells (69), although in human B cells BCR and CD40 activation enhance IL-21’s ability to induce plasmacytic differentiation and Blimp-1 expression (70). There has, however, been a report that a stress response in macrophage and B cell lines induces Blimp-1 in a way that depends on NF-κB (71). Other transcription factors, including NF-IL6 and IRF1, IRF3, and IRF8 are also induced by TLR signaling (72) and may also induce Blimp-1, especially www.annualreviews.org • Blimp-1 in T and B Lymphocytes
BAFF: B cell activating factor
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Signals that regulate Blimp-1 expression
Function
Signal
B cells
References
T cells
References
IL-2
Yes (BCL1 line)
9
Yes
74, 76
IL-4
n.d.
—
Yes
132
IL-5
Yes
9
n.d.
—
IL-6
Yes (lymphoma lines, bone marrow)
K.L. Lin & K. Calame, unpublished
n.d.
—
IL-10
Yes
27
n.d.
—
IL-21
Yes
77
n.d.
—
B/TCR
Indirect via Bcl-6 or others
78
Yes
76, 35
LPS
Yes
47
n.d.
—
CpG
Yes
29
n.d.
—
Cytokine
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Clonotypic receptor TLR ligand
n.d., not determined.
because IRF8 induces Blimp-1 in myeloid cells (73). Several cytokines, including IL-2, IL5, IL-6, IL-10, and IL-21, induce Blimp1 mRNA, as first noted by Davis and colleagues (9) who showed that Blimp-1 mRNA was induced by IL-2+IL-5 in BCL1 cells (Table 2). Indeed, in T cells as well as B cells, IL-2 is a strong inducer of Blimp-1 mRNA (74). IL-6 induces plasmacytic differentiation of certain human B cell lines (75), and this is accompanied by induction of Blimp-1 mRNA (K.-I. Lin & K. Calame, unpublished). Although there is little evidence that IL-6 is important for driving plasmacytic differentiation during a primary response in vivo, IL-6, secreted by stromal cells, is critical for maintenance of LLPCs in the bone marrow (41). One of its important functions in this setting may be to induce Blimp-1, which is continuously required for the maintenance of these plasma cells (39), although this has not been directly demonstrated. Plasmacytic differentiation of human B cells can be induced by IL-10 following activation by BCR and CD40 signals (79–81). Indeed, if IL-10 is added to human memory cell cultures, rapid plasmacytic differentiation
STAT: signal transducer and activator of transcription
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ensues (82) and is accompanied by induction of Blimp-1 mRNA (27). IL-21 is necessary for normal Ig secretion (83, 84) and induces differentiation of B cells to plasma cells in mice (77). Interestingly, IL21 induces both Blimp-1 and Bcl-6 mRNA (77). Similarly, when human B cells are stimulated via BCR and CD40, IL-21 is a strong inducer of both plasmacytic differentiation and Blimp-1 mRNA, and the effect of IL-21 is enhanced in combination with IL-2 (70). IL-2, IL-6, IL-10, and IL-21 all activate signal transducer and activator of transcription 3 (STAT3), strongly implicating STAT3 as a direct activator of prdm1 transcription. Although this has not been definitely demonstrated, forced expression of a dominantnegative form of STAT3 inhibited Blimp-1 mRNA induction in BCL1 cells (85), providing evidence that STAT3 does activate prdm1 transcription. In addition, and consistent with early observations in BCL1 cells, IL-5, which primarily activates STAT5 (86), induces Blimp-1 mRNA and, like IL-21, also induces genes involved in GC B cells such as bcl6 and aicda (87). IL-2 also activates STAT5 (88), and STAT5 may be important in the IL-2-dependent activation of Blimp-1. However, one study (89) has shown that activated
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Table 3
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Transcription factors that regulate prdm1 transcriptiona
Transcription factor
Activity
B cell
References
T cell
References
AP-1 (fos-Jun)
Activator
Yes
90
(Yes)
—
Bach2
Repressor
Yes
95
Not expressed
96
Bcl-6
Repressor
Yes
97
Yes
L. Cimmino & K. Calame, unpublished
Blimp-1
Autorepressor
n.d.
—
Yes
L. Cimmino & K. Calame, unpublished; 162a
IRF4
Activator
Yes
93
n.d.
—
Foxp3
Activator
Not expressed
—
Yes
98
NFAT
Activator
Yes
99
(Yes)
—
NF-κB
Activator
Yes
T. Kuo and K. Calame, unpublished
(Yes)
—
Pax5
Repressor
Yes
102a
(No)
—
STAT3
Activator
Yes
85
(Yes)
—
STAT5
Activator
n.d.
—
Yes
D. Gong & T. Malek, personal communication
a Parentheses indicate activities implied but not experimentally demonstrated. n.d., not determined.
STAT5 blocks plasmacytic differentiation, so the role of STAT5 in Blimp-1 regulation in B cells is currently unclear. In addition to Jak/STAT pathways, these cytokines also activate other signaling pathways, including the Ras-Raf-ERK, the phosphatidylinositol 3kinase (PI3K), the JNK/SAPK, and the p38 signaling pathways, and these may play a role in induction of Blimp-1 as well, although most of these possibilities remain unexplored. Two other transcriptional regulators, IRF4 and AP-1, bind prdm1 and directly activate its transcription (Table 3). AP-1 was first implicated as an activator of the human gene when it was found that Bcl-6 repressed Blimp-1 transcription by associating with c-Jun and inhibiting the ability of AP-1 to activate PRDM1 (90). Evidence that AP-1 also induces murine prdm1 transcription comes from studies using c-Fos transgenic mice. Splenic B cells from these mice undergo more significant plasmacytic differentiation in response to CD40 and IL-4 than do controls. Further studies on these mice also demonstrated binding of AP-1 to the prdm1 gene by chromatin
immunoprecipitation (ChIP) (91). Because Blimp-1 can be induced in mice lacking c-Fos, it seems that, although AP-1 activates Blimp-1 transcription, AP-1 is not essential (91). IRF4 is necessary for plasma cell formation (92) and more recently has also been shown as a requirement for CSR (93, 94). Mice lacking IRF4 in their B cells have been analyzed to determine if IRF4 might be upstream of Blimp-1 in a regulatory cascade. Two groups obtained different answers to this question. Klein et al. (94) created mice with a conditional deletion of irf4 in GC B cells. Upon LPS stimulation of splenic B cells in vitro, plasmacytic differentiation was blocked, but Blimp-1 mRNA was similarly induced in both wild-type and CKO, providing evidence that IRF4 does not act upstream of Blimp-1 and is not required for Blimp-1 induction. However, when Sciammas et al. (93) studied B cells from the original knockout mice (92), they also observed a failure in plasmacytic development after LPS stimulation, but in their studies, Blimp-1 mRNA failed to be induced. They went on to perform ChIP studies, which www.annualreviews.org • Blimp-1 in T and B Lymphocytes
ChIP: chromatin immunoprecipitation
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identified a site between exon 5 and 6 of prdm1 that was occupied by IRF4 in vivo in stimulated, but not in naive, B cells. They concluded that IRF4 is a direct transcriptional activator of prdm1. Although the discrepancy between the two studies remains unexplained, it may be that minor differences in activation conditions or the developmental stage of the cells studied altered the availability of IRF4 partners or other regulators of prdm1 in the two studies, accounting for different results. The ChIP studies (93), however, strongly suggest that IRF4 does indeed induce prdm1 transcription in at least some conditions.
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Repressors of prdm1 transcription. It is becoming increasingly clear that repression of Blimp-1 is important for its regulated expression in B cells. Bcl-6 was the first repressor of Blimp-1 to be identified, based on microarray analyses of Burkitt cell lines expressing Bcl-6 or a dominant-negative Bcl-6 (97). Forced expression of Bcl-6 also inhibited plasmacytic differentiation and Blimp-1 expression in murine splenic B cells following activation (85). Bcl-6 represses prdm1 transcription by interfering with the AP-1 activator (90) and by binding directly to a conserved site in exon 5 of the murine gene (100). MTA3, a cell type-specific subunit of the corepressor complex Mi-2/NuRD, acts as a corepressor with Bcl-6, and when MTA3 and Bcl-6 expression is forced in myeloma cell lines, Ig secretion and Blimp-1 mRNA expression are inhibited, essentially causing dedifferentiation of these transformed plasma cells (101). Signals that lead to strong activation of PI3K in B cells favor plasmacytic differentiation and inhibit CSR (102). Part of this effect appears to depend on Blimp-1. The mechanism involves PI3K-dependent activation of Akt, which inhibits FoxO-dependent activation of Bcl-6, thus decreasing Bcl-6 and allowing derepression of prdm1 when PI3K is strongly activated (102). Loss of Pax5 in mature murine B cells leads to increased expression of Blimp-1 (60), 144
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and similar results are observed in chicken DT40 cells (61). However, whether this effect is due to direct repression of prdm1 by Pax5 or to Pax5-dependent induction of Bcl-6, which then represses prdm1, or both was not clear in those studies. In mice, loss of Pax5 did not alter Bcl-6 mRNA levels, but in DT40 cells, Bcl-6 was diminished in the absence of Pax5, and induction of Blimp-1 in the absence of Pax5 could be blocked by Bcl-6 (61). A very recent report shows that Pax5 binds to prdm1 and directly represses it (102a). Another repressor of prdm1 transcription is Bach2, a repressor that interacts with small Maf proteins (95). Bach2 is specifically expressed in B cells and required for normal CSR and SHM. Bach2−/− mice have a hyperIgM syndrome and spontaneous plasmacytic differentiation of IgM-secreting cells (95). LPS treatment of Bach2−/− splenic B cells led to abnormally elevated Blimp-1 and XBP-1 mRNA and to repression of AID mRNA (95). Subsequently, a binding site for the Bach2MalK heterodimer in the prdm1 promoter region was identified, and binding of MalK in vivo was demonstrated by ChIP (103), providing additional evidence that Bach2 directly represses prdm1. Repression of plasmacytic differentiation and Blimp-1 expression. There are several mechanisms that prevent premature plasmacytic differentiation by repressing transcription factors required by plasma cells, and most of these mechanisms involve Blimp-1 (Figure 3). Of the three prdm1 repressors discussed above, Bach2 and Pax5 are expressed in preB and naive B cells (96), as well as in GC B cells. Additionally, Pax5 has been reported to repress xbp1 (59, 61), although there are data to the contrary (60). Finally, microphthalmiaassociated transcription factor MITF, which is most abundant in naive B cells, represses IRF4 mRNA by an undetermined mechanism. B cells lacking MITF have spontaneous plasmacytic differentiation (106), providing direct evidence that MITF is important for normal control of terminal differentiation.
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Because IRF4 is a direct activator of prdm1 (93), its repression indirectly represses prdm1. Expression of Bcl-6 protein is highly restricted to GC B cells (33, 104, 105). Thus, Bcl-6 appears to add a second layer of prdm1 repression specifically at the GC stage. Thus, Bach2, MITF, and Pax5 repress plasmacytic differentiation in naive B cells and at developmental stages before and during the GC reaction; in the GC, Bcl-6 is present to further ensure that plasmacytic differentiation is inhibited. Interestingly, when human memory B cells develop in vitro from tonsillar centrocytes, Bach2, Pax5, and Bcl-6 mRNA levels decrease significantly, suggesting that one reason memory cells can differentiate into plasma cells quickly is because they lack these repressors (27). Induction and establishment of plasmacytic differentiation. Current understanding of Blimp-1 regulators, as detailed above, shows that Blimp-1 expression and the plasmacytic differentiation that ensues require a combination of two kinds of events: (a) removal of inhibitors Bcl-6, Pax5, MITF, and Bach2 and (b) induction of activators including IRF4, AP-1, NF-κB, and STAT3 (Figure 4). Interestingly, all three general signals necessary for Ig secretion—antigen, TLR ligands, and cytokines—provide one or more of these signals. The requirement both to remove inhibitors and to supply activators may help explain why LPS is such a potent immunogen because TLR4 activates both MyD88-dependent and -independent pathways (107). The requirement may also explain why activated NF-κB present in B cells at earlier developmental stages or BCR signals alone are unable to induce Blimp-1 mRNA. How are the inhibitors removed? This is a critical question that relates directly to the question of how exit of plasmablasts from the GC is regulated. Unfortunately, information is far from complete, but dissecting the regulation of Blimp-1 in GC and post-GC B cells provides one way to ap-
B cell
Plasma cell
BCR PI3K
MITF
NFAT
irf4
IL-21 FoxO Mad1
Bcl-6
STAT3
prdm1
NF-κB TLR
Pax5
Bach2
xbp1
Provide activation
Remove inhibition Figure 4 Two signals necessary for plasma cell differentiation. Arrows and bars indicate positive or negative regulation, and the orange star indicates protein degradation (27, 29, 30, 47, 78, 93, 99, 100, 108–112).
proach the question. Recent studies establish that high-affinity BCRs direct GC B cells to a plasmacytic fate (108, 109), so models must incorporate BCR signals. Studies using in vitro cultures of human tonsillar centrocytes that develop into plasma cells in response to IL-10 (27) show that levels of Bcl6, Pax5, and Bach2 mRNA drop significantly before large increases in Blimp-1 mRNA occur. There is little information available concerning the mechanisms responsible for loss of Pax5 and Bach2 expression, although decreased Pax5 was observed in preplasmablasts prior to Blimp-1 induction (110). Several mechanisms remove Bcl-6 from GC B cells. BCR-dependent activation of mitogen-activated protein kinase (MAPK) leads to phosphorylation of Bcl-6, which targets Bcl-6 for ubiquitin-dependent degradation (78). Because Bcl-6 is abundant in GC B cells, this mechanism may only be operative in response to strong BCR signals or in combination with other signals, and it may initiate exit of B cells from the GC, as a decrease in Bcl-6 activity is required for both post-GC plasma cell and memory B cell differentiation www.annualreviews.org • Blimp-1 in T and B Lymphocytes
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(27). Acetylation inactivates the ability of Bcl6 to repress transcription, and Bcl-6 is acetylated in GC B cells, although there is no knowledge of if or how acetylation of Bcl-6 may be regulated in GC B cells (111). The E box factor Mad1 is elevated in plasma cells and directly represses Bcl-6 (112). Finally, because FoxO3A activates Bcl-6 (113) and Akt inactivates FoxO transcription factors (114), strong BCR signals, activating PI3K and Akt and inactivating FoxO, lead to a reduction in Bcl-6 and an increase in Blimp-1 in B cells (102). Interestingly, Bcl-6 is not abundant in marginal zone B cells or B1 B cells, and neither Bach2, Pax5, nor Bcl-6 mRNA are found in human memory B cells formed in vitro (27). Thus, in these settings, induction of Blimp-1 can occur more rapidly when appropriate activators are induced. Mice lacking OBF-1 have impaired plasmacytic differentiation in response to certain kinds of stimulation (115). Without OBF-1, bcl6 and pax5 are not repressed, and prdm1 is not induced when B cells are activated in vitro with CD40L and IL-4. However, stimulation by LPS is normal in the absence of OBF-1 (115). The mechanism requiring OBF-1 for induction of Blimp-1 is not clear, although ChIP assays provided no evidence for direct binding of octamer-OBF-1 complexes to prdm1. OBF-1 may indeed be needed to remove one or more repressors such as Bcl-6 in response to certain signals. Many mechanisms are likely to induce or activate activators of prdm1. TLR signals, activating NF-κB, induce Blimp-1 in GC B cells (27) and B-1 B cells (29, 30) and probably in naive and marginal zone B cells present in splenic B cell preparations following treatment with LPS (47). Vav signaling is required downstream of TLR signals to induce Blimp-1 mRNA and to form Igsecreting plasma cells (116). Mature marginal zone B cells, stimulated with TLR ligands, proliferate and express IRF4 but do not express Blimp-1 when they lack Vav proteins, demonstrating that IRF4 alone is not suffi-
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cient to induce Blimp-1. NFAT (nuclear factor of activated T cells) factors are important in B cells, and calcineurin/NFAT-dependent induction of IRF4 is important for post-GC plasmacytic development (99). Because IRF4 is probably a direct activator of prdm1 (93), it follows that NFAT signaling indirectly induces Blimp-1 mRNA in post-GC plasma cells. The role of BCR in regulating prdm1 is interesting and, given rather fragmentary data, certainly deserves further study. There is no evidence that BCR signals alone are sufficient to induce prdm1, and in combination with TLR signals, BCR signals actually block plasma cell formation in vitro (117) and Blimp-1 expression (47). However, NFAT, an indirect activator of prdm1 (99), and AP-1, a direct activator (90), are activated by BCR signals (118). Furthermore, in anergic B cells that do not induce Blimp-1 or develop into plasma cells, NFAT signaling downstream of BCR is uncoupled, whereas extracellular signal regulated kinase (ERK) signaling downstream of BCR is maintained (119). BCR signaling via Ras and MAPK kinase (MEK) to ERK integrates BCR and cytokine signals. ERK activation, via continuous BCR signaling, inhibits Blimp-1 induction, and IL-2 and IL-5 inactivate ERK via induction of the DUSP 5 phosphatase (120). The mechanism for ERK-dependent inhibition of Blimp-1 was not identified, but it might involve Bcl-6 or its cofactors. It is also interesting that in mice lacking Bruton’s tyrosine kinase, TI-2 activation of B cells initially induces Blimp-1, but this is not sustained, and the cells do not progress to become plasmablasts (121). Once Blimp-1 is expressed, it is sufficient to cause plasmacytic differentiation. Blimp-1 also specifically represses genes encoding two critical transcription factors required for GC B cells—pax5 (53) and bcl6 (90, 100). Thus, the plasma cell program is enforced, and earlier stages of B cell development are inhibited by Blimp-1.
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Blimp-1 in B Cell Malignancies
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Recent studies provide evidence that abnormal regulation or abnormal activity of Blimp1 may be one causal event in some B cell malignancies. If Blimp-1 acts as a tumor suppressor, lack of its activity could be important in some forms of lymphoma. Alternatively, its ability to enforce a plasma cell phenotype may be important in plasma cell tumors.
Diffuse large B cell lymphoma. When an early study identified myc as a direct target of Blimp-1-dependent transcriptional repression (51), it was logical to speculate that Blimp-1 might function as a tumor suppressor, especially given the prominent role of dysregulated c-Myc expression in B cell tumors (122). Interestingly, however, aged mice with conditional deletion of prdm1 in the B cell lineage do not develop B cell tumors spontaneously (M. Shapiro-Shelef & K. Calame, unpublished), indicating that loss of Blimp-1 alone is not sufficient for B lymphomagenesis. Nevertheless, there is growing evidence that deletion or mutation of PRDM1 is frequently found in a subset of diffuse large B cell lymphoma (DLBCL), providing evidence that it may indeed function as a tumor suppressor (123–125). Similar PRDM1 mutations were not found in B or T or myeloid leukemias or in the 467 common carcinomas examined (126). In the most thorough study on DLBCL, PRDM1 was inactivated by structural alterations in 24% (8 out of 34) activated B cell–like diffuse large cell lymphomas but not in GC B cell–like (n = 0/37) or unclassified (n = 0/21) DLBCLs (125). However, a subset of DLBCL, which expressed Blimp-1, lacked detectable plasmablastic or immunoblastic changes and displayed more aggressive behavior, with a shorter failure-free survival (127). Thus, further studies are warranted to determine how expression and lack of expression of Blimp-1 affect the formation and properties of different subsets of DLBCL.
Murine plasmacytoma and human multiple myeloma. Malignant plasma cells in both mice (plasmacytoma) and humans (multiple myeloma) express abundant levels of Blimp-1, which likely reflects their differentiated state as plasma cells and the fact that they usually secrete Ig. Blimp-1 is also present in a subset of DLBCL but not in marginal zone lymphomas or chronic lymphocytic leukemia (32), and abortive plasmacytic differentiation in some Hodgkin and Reed Sternberg cells is indicated by the presence of Blimp-1 (128). Apparently, the ability of Blimp-1 to repress myc is overcome in these tumors by oncogenic changes, such as chromosomal translocation, that activate and dysregulate myc transcription or the dominant activity of other oncoproteins. [However, Blimp-1 is apparently able to repress myc in other tumors, such as myeloid tumors, where it is induced by IRF8 (73).] There is active interest in determining how forcing expression of Blimp-1 or, alternatively, blocking its activity or knocking down its expression might affect the growth and phenotypic properties of myeloma or other B cell tumors. In a recent study, treatment of myeloma cell lines with 2-methoxyestradiol, which suppresses their growth and induces apoptosis, also led to an elevation of Blimp1 and XBP-1 and repressed MYC and PAX5 (129). In some myeloma cell lines, the proportion of the beta form of Blimp-1 is elevated in comparison with normal plasma cells (62, 130), which might decrease the overall activity of Blimp-1, but the functional consequences of elevated beta form have not been elucidated clearly. Assuming Blimp-1 is necessary for the Ig secretion program in myeloma, as it is in normal plasma cells, one reasonable prediction is that blocking Blimp-1 in the tumors might block Ig secretion. Whether this would cause apoptosis owing to endoplasmic reticulum stress as observed upon administration of protease inhibitors (131) or to failure of other survival mechanisms (39) or dedifferentiation (101) remains to be determined. www.annualreviews.org • Blimp-1 in T and B Lymphocytes
DLBCL: diffuse large B cell lymphoma
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BLIMP-1 IN T CELL BIOLOGY
LCMV: lymphocytic choriomeningitis virus
The understanding that Blimp-1 is also important in the T lymphocyte lineage emerged only within the past 2–3 years. Thus, this work is at an earlier stage. Although the overall effect of lacking Blimp-1 T cells is fatal, owing to spontaneous inflammatory disease, the cellular and molecular effects are more subtle and complex than the effects in B cells.
Expression of Blimp-1 in T Cells Blimp-1 protein is expressed in human (32, 132) and mouse (35, 74) T cells, and in both species Blimp-1 levels are significantly higher in antigen-experienced cells. Indeed, the levels of Blimp-1 mRNA and protein in antigen-experienced murine and human T
Treg
Naive
Activated/effector
Memory
Naive
Activated/ effector
Memory
Blimp-1 transcripts
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Regulatory T (Treg) cells: those CD4+ CD25+ regulatory T cells, both constitutive and inducible, that express FoxP3 and suppress T cell responses
Activation and differentiation status Figure 5 Blimp-1 expression in T cells. Blimp-1 mRNA (represented by arbitrary units on the y-axis) is present in low levels in naive CD4+ and CD8+ T cells but is abundant in ex vivo isolated antigen-experienced (CD62LLo CD44Hi and CD62LHi CD44Hi ) cells. Memory CD8+ T cells and some of the memory CD4+ T cells are contained in the CD62LHi CD44Hi subpopulation, which expresses slightly lower levels of Blimp-1 mRNA than the CD62LLo CD44Hi cells. In vitro stimulation (not depicted) of the naive T cells results in a slow increase in Blimp-1 expression, reaching levels similar to that observed in the ex vivo isolated antigen-experienced cells. Ex vivo isolated CD4+ CD25+ naturally occurring, regulatory T (Treg) cells express Blimp-1 transcripts at the same levels as effector nonregulatory CD4+ T cells (35, 76, 132). 148
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cells are similar to those observed in cultures where plasma cells are generated in vitro by LPS treatment of splenic B cells (76, 132). Although steady-state Blimp-1 mRNA is present in low levels in mouse thymocytes (76, 133) and naive CD4+ and CD8+ T cells (76, 132), levels increase 20–40 times upon stimulation with α-CD3, α-CD28, and IL-2 (35, 76, 132). Induction of Blimp-1 mRNA and protein in vitro is slow, with maximum levels achieved 3–5 days poststimulation (76, 132). T cell receptor (TCR) restimulation in the presence of α-CD28 leads to a further increase in Blimp-1 mRNA expression (132; L. Cimmino & K. Calame unpublished). Blimp-1 mRNA is also found in high levels in ex vivo purified CD4+ or CD8+ effector/memory (CD62LLo /CD44Hi ) and memory phenotype (CD62LHi /CD44Hi ) T cells, with the first subpopulation showing slightly more abundant Blimp-1 transcripts (Figure 5) (76). Finally, Blimp-1 transcripts are observed in high levels in ex vivo purified CD4+ CD25+ CD62LHi , which are mostly composed of Foxp3+ cells, known as naturally occurring, regulatory T (Treg) cells (35, 76). Prdm1-GFP knockin (Figure 1c) reporter mice (24) have been used to monitor Blimp-1 expression in T cells (24). GFP expression is not detected in the thymus or in naive peripheral T cells, but it was observed in in vitro– activated T cells, in vivo antigen-experienced CD4+ and CD8+ peripheral T cells, and in CD4+ CD25+ CD62LHi cells, which are primarily Foxp3+ Treg cells (24). Thus, despite the limitations of using GFP as a reporter for Blimp-1 expression, these data are consistent with observations described above showing that within the T cell lineage Blimp-1 is found in highest levels in antigen-experienced cells and in naturally occurring Treg cells. In agreement with these patterns, Blimp-1 is upregulated in vivo in CD8+ antigen-specific T cells upon infection with herpes simplex virus (HSV) (35) and with lymphocytic choriomeningitis virus (LCMV) (R. Rutishauser & S. Kaech, unpublished).
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Although Blimp-1 expression is consistently elevated in antigen-experienced CD4+ T cells, levels vary: Naive CD4+ T cells stimulated under Th2 conditions (IL-2, IL-4, and anti-IFN-γ) express higher levels of Blimp1 steady-state mRNA than do cells stimulated under Th1 (IL-2, IL-12, and anti-IL4) or nonpolarizing conditions (IL-2) (132; L. Cimmino & K. Calame, unpublished). Indeed, Blimp-1 mRNA expression seems to be repressed as cells differentiate under Th1 conditions because at the end of a 6-day culture, Th1 cells express less Blimp-1 steadystate mRNA than do cells stimulated under nonpolarizing conditions (L. Cimmino & K. Calame, unpublished). However, differential expression of Blimp-1 in Th subsets was not observed in the Blimp-1-GFP knockin reporter mice (35). Nonetheless, immunoblotting reveals that Blimp-1 protein is higher in Th2 than in Th1 cells after two rounds of polarization in vitro (L. Cimmino & K. Calame, unpublished). Importantly, these differences are observed before any restimulation at the end of the differentiation rounds, suggesting that the differential levels of Blimp-1 expression are maintained in resting Th1 and Th2 cells and might be related to the maintenance of the respective T helper phenotype.
Blimp-1 and T Cell Development The pattern of Blimp-1 mRNA expression in T cells—low in thymocytes and naive T cells, high in antigen-experienced T cells—is consistent with the idea that Blimp-1 is more important for T cell function than development; however, conditional deletion of Blimp1 in T cells (prdm1F/F Lck-Cre mice) resulted in significant alterations in the thymus (76). The prdm1F/F Lck-Cre mice have a threefold decrease in the numbers of total thymocytes (76), which can be attributed to a marked reduction in the absolute numbers of CD4+ and CD8+ double-positive (DP) as well as singlepositive (SP) CD4+ or CD8+ thymocytes. This defect is observed as early as 4 weeks after birth and progresses with age. There
is no significant alteration in the number of double-negative (DN) and γδ thymocytes and no significant differences in the distribution of the various DN thymocyte subsets between control and prdm1F/F Lck-Cre mice, as determined by CD25 and CD44 expression. Also, developmental stage-specific surface markers (CD5, TCRβ, HSA, CD24, and CD69) and short-term BrdU incorporation are indistinguishable between control and prdm1F/F LckCre mice, suggesting that the maturation and proliferation of each subset are preserved in the absence of Blimp-1. However, DP thymocytes are more susceptible to cell death, suggesting that Blimp-1 may regulate survival during negative selection of DP thymocytes (76). Nevertheless, the possibility that decreased survival of the prdm1F/F Lck-Cre mice DP thymocytes is secondary to the immune activation in the periphery cannot be excluded, and more work is required to clarify the role of Blimp-1 in thymocyte development.
Functions of Blimp-1 in T Cells Mice lacking Blimp-1 in their T cells have provided valuable information about the role(s) of Blimp-1 in the T lineage. Although these CKO mice were created in different ways in two laboratories, most of the observations from the two groups were consistent. However, one key difference is the possible role Blimp-1 may play in CD4+ Treg cells. Spontaneous inflammatory disease in mice with T cells lacking Blimp-1. Two strategies were used to generate mice with Blimp1-deficient T cells. One group crossed the prdm1F/F mice (Figure 1d ) with proximal Lck-Cre or CD4-Cre transgenic mice, generating mice in which Blimp-1 deletion was specifically restricted to T lymphocytes (76; G. Martins & K. Calame, unpublished). The other group used fetal liver cells from prdm1gfp/gfp (Figure 1c) embryos to reconstitute the hematopoietic compartment of Rag-1-deficient mice, resulting in the www.annualreviews.org • Blimp-1 in T and B Lymphocytes
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generation of chimeric mice in which cells from the myeloid and lymphoid lineages were prdm1gfp/gfp and Blimp-1 deficient (35). Despite the differences in the two approaches, both studies revealed that lack of Blimp-1 results in profound alterations of T cell function and homeostasis, culminating with the spontaneous development of inflammatory disease (35, 76). Whereas in the first model (T cell–specific deletion of Blimp-1) the inflammatory disease was concentrated in the colon (35, 76), mice reconstituted with prdm1gfp/gfp fetal liver cells also had inflammation in other organs, including lungs and liver (35). Although the nature of this difference has not yet been systematically addressed, it may simply reflect the different approaches used (deletion of Blimp-1 in T cells only versus deletion of Blimp-1 in the lymphoid and myeloid compartments). If so, one would predict that Blimp-1 might be important for regulating the function of hematopoietic cells other than T and B lymphocytes, a possibility that remains to be investigated. It is also possible that the difference in severity of the inflammatory disease observed in the two models is related to differences in the genetic background: The prdm1F/F LckCre mice were of mixed 129xC57BL/6 background, whereas the prdm1gfp/gfp mice where backcrossed into C57BL/6. In other models of spontaneous development of inflammatory diseases (134) the severity and target organs might vary in different genetic backgrounds. Finally, differences in the animal facilities used to house the different Blimp-1 CKOs could also explain differences in the inflammatory phenotype. The cellular and molecular mechanisms associated with development of colitis in mice with Blimp-1-deficient T cells are not completely understood. T cell dysfunction is associated with colitis in many murine models, which are generally characterized by deregulated activation of effector T cells with excessive production of IFN-γ and decreased production of IL-10 and/or defective devel-
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opment/function of Tregs (135, 136). Current data indicate several probable causes of colitis development in the prdm1F/F Lck-Cre mice. Blimp-1-deficient CD4+ T cells produce increased amounts of IFN-γ, and their production of IL-10 is significantly impaired (see below), indicating deregulated T cell activation and/or biased Th1 differentiation. There is also partial impairment of Treg function in the absence of Blimp-1, discussed below. Interestingly, a small population of CD4+ T cells with colitogenic potential can be found in normal mice (137). Apparently, these cells can be driven into the antigen-experienced pool by the presence of commensal bacteria but are normally kept under control by Treg cells in an IL-10-dependent manner (137). Hence, it would be interesting to know if the antigen-experienced cells that accumulate in mice with T cell–specific deletion of Blimp-1 contain these potentially colitogenic cells. If that is indeed the case, the defective production of IL-10 by Blimp-1-deficient Treg cells (see below) could provide a mechanistic explanation for their accumulation. Nonetheless, direct evidence linking the accumulation of the antigen-experienced cells with the spontaneous development of colitis in the T cell– specific Blimp-deficient mice is still lacking, and it is not known if the defect in IL-10 production is associated with colitis in these mice. T cell homeostasis and attenuation of IL2 production. The elevated expression of Blimp-1 in peripheral antigen-experienced T cells and the substantial accumulation of these cells in both prdm1F/F Lck-Cre and prdm1gfp/gfp mice, despite the different genetic backgrounds of the mice, provide strong evidence that Blimp-1 is important in T cell homeostasis. Evidence from studies in which Blimp-1 is ectopically expressed (74, 132) or deleted from T cells (35, 76) indicates that Blimp1 regulates responsiveness and homeostasis of peripheral T cells by attenuating both proliferation and survival. Blimp-1-deficient antigen-experienced CD4+ T cells are less susceptible to apoptosis upon restimulation
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in vitro (35; G. Martins & K. Calame, unpublished), and in vitro–differentiated Blimp1-deficient Th1 cells are more resistant to cell death caused by cytokine withdrawal (35), suggesting that Blimp-1 normally promotes apoptosis of effector T cells. In addition, it appears that Blimp-1 attenuates proliferation induced upon TCR stimulation of naive T cells. Ectopic expression of Blimp-1 resulted in decreased proliferation of CD4+ T cells (132), and naive CD4+ T cells from the prdm1F/F Lck-Cre mice proliferate better than wild-type cells when stimulated in suboptimal conditions (76). Stimulation in optimal conditions, including CD28-mediated costimulation and addition of exogenous IL-2, abrogates the proliferation differences between Blimp-1-sufficient and -deficient cells (35, 76), suggesting that regulation of proliferation by Blimp-1 is limited to conditions in which costimulation is absent or weak, such as presentation of a self-antigen in the periphery where the normal result is anergy of the responder T cell (138, 139). Thus, lack of Blimp-1 may cause increased responsiveness to self-antigens. Furthermore, one may speculate that Blimp-1 normally attenuates tonic signaling through the TCR (140). Both possibilities remain to be experimentally evaluated. Blimp-1-deficient CD8+ T cells seem to respond abnormally to exogenous antigens, as indicated by the increased accumulation of antigen-specific CD8+ T cells after infection of prdm1gfp/gfp mice with HSV (35). Also, in a system where P14 TCR transgenic, prdm1deficient or control naive CD8+ T cells were transferred to wild-type recipient mice and the recipients infected with LCMV, there was significantly more accumulation of Blimp-1deficient cells (R. Rutishauser & S. Kaech, unpublished). One key mechanism by which Blimp-1 modulates T cell responsiveness is likely to be through repression of IL-2. IL-2, acting in both autocrine and paracrine manners, regulates the initial expansion of naive T cells upon TCR stimulation in vitro (141, 142) and
possibly in vivo. Paracrine IL-2 is also important for the in vivo survival of Tregs, which in turn regulate the proliferation of peripheral T cells (142, 143). Multiple observations support the idea that Blimp-1 represses IL-2. Production of IL-2 is elevated in naive Blimp1-deficient CD4+ T cells following activation in vitro (76), and IL-2 steady-state mRNA levels in naive Blimp-1-deficient CD4+ T cells are elevated relative to controls both before and following activation in vitro (G. Martins & K. Calame, unpublished). Ectopic expression of Blimp-1 significantly decreases IL-2 production in wild-type CD4+ and CD8+ T cells, and IL-2 production declines when Blimp-1 levels are highest after TCR stimulation (74, 132). Moreover, ectopic expression of Blimp-1 inhibited the expression of an IL-2 promoter-GFP reporter (74) in vitro. However, the relationship between IL-2 and Blimp-1 is additionally complicated and interesting. As detailed below, IL-2 signaling strongly induces prdm1 transcription (74). Thus, T cell activation induces il2 transcription, IL-2 signaling induces prdm1 transcription, and Blimp-1 feeds back to repress il2 transcription (Figure 6). Blimp-1 therefore appears to be a key component of the pathway by which IL-2 downregulates its own expression during later phases of T cell activation (144) (Figure 6). Together these data suggest a model (Figure 7) in which Blimp-1 controls T cell function in two different stages: At the initial activation stage it may regulate responsiveness by attenuating IL-2 production and proliferation, and, subsequently, it may enhance the elimination of effector cells via apoptosis. Additionally, Blimp-1 might be required for the proper function of Treg cells, another pathway by which Blimp-1 regulates T cell responses. Thus, Blimp-1-deficient T cells would proliferate more when differentiating into effectors, and the effectors would survive better. This could help to explain the abnormal accumulation of antigen-experienced cells observed in the Blimp-1-deficient mice. www.annualreviews.org • Blimp-1 in T and B Lymphocytes
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Figure 6 The regulatory feedback loop involving Blimp-1 and IL-2 in T cells. (1) Antigen and costimulation induce il2 (pink rectangle) transcription via NFAT, AP-1, and NF-κB. (2) IL-2 secreted from the cell, in either an autocrine or paracrine manner, binds the IL-2 receptor. (3) IL-2 signaling, probably via activated STAT3 or STAT5, induces prdm1 transcription and Blimp-1 protein (74). Blimp-1 represses il2 directly and also represses fos, a component of AP-1 which activates il2 (4) (G. Martins & K. Calame, unpublished).
T helper differentiation. Blimp-1 appears to play a role in Th2 cells by repressing Th1 genes (Figure 8). Deletion of Blimp1 in T cells causes increased production of IFN-γ and decreased production of IL-10 (35, 76). Production of IL-4 was decreased in one model of T cell deletion of Blimp-1 (35) but not significantly altered in another (76). The increased production of IFN-γ by Blimp-1-deficient T cells suggests that Blimp1 may attenuate Th1 differentiation. Consistent with that, Blimp-1 transcripts and protein are more abundant in Th2 than in Th1 cells differentiated in vitro (132; L. Cimmino & K. Calame, unpublished). Despite these observations, Blimp-1-deficient CD4+ T cells can be polarized into Th1 or Th2 cells in vitro, and IL-4 production seems unaffected, although IFN-γ production is slightly increased in both Th1 and Th2 cells derived from Blimp-1deficient mice (L. Cimmino & K. Calame, unpublished). It will be important to determine if Blimp-1-deficient Th cells can still 152
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polarize normally in an in vivo immune response, where the factors directing Th polarization, such as strength of TCR stimulation and concentration of different cytokines, are more complex than in the in vitro cultures. Consistent with increased IFN-γ production, Blimp-1-deficient T cells show increased levels of IFN-γ and Tbet steady-state mRNA (L. Cimmino & K. Calame, unpublished). Another important player in the regulation of Th differentiation by Blimp-1 appears to be Bcl-6. Blimp-1-deficient T cells have increased Bcl-6 mRNA levels (L. Cimmino & K. Calame, unpublished), and Bcl-6 proteins can repress Th2 differentiation by interfering with the function of GATA-3 (145), a master regulator of Th2 differentiation (reviewed in 146), and by direct repression of il5 transcription (147). Thus, alleviating bcl6 repression could be one mechanism responsible for increased production of Th1 cytokines in Blimp-1-deficient T cells. The idea that Blimp-1 might be required to inhibit Th1
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Other genes
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Proliferation and survival Figure 7 A model for Blimp-1 attenuation of proliferation and survival in CD4+ T cells. TCR stimulation of naive T cells induces IL-2 production and Blimp-1 expression. Blimp-1 attenuates T cell proliferation and survival following primary activation in several ways. (1) Blimp-1 attenuates induction of the il2 gene indirectly by repressing fos and directly by repressing il2. (2) Blimp-1 also represses transcription of bcl2a1 (although it is not known if this occurs directly or indirectly). By interfering with pathways 1 and 2, Blimp-1 might regulate proliferation and survival upon primary TCR stimulation. Pathway 2 could also remain operative in antigen-experienced cells at later stages of differentiation because Blimp-1-deficient Th1 effector cells seem more resistant to cytokine deprivation cell death (35). Additionally, Blimp-1 might repress genes related to activation-induced cell death (AICD) induction (not shown). This latter pathway is more likely to be operative in antigen-experienced cells, at later stages of differentiation, as indicated by the phenotype of mice with Blimp-1-deficient T cells (35, 76).
Activation IL-12 AP-1 NFAT NF-κB
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Figure 8 A model for Blimp-1 attenuation of Th1 cell differentiation. Blimp-1 represses ifng directly and indirectly via repression of tbet. It also represses bcl6 and tbet directly and indirectly via repression of ifng (L. Cimmino and K. Calame, unpublished).
differentiation also fits with the observation that ablation of Blimp-1 in T cells results in spontaneous development of colitis, which, in most of the cases, is mediated by IFNγ-producing cells (135, 136). However, to date there is no direct evidence that a biased Th1 response is a cause of the spontaneous colitis/inflammatory disease observed in mice with Blimp-1-deficient T cells. Colitis development in the prdm1F/F LckCre mice might also be associated with the impaired production of IL-10. The decreased production of IL-10 by the Blimp1-deficient cells is most likely a cell-intrinsic defect because it is observed in conditions in which IFN-γ is minimal or nonexistent, such as when purified CD4+ CD25+ Foxp3+ Treg cells are stimulated in vitro (G. Martins & K. Calame, unpublished). This finding also www.annualreviews.org • Blimp-1 in T and B Lymphocytes
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indicates that regulation of IL-10 production by Blimp-1 extends to the Treg cells, and this defect could be one of the triggers of the inflammatory disease observed in these mice, as discussed below.
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Differentiation of CD8+ T cells. The expression pattern of Blimp-1 is similar in CD4+ and CD8+ cells (35, 74, 76, 132), but little is known about the role of Blimp-1 in CD8 cells. As mentioned above, prdm1gfp/gfp mice are able to mount an efficient CD8+ -mediated response to HSV infection, and in this model, Blimp-1-deficient CD8+ T cells performed immediate effector functions, such as IFN-γ production and cytotoxicity, normally. Interestingly, there was significant accumulation of antigen-specific CD8+ T cells by day 55 postinfection in the prdm1gfp/gfp mice. Kallies et al. (35) suggested that these were memory cells, but neither their phenotype nor function was evaluated. If these cells are indeed memory cells, these results would indicate that Blimp-1 attenuates the formation of memory cells or enhances their elimination. This would be consistent with the idea that Blimp-1 is important for the elimination of antigen-experienced cells and, in the CD8+ lineage, may limit the transition from effectors to memory cells. Blimp-1-deficient antigen-specific cells also accumulate in vivo after infection with LCMV, in a transfer system where only the antigen-specific CD8+ T cells were Blimp-1 deficient (R. Rutishauser & S. Kaech, personal communication). In this system, the accumulated cells have a memory precursor effectorlike phenotype (CD127Hi KLRG1Lo ) characterized by high levels of expression of the IL-7 receptor. Taken together, these results suggest that Blimp-1 might play an important role in the differentiation of CD8+ T cells, but this requires further investigation. It will be important to know if the memory cells that accumulate in the absence of Blimp-1 in both systems can actually provide protection upon infection when transferred to a naive recipient. Also, identification of Blimp-1 154
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target genes in these systems could provide important insights into the molecular mechanisms regulating the differentiation of memory cells in the CD8+ lineage. In this context, an important player could be Bcl-6, which is a target of Blimp-1 in B and T cells and is known to support the survival of memory CD8+ T cells (148, 149). Treg cell function in vivo. The expression of high levels of Blimp-1 in Treg cells and the inflammatory disease associated with Blimp-1 ablation in T cells suggest a role for Blimp-1 in Treg cell differentiation and/or function. However, CD4+ CD25+ Foxp3+ Treg cells develop normally in the absence of Blimp-1 (35, 76). Indeed, prdm1gfp/gfp mice show increased frequency of splenic CD4+ /FoxP3+ cells (35), and peripheral CD4+ /Foxp3+ cells numbers increase with age in the prdm1F/F Lck-Cre mice (G. Martins & K. Calame, unpublished observations). It is important to determine if this expansion is due to increased IL-2 in the mice. Blimp-1-deficient Treg cells perform normally in in vitro suppression assays and are also able to suppress colitis caused by homeostatic expansion of naive CD4+ T cells in Rag1-deficient mice (35, 76). Nevertheless, Blimp-1-deficient Treg cells cannot suppress acute colitis induced by dextran sodium sulfate (DSS) administration (76) and do not prevent inflammatory disease in Blimp-1-deficient mice (35, 76), demonstrating a functional impairment. The reason that Blimp-1-deficient Tregs control colitis in the RAG reconstitution system but not in the DSS system is not clear but may be related to the differential requirement for IL-10. IL-10 is associated with resistance to DSS-induced colitis (150, 151) but may not be as critical for preventing colitis induced by homeostatic proliferation of naive CD4+ cells (137). Available data indicate that Blimp-1 is required for IL-10 production by Treg cells (G. Martins & K. Calame, unpublished observations) as well as for nonregulatory CD4+ T cells (35, 76). Because Blimp-1 is a repressor,
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it is likely that Blimp-1 represses a gene that negatively regulates IL-10 expression, but this remains to be determined.
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Targets of Blimp-1 in T Cells RNA microarray analyses and gene expression studies using a quantitative reverse transcriptase PCR (qRT-PCR) have begun to reveal genes that are targets of Blimp-1 repression in T cells. This list includes bcl2a1, bcl6, il2, erg2, ifng, prdm1, tbet, and fos. Some of these targets (bcl2a1 and bcl6 ) are in common with B cells; others seem to be unique to T cells (Table 1). qRT-PCR studies, showing higher levels of mRNA in Blimp-1-deficient T cells compared with controls, combined with ChIP assays, demonstrating binding of endogenous Blimp-1 in primary T cells, have shown that il2, fos, ifng, tbet, and bcl6 are direct targets of Blimp-1-dependent repression in T cells (G. Martins, L. Cimmino & K. Calame, unpublished). The evidence that Blimp-1 represses IL-2 production was discussed above, and it makes sense that il2 is a direct target of Blimp-1 repression. It seems likely that, in addition to direct repression of il2, repression of fos is important for the Blimp-1-dependent attenuation of T cell activation and IL-2 production. mRNA encoding Fos, a member of the AP1 family of transcription factors, is elevated in Blimp-1-deficient CD4+ T cells following TCR stimulation. Fos is an important activator of IL-2 production upon TCR stimulation in T cells (152, 153). Thus, repression of il2 transcription by Blimp-1 in T cells seems to occur both directly and indirectly. Although not yet directly tested, Blimp-1 may repress il2 in Treg as well as in nonregulatory CD4+ T cells (Figure 9). Repression of ifng, tbet, and bcl6 is very likely to be important for Blimp-1-dependent repression of Th1 differentiation. Ifng is not only directly repressed by Blimp-1 but may also be indirectly repressed by suppression of tbet. In turn, decreased IFN-γ production would decrease expression of both tbet
and bcl6. In yet another example of redundant regulation, Blimp-1 also directly represses both of these genes. Thus, Blimp-1 is part of a complicated network of regulation that inhibits Th1 differentiation (Figure 8). However, the functional importance of this aspect of Blimp-1’s activity remains largely untested. An interesting common target gene for Blimp-1 in both B and T cells is bcl2a1, encoding A1, an antiapoptotic member from the Bcl-2 family of proteins (reviewed in Reference 154). A1 (a and b) are highly expressed by Blimp-1-deficient cells in microarray studies comparing in vitro stimulated CD4+ T cells from control and prdm1F/F Lck-Cre mice (G. Martins & K. Calame, unpublished). Accordingly, A1 transcripts, measured by qRTPCR, are more abundant in Blimp-1-deficient CD4+ T cells stimulated in vitro. In B cells, bcl2a1 is repressed by Blimp-1 (50), and enforced expression of A1 rescued Blimp-1induced cell death (155). In T cells, A1 is expressed upon TCR stimulation (156), and it may play a role in protecting cells from cytokine deprivation–induced cell death (157). A CD2-driven bcl2a1 transgenic mouse showed an increased number of peripheral T cells, but their activation status was not evaluated. T cells from these transgenic mice also show decreased death upon stimulation with T cell mitogens (157). Similar to other Bcl-2 family members, A1 does not seem to play any nonredundant role in protecting T cells from activation-induced cell death (AICD) (157). This is consistent with the fact that AICD, as assayed following in vitro activation of naive CD4+ T cells, was unaltered in CD4+ T cells from the prdm1f /f mice (76). Nonetheless, Blimp-1-deficient in vitro–generated CD4+ effector T cells are more resistant to cytokine withdrawal–induced cell death (76; G. Martins & K. Calame, unpublished). Thus, derepression of bcl2a1 in the Blimp-1deficient T cells might contribute to the accumulation of the antigen-experienced cells in the periphery of the prdm1f /f LckCre mice. Sequence inspections reveal the www.annualreviews.org • Blimp-1 in T and B Lymphocytes
AICD: activation-induced cell death
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A model for Blimp-1 in Treg cells. Blimp-1 is expressed in high levels in Treg cells, induced by Foxp3 directly and probably also by IL-2, to which Treg cells are highly responsive. Blimp-1 could promote IL-10 expression by repressing a factor that normally inhibits its expression. IL-2 production is normally repressed in Treg cells by Foxp3, which interferes with NFAT induction of the il2 gene. Direct or indirect repression of il2 by Blimp-1 may also occur, as discussed in the text. Dotted lines represent regulation that is predicted based on findings in nonregulatory T cells but not yet confirmed in Treg cells.
presence of Blimp-1 putative-binding sites in the promoter region of the murine bcl2a1 gene (G. Martins & K. Calame, unpublished observations). ChIP studies are needed to clarify if A1 is a direct target of Blimp-1 in T cells.
Regulation of Blimp-1 Expression in T Cells While several aspects of transcriptional regulation of prdm1 appear to be conserved in T cells and B cells, the overall regulatory pathways in T cells are distinct, and in T cells there is a clear role for antigen receptor stimulation in Blimp-1 induction. TCR and IL-2. Blimp-1 mRNA and proteins are induced during T cell activation. In vitro stimulation of naive CD4+ T cells with α-CD3, or α-CD3 and α-CD28, results in Blimp-1 mRNA induction, but maximum levels are induced when exogenous IL2 is administered together with α-CD3 and α-CD28 (132; L. Cimmino & K. Calame unpublished), suggesting that IL-2 greatly po156
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tentiates prdm1 induction upon TCR stimulation. Indeed, T cells lacking the β-chain of the IL-2 receptor (IL-2Rβ−/− ) express significantly less Blimp-1 than wild-type cells upon TCR stimulation, and TCR stimulation in the presence of IL-2-neutralizing antibodies resulted in very low/undetectable Blimp1 protein (74). Therefore, a large portion, but not all, of prdm1 induction upon TCR stimulation seems to be secondary to induction of IL-2. Furthermore, IL-2 is required to maintain Blimp-1 expression after the initial in vitro activation of CD8+ T cells, a function that IL-15, another common gamma chain cytokine, was unable to perform (74). The importance of IL-2 for Blimp-1 expression is consistent with the late expression of Blimp-1 during T cell activation in vitro, and it is likely to have important regulatory functions because Blimp-1 represses il2, as discussed above. The components downstream of IL-2 signaling required for Blimp-1 induction remain to be identified, but STAT5 is probably an important element in this pathway.
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Other regulators. High levels of Blimp-1 in naturally occurring Foxp3+ Treg cells are likely to be caused by IL-2 signaling, which is critical for maintenance and proliferation of Treg cells in the periphery (158) (Figure 9). In addition, a genome-wide analysis of Foxp3 targets showed that prdm1 is directly activated by Foxp3 (159), adding further support to the idea that Blimp-1 is required for proper function of Treg cells. Extrapolating from the data in nonregulatory cells, we can surmise that Blimp-1 likely represses il2 transcription in Treg cells. This would provide another mechanism, in addition to competition with NFAT (160), by which Foxp3 represses il2 in Treg cells (Figure 9). Comparative analysis of gene expression profiles in Blimp-1-sufficient and -deficient Treg cells will be necessary to further elucidate Blimp-1’s mechanisms of action in Treg cells. The fact that Blimp-1 transcripts can be induced, albeit to low levels, in the IL-2Rβ−/− T cells upon TCR stimulation, indicates the existence of IL-2-independent pathways for Blimp-1 induction. Blimp-1 protein levels were increased in these cells upon TCR stimulation in the presence of IL-4 or IL-12, suggesting that these cytokines can also induce Blimp-1 expression (74). Interestingly, in these studies IL-4 seems to be a stronger inducer of Blimp-1 protein than IL-12 (74). In wild-type naive CD4+ T cells, Blimp-1 mRNA is also induced more strongly by IL4 than by IL-12, and in this same system, administration of exogenous IFN-γ reduces the induction of Blimp-1 transcripts upon TCR stimulation (L. Cimmino & K. Calame, unpublished). Thus, consistent with the expression patterns discussed above, TCR stimulation in Th2-promoting conditions (IL4) results in strong induction of Blimp-1, whereas Th1-promoting conditions (IL-12 and IFN-γ) result in weak Blimp-1 induction. IL-21 is expressed in T cells as well as B cells (160a), and although IL-21 induces prdm1 in B cells, there is currently no information as to whether IL-21 induces prdm1 in T cells. IL21 is expressed at high levels in inflammatory
conditions (161, 162), and if it induces Blimp1 in T cells, this could be a mechanism for downregulation of T cell function and containment of inflammation. In addition to being regulated by TCR stimulation and cytokines, preliminary data indicate that prdm1 is autoregulated by Blimp1. This was first discovered in epidermal keratinocytes, where a Blimp-1 deficiency results in elevated amounts of transcripts from the deleted allele relative to transcripts from the wild-type allele. In this same system, ChIP assays show that Blimp-1 directly binds the prdm1 gene (162a), thus indicating that lack of Blimp-1 results in increased transcription of Blimp-1 mRNA. Similarly, in vitro– stimulated CD4+ T cells from prdm1 CKO mice show an increase in Blimp-1 mRNA as detected by real-time PCR using primers for the region upstream of the deleted region (L. Cimmino & K. Calame, unpublished). CD4+ CD25+ T cells from prdm1gfp/gfp mice also seem to have increased amounts of prdm1 mRNA, as demonstrated by semiquantitative RT-PCR (35). The physiological relevance of Blimp-1 autoregulation in T lymphocytes still remains to be addressed, but given the general action of Blimp-1 in attenuating T cell responses, it might be that autoregulation was selected to avoid inappropriate termination of immune responses. In this context, it would be interesting to learn if Blimp-1 autoregulation only occurs when Blimp-1 is expressed in very high levels or, in other words, if prdm1 itself is among the set of Blimp-1 targets that are susceptible to regulation only when Blimp-1 is available at very high levels.
OVERVIEW Interestingly, although mice lacking Blimp1 in their B cells are deficient in antibodies, they survive well in pathogen-free conditions. In contrast, mice lacking Blimp-1 in T cells die of inflammatory disease within a few months. In B cells, Blimp-1 is clearly required and sufficient for terminal differentiation of plasma cells. In T cells, its roles www.annualreviews.org • Blimp-1 in T and B Lymphocytes
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appear more complicated, probably reflecting the more complicated pathways of activation, effector and memory differentiation, and homeostatic maintenance in this lineage. Whereas a common role for Blimp-1 in both lineages may involve terminally differentiated functions, the apparent roles of Blimp-1 in memory T cells and in attenuating responses to activation appear to be unique and not found in the B lineage. While it is too early to understand fully how the molecular mechanisms of Blimp-1 action and regulation may differ in T and B cells, there appear to be interesting commonalities between the two lineages.
fine-tuning of these regulatory networks. A final common theme is that Blimp-1 is often involved in feedback loops. In both B and T cells, Blimp-1 represses bcl6, and Bcl-6 represses prdm1. Such mutual repression loops can help establish mutually exclusive states—a GC B cell versus a plasma cell in the B lineage and Th1 versus Th2 in the CD4+ T cell lineage. A different feedback loop is present in naive T cells where activation induces IL-2 (Figure 6), IL-2 in turn induces Blimp-1, and Blimp-1 then represses il2 itself as well as fos, and Fos is a mediator of activation. In this setting, Blimp-1 is apparently important in the attenuation of the immune response.
Common Themes
Remaining Questions
In spite of apparently serving quite different regulatory roles in the life of B and T lymphocytes, there are some aspects of Blimp-1-dependent regulation that are strikingly similar. First, the majority (8 of the 10) identified direct targets of Blimp-1 repression (Table 1) are themselves transcriptional regulators with their own, often extensive and important, sets of gene targets. Thus, Blimp-1 acts early in specific transcriptional regulatory cascades. For example, direct target Pax5 both activates genes required for B cell commitment (163) and function (164) and represses genes expressed in other hematopoietic lineages and genes expressed in plasma cells (60). A second common theme is the redundancy in how Blimp-1 regulates some genes. For example, in B cells, myc is repressed by Blimp-1 both directly and indirectly by repression of an important activator, E2F (50). AID mRNA is repressed indirectly by Blimp-1-dependent repression of two activators, Pax5 and E2A (50). In T cells, Blimp-1 represses il2 directly and indirectly by repressing an activator of IL2 transcription, fos. Tbet is repressed both directly and indirectly by repression of its strong inducer, IFN-γ. It seems reasonable to suggest that this redundancy reflects the importance of repressing given target genes and/or provides the possibility for multiple ways of
Important and interesting questions remain to be answered regarding Blimp-1’s role in lymphocytes in both a short-term and a longterm sense. In the short-term, a complete understanding of Blimp-1’s roles in various T cell subsets and in lymphoid malignancies remains to be established. It will be of interest to identify additional direct and indirect targets to understand more fully the regulatory pathways dependent on Blimp-1, especially in Treg cells and CD8+ T cells, which have not yet been studied in detail. Many groups are currently identifying various signals and transcriptional mechanisms that regulate Blimp-1, and given the importance of Blimp-1 action, understanding its regulation is a key issue. The functional importance of alternate promoter usage to generate the beta form needs further study, as does the possibility that Blimp-1 mRNA or protein may be regulated posttranscriptionally by degradation, covalent modification or other mechanisms. The mechanism of action of Blimp-1 requires more study to identify corepressors that are required for its activity. Structural determination of a repressorcorepressor complex would provide molecular information that might aid in designing small-molecule inhibitors of Blimp-1. The possibility of competition between Blimp-1
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and IRF1 or IRF2 also deserves additional study. Finally, it is intriguing to speculate that, although Blimp-1 appears normal in some forms of common variable immune deficiency (CVID) (165), there could be mutations in prdm1 in other forms of CVID. In a long-term sense, as more information is obtained on the role, regulation, and mechanism of action of Blimp-1 in both normal and abnormal or malignant lymphocytes, it can be compared with the growing understanding of the roles of Blimp-1 in early embryogenesis in many species including Drosophila
(166), Xenopus (167), Zebrafish (168–172), Fugu (173), and mouse (22, 36, 174) as well as with results of studies showing roles for Blimp-1 in other adult murine cell lineages such as sebocytes (175) and epidermal keratinocytes (162a). Hopefully, when more data are available, such comparisons will reveal information about how transcriptional regulatory pathways involving Blimp-1 have evolved and may provide insight into the currently unanswered question of why this single transcription factor plays such important and varied roles in multiple cell lineages.
DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS We are grateful to members of the Calame laboratory and many colleagues for helpful discussions. This work was supported by RO1AI 50569 and RO1AI43576 to K.C.
LITERATURE CITED 1. Rousseau-Merck MF, Koczan D, Legrand I, Moller S, Autran S, Thiesen HJ. 2002. The KOX zinc finger genes: genome wide mapping of 368 ZNF PAC clones with zinc finger gene clusters predominantly in 23 chromosomal loci are confirmed by human sequences annotated in EnsEMBL. Cytogenet. Genome Res. 98:147–53 2. Kallies A, Nutt SL. 2007. Terminal differentiation of lymphocytes depends on Blimp-1. Curr. Opin. Immunol. 19:156–62 3. Shaffer AL, Wright G, Yang L, Powell J, Ngo V, et al. 2006. A library of gene expression signatures to illuminate normal and pathological lymphoid biology. Immunol. Rev. 210:67–85 4. Sciammas R, Davis MM. 2005. Blimp-1; immunoglobulin secretion and the switch to plasma cells. Curr. Top. Microbiol. Immunol. 290:201–24 5. Johnson K, Shapiro-Shelef M, Tunyaplin C, Calame K. 2005. Regulatory events in early and late B-cell differentiation. Mol. Immunol. 42:749–61 6. Shapiro-Shelef M, Calame K. 2005. Regulation of plasma cell development. Nat. Rev. Immunol. 5:230–42 7. Calame K. 2006. Transcription factors that regulate memory in humoral responses. Immunol. Rev. 211:269–79 8. Keller AD, Maniatis T. 1991. Identification and characterization of a novel repressor of beta-interferon gene expression. Genes Dev. 5:868–79 9. Turner CA Jr, Mack DH, Davis MM. 1994. Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulinsecreting cells. Cell 77:297–306 www.annualreviews.org • Blimp-1 in T and B Lymphocytes
9. Describes cloning of murine Blimp-1 cDNA. Shows that forced expression of Blimp-1 is sufficient to drive BCL1 lymphoma cells to secrete Ig.
159
ARI
24 February 2008
9:40
10. Huang S. 1994. Blimp-1 is the murine homolog of the human transcriptional repressor PRDI-BF1. Cell 78:9 11. Tunyaplin C, Shapiro MA, Calame KL. 2000. Characterization of the B lymphocyteinduced maturation protein-1 (Blimp-1) gene, mRNA isoforms and basal promoter. Nucleic Acids Res. 28:4846–55 12. Mock BA, Liu L, LePaslier D, Huang S. 1996. The B-lymphocyte maturation promoting transcription factor BLIMP1/PRDI-BF1 maps to D6S447 on human chromosome 6q21-q22.1 and the syntenic region of mouse chromosome 10. Genomics 37:24– 28 13. Keller AD, Maniatis T. 1992. Only two of the five zinc fingers of the eukaryotic transcriptional repressor PRDI-BF1 are required for sequence-specific DNA binding. Mol. Cell. Biol. 12:1940–49 14. Kuo TC, Calame KL. 2004. B lymphocyte-induced maturation protein (Blimp)-1, IFN regulatory factor (IRF)-1, and IRF-2 can bind to the same regulatory sites. J. Immunol. 173:5556–63 15. Canote R, Du Y, Carling T, Tian F, Peng Z, Huang S. 2002. The tumor suppressor gene RIZ in cancer gene therapy (review). Oncol. Rep. 9:57–60 16. Huang S, Shao G, Liu L. 1998. The PR domain of the Rb-binding zinc finger protein RIZ1 is a protein binding interface and is related to the SET domain functioning in chromatin-mediated gene expression. J. Biol. Chem. 273:15933–39 17. Ren B, Chee KJ, Kim TH, Maniatis T. 1999. PRDI-BF1/Blimp-1 repression is mediated by corepressors of the Groucho family of proteins. Genes Dev. 13:125– 37 18. Yu J, Angelin-Duclos C, Greenwood J, Liao J, Calame K. 2000. Transcriptional repression by Blimp-1 (PRDI-BF1) involves recruitment of histone deacetylase. Mol. Cell. Biol. 20:2592–603 19. Dillon SC, Zhang X, Trievel RC, Cheng X. 2005. The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol. 6:227 20. Derunes C, Briknarova K, Geng L, Li S, Gessner CR, et al. 2005. Characterization of the PR domain of RIZ1 histone methyltransferase. Biochem. Biophys. Res. Commun. 333:925–34 21. Gyory I, Wu J, Fejer G, Seto E, Wright KL. 2004. PRDI-BF1 recruits the histone H3 methyltransferase G9a in transcriptional silencing. Nat. Immunol. 5:299– 308 22. Ancelin K, Lange UC, Hajkova P, Schneider R, Bannister AJ, et al. 2006. Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells. Nat. Cell Biol. 8:623–30 23. Angelin-Duclos C, Cattoretti G, Lin KI, Calame K. 2000. Commitment of B lymphocytes to a plasma cell fate is associated with Blimp-1 expression in vivo. J. Immunol. 165:5462–71 24. Kallies A, Hasbold J, Tarlinton DM, Dietrich W, Corcoran LM, et al. 2004. Plasma cell ontogeny defined by quantitative changes in Blimp-1 expression. J. Exp. Med. 200:967– 77 25. Gonzalez-Garcia I, Ocana E, Jimenez-Gomez G, Campos-Caro A, Brieva JA. 2006. Immunization-induced perturbation of human blood plasma cell pool: progressive maturation, IL-6 responsiveness, and high PRDI-BF1/BLIMP1 expression are critical distinctions between antigen-specific and nonspecific plasma cells. J. Immunol. 176:4042– 50
Annu. Rev. Immunol. 2008.26:133-169. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-05
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Martins
·
Calame
Annu. Rev. Immunol. 2008.26:133-169. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-05
ARI
24 February 2008
9:40
26. Blink EJ, Light A, Kallies A, Nutt SL, Hodgkin PD, Tarlinton DM. 2005. Early appearance of germinal center-derived memory B cells and plasma cells in blood after primary immunization. J. Exp. Med. 201:545–54 27. Kuo TC, Shaffer AL, Haddad J Jr, Choi YS, Staudt LM, Calame K. 2007. Repression of BCL-6 is required for the formation of human memory B cells in vitro. J. Exp. Med. 204:819–30 28. Tumang JR, Frances R, Yeo SG, Rothstein TL. 2005. Spontaneously Ig-secreting B-1 cells violate the accepted paradigm for expression of differentiation-associated transcription factors. J. Immunol. 174:3173–77 29. Fairfax KA, Corcoran LM, Pridans C, Huntington ND, Kallies A, et al. 2007. Different kinetics of Blimp-1 induction in B cell subsets revealed by reporter gene. J. Immunol. 178:4104–11 30. Savitsky D, Calame K. 2006. B-1 B lymphocytes require Blimp-1 for immunoglobulin secretion. J. Exp. Med. 203:2305–14 31. Lampert IA, Van Noorden S, Wotherspoon AC. 2005. Centrocytoid plasma cells of the germinal center. Appl. Immunohistochem. Mol. Morphol. 13:124–31 32. Cattoretti G, Angelin-Duclos C, Shaknovich R, Zhou H, Wang D, Alobeid B. 2005. PRDM1/Blimp-1 is expressed in human B-lymphocytes committed to the plasma cell lineage. J. Pathol. 206:76–86 33. Cattoretti G, Shaknovich R, Smith PM, Jack HM, Murty VV, Alobeid B. 2006. Stages of germinal center transit are defined by B cell transcription factor coexpression and relative abundance. J. Immunol. 177:6930–39 34. Shapiro-Shelef M, Lin KI, McHeyzer-Williams LJ, Liao J, McHeyzer-Williams MG, Calame K. 2003. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and preplasma memory B cells. Immunity 19:607– 20 35. Kallies A, Hawkins ED, Belz GT, Metcalf D, Hommel M, et al. 2006. Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance. Nat. Immunol. 7:466–74 36. Vincent SD, Dunn NR, Sciammas R, Shapiro-Shalef M, Davis MM, et al. 2005. The zinc finger transcriptional repressor Blimp1/Prdm1 is dispensable for early axis formation but is required for specification of primordial germ cells in the mouse. Development 132:1315–25 37. Driver DJ, McHeyzer-Williams LJ, Cool M, Stetson DB, McHeyzer-Williams MG. 2001. Development and maintenance of a B220− memory B cell compartment. J. Immunol. 167:1393–405 38. Bell J, Gray D. 2003. Antigen-capturing cells can masquerade as memory B cells. J. Exp. Med. 197:1233–44 39. Shapiro-Shelef M, Lin KI, Savitsky D, Liao J, Calame K. 2005. Blimp-1 is required for maintenance of long-lived plasma cells in the bone marrow. J. Exp. Med. 202:1471– 76 40. Radbruch A, Muehlinghaus G, Luger EO, Inamine A, Smith KG, et al. 2006. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat. Rev. Immunol. 6:741–50 41. Minges Wols HA, Underhill GH, Kansas GS, Witte PL. 2002. The role of bone marrowderived stromal cells in the maintenance of plasma cell longevity. J. Immunol. 169:4213– 21 42. O’Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, et al. 2004. BCMA is essential for the survival of long-lived bone marrow plasma cells. J. Exp. Med. 199:91–98 www.annualreviews.org • Blimp-1 in T and B Lymphocytes
34. Describes mice with B cells lacking prdm1 and shows that Blimp-1 is necessary for formation of plasma cells and for Ig secretion. 35. One of two independent studies that reported a nonredundant role for Blimp-1 in T cell homeostasis and function.
161
Annu. Rev. Immunol. 2008.26:133-169. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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51. Identified myc as the first known target of Blimp-1dependent repression in B cells.
56. Showed that XBP-1 is required for plasma cell differentiation.
162
9:40
43. Slifka MK, Matloubian M, Ahmed R. 1995. Bone marrow is a major site of long-term antibody production after acute viral infection. J. Virol. 69:1895–902 44. Manz RA, Lohning M, Cassese G, Thiel A, Radbruch A. 1998. Survival of long-lived plasma cells is independent of antigen. Int. Immunol. 10:1703–11 45. Manz RA, Thiel A, Radbruch A. 1997. Lifetime of plasma cells in the bone marrow. Nature 388:133–34 46. Odendahl M, Mei H, Hoyer BF, Jacobi AM, Hansen A, et al. 2005. Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response. Blood 105:1614–21 47. Schliephake DE, Schimpl A. 1996. Blimp-1 overcomes the block in IgM secretion in lipopolysaccharide/antimu F(ab’)2-costimulated B lymphocytes. Eur. J. Immunol. 26:268–71 48. Piskurich JF, Lin KI, Lin Y, Wang Y, Ting JP, Calame K. 2000. BLIMP-I mediates extinction of major histocompatibility class II transactivator expression in plasma cells. Nat. Immunol. 1:526–32 49. Messika EJ, Lu PS, Sung YJ, Yao T, Chi JT, et al. 1998. Differential effect of B lymphocyte-induced maturation protein (Blimp-1) expression on cell fate during B cell development. J. Exp. Med. 188:515–25 50. Shaffer AL, Lin KI, Kuo TC, Yu X, Hurt EM, et al. 2002. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17:51–62 51. Lin Y, Wong K, Calame K. 1997. Repression of c-myc transcription by Blimp-1, an inducer of terminal B cell differentiation. Science 276:596–99 52. Lin KI, Lin Y, Calame K. 2000. Repression of c-myc is necessary but not sufficient for terminal differentiation of B lymphocytes in vitro. Mol. Cell. Biol. 20:8684– 95 53. Lin KI, Angelin-Duclos C, Kuo TC, Calame K. 2002. Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells. Mol. Cell. Biol. 22:4771–80 54. Ghosh N, Gyory I, Wright G, Wood J, Wright KL. 2001. Positive regulatory domain I binding factor 1 silences class II transactivator expression in multiple myeloma cells. J. Biol. Chem. 276:15264–68 55. Sciammas R, Davis MM. 2004. Modular nature of Blimp-1 in the regulation of gene expression during B cell maturation. J. Immunol. 172:5427–40 56. Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, et al. 2001. Plasma cell differentiation requires the transcription factor XBP-1. Nature 412:300–7 57. Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, Lee AH, Qian SB, et al. 2004. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 21:81–93 58. Lin KI, Angelin-Duclos C, Kuo TC, Calame K. 2002. Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells. Mol. Cell. Biol. 22:4771–80 59. Reimold AM, Ponath PD, Li YS, Hardy RR, David CS, et al. 1996. Transcription factor B cell lineage-specific activator protein regulates the gene for human X-box binding protein 1. J. Exp. Med. 183:393–401 60. Delogu A, Schebesta A, Sun Q, Aschenbrenner K, Perlot T, Busslinger M. 2006. Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells. Immunity 24:269–81 Martins
·
Calame
Annu. Rev. Immunol. 2008.26:133-169. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-05
ARI
24 February 2008
9:40
61. Nera KP, Kohonen P, Narvi E, Peippo A, Mustonen L, et al. 2006. Loss of Pax5 promotes plasma cell differentiation. Immunity 24:283–93 62. Gyory I, Fejer G, Ghosh N, Seto E, Wright KL. 2003. Identification of a functionally impaired positive regulatory domain I binding factor 1 transcription repressor in myeloma cell lines. J. Immunol. 170:3125–33 63. Trinchieri G, Sher A. 2007. Cooperation of Toll-like receptor signals in innate immune defence. Nat. Rev. Immunol. 7:179–90 64. Lin KI, Kao YY, Kuo HK, Yang WB, Chou A, et al. 2006. Reishi polysaccharides induce immunoglobulin production through the TLR4/TLR2-mediated induction of transcription factor Blimp-1. J. Biol. Chem. 281:24111–23 65. Pasare C, Medzhitov R. 2005. Control of B-cell responses by Toll-like receptors. Nature 438:364–68 66. Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, et al. 2003. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301:640– 43 67. Gavin AL, Hoebe K, Duong B, Ota T, Martin C, et al. 2006. Adjuvant-enhanced antibody responses in the absence of Toll-like receptor signaling. Science 314:1936–38 68. Sen R. 2006. Control of B lymphocyte apoptosis by the transcription factor NF-κB. Immunity 25:871–83 69. Knodel M, Kuss AW, Berberich I, Schimpl A. 2001. Blimp-1 overexpression abrogates IL-4- and CD40-mediated suppression of terminal B cell differentiation but arrests isotype switching. Eur. J. Immunol. 31:1972–80 70. Ettinger R, Sims GP, Fairhurst AM, Robbins R, da Silva YS, et al. 2005. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. J. Immunol. 175:7867–79 71. Doody GM, Stephenson S, Tooze RM. 2006. BLIMP-1 is a target of cellular stress and downstream of the unfolded protein response. Eur. J. Immunol. 36:1572–82 72. Takeda K, Kaisho T, Akira S. 2003. Toll-like receptors. Annu. Rev. Immunol. 21:335– 76 73. Tamura T, Kong HJ, Tunyaplin C, Tsujimura H, Calame K, Ozato K. 2003. ICSBP/IRF8 inhibits mitogenic activity of p210 Bcr/Abl in differentiating myeloid progenitor cells. Blood 102:4547–54 74. Gong D, Malek TR. 2007. Cytokine-dependent Blimp-1 expression in activated T cells inhibits IL-2 production. J. Immunol. 178:242–52 75. Chen-Kiang S. 1995. Regulation of terminal differentiation of human B-cells by IL-6. Curr. Top. Microbiol. Immunol. 194:189–98 76. Martins GA, Cimmino L, Shapiro-Shelef M, Szabolcs M, Herron A, et al. 2006. Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat. Immunol. 7:457–65 77. Ozaki K, Spolski R, Ettinger R, Kim HP, Wang G, et al. 2004. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J. Immunol. 173:5361–71 78. Niu H, Ye BH, Dalla-Favera R. 1998. Antigen receptor signaling induces MAP kinasemediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev. 12:1953–61 79. Rousset F, Garcia E, Defrance T, Peronne C, Vezzio N, et al. 1992. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc. Natl. Acad. Sci. USA 89:1890–93 www.annualreviews.org • Blimp-1 in T and B Lymphocytes
74. Shows that IL-2 induces prdm1 and shows that Blimp-1 downregulates IL-2 production upon T cell activation. 76. One of two independent studies that reported a nonredundant role for Blimp-1 in T cell homeostasis and function.
163
ARI
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9:40
80. Avery DT, Ellyard JI, Mackay F, Corcoran LM, Hodgkin PD, Tangye SG. 2005. Increased expression of CD27 on activated human memory B cells correlates with their commitment to the plasma cell lineage. J. Immunol. 174:4034–42 81. Choe J, Kim HS, Zhang X, Armitage RJ, Choi YS. 1996. Cellular and molecular factors that regulate the differentiation and apoptosis of germinal center B cells. Anti-Ig downregulates Fas expression of CD40 ligand-stimulated germinal center B cells and inhibits Fas-mediated apoptosis. J. Immunol. 157:1006–16 82. Choe J, Choi YS. 1998. IL-10 interrupts memory B cell expansion in the germinal center by inducing differentiation into plasma cells. Eur. J. Immunol. 28:508–15 83. Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, et al. 2002. A critical role for IL-21 in regulating immunoglobulin production. Science 298:1630–34 84. Leonard WJ, Spolski R. 2005. Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nat. Rev. Immunol. 5:688–98 85. Reljic R, Wagner SD, Peakman LJ, Fearon DT. 2000. Suppression of signal transducer and activator of transcription 3-dependent B lymphocyte terminal differentiation by BCL-6. J. Exp. Med. 192:1841–48 86. de Groot RP, Coffer PJ, Koenderman L. 1998. Regulation of proliferation, differentiation and survival by the IL-3/IL-5/GM-CSF receptor family. Cell Signal. 10:619– 28 87. Horikawa K, Takatsu K. 2006. Interleukin-5 regulates genes involved in B-cell terminal maturation. Immunology 118:497–508 88. Moriggl R, Topham DJ, Teglund S, Sexl V, McKay C, et al. 1999. Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 10:249– 59 89. Scheeren FA, Naspetti M, Diehl S, Schotte R, Nagasawa M, et al. 2005. STAT5 regulates the self-renewal capacity and differentiation of human memory B cells and controls Bcl-6 expression. Nat. Immunol. 6:303–13 90. Vasanwala FH, Kusam S, Toney LM, Dent AL. 2002. Repression of AP-1 function: a mechanism for the regulation of Blimp-1 expression and B lymphocyte differentiation by the B cell lymphoma-6 protooncogene. J. Immunol. 169:1922–29 91. Ohkubo Y, Arima M, Arguni E, Okada S, Yamashita K, et al. 2005. A role for cfos/activator protein 1 in B lymphocyte terminal differentiation. J. Immunol. 174:7703– 10 92. Mittrucker HW, Matsuyama T, Grossman A, Kundig TM, Potter J, et al. 1997. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 275:540–43 93. Sciammas R, Shaffer AL, Schatz JH, Zhao H, Staudt LM, Singh H. 2006. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 25:225–36 94. Klein U, Casola S, Cattoretti G, Shen Q, Lia M, et al. 2006. Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat. Immunol. 7:773–82 95. Muto A, Tashiro S, Nakajima O, Hoshino H, Takahashi S, et al. 2004. The transcriptional programme of antibody class switching involves the repressor Bach2. Nature 429:566–71 96. Muto A, Hoshino H, Madisen L, Yanai N, Obinata M, et al. 1998. Identification of Bach2 as a B-cell-specific partner for small maf proteins that negatively regulate the immunoglobulin heavy chain gene 3 enhancer. EMBO J. 17:5734–43
Annu. Rev. Immunol. 2008.26:133-169. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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Annu. Rev. Immunol. 2008.26:133-169. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-05
ARI
24 February 2008
9:40
97. Shaffer AL, Yu X, He Y, Boldrick J, Chan EP, Staudt LM. 2000. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13:199–212 98. Zheng YJS, Kas A, Chu TT, Gavin MA, Rudensky AY. 2007. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445:936–40 99. Winslow MM, Gallo EM, Neilson JR, Crabtree GR. 2006. The calcineurin phosphatase complex modulates immunogenic B cell responses. Immunity 24:141–52 100. Tunyaplin C, Shaffer AL, Angelin-Duclos CD, Yu X, Staudt LM, Calame KL. 2004. Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J. Immunol. 173:1158–65 101. Fujita N, Jaye DL, Geigerman C, Akyildiz A, Mooney MR, et al. 2004. MTA3 and the Mi-2/NuRD complex regulate cell fate during B lymphocyte differentiation. Cell 119:75–86 102. Omori SA, Cato MH, Anzelon-Mills A, Puri KD, Shapiro-Shelef M, et al. 2006. Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling. Immunity 25:545–57 102a. Mora-Lopez F, Reales E, Brieva JA, Campos-Caro A. 2007. Human B SAP and BLIMP1 conform an autoregulatory loop. Blood. In press 103. Ochiai K, Katoh Y, Ikura T, Hoshikawa Y, Noda T, et al. 2006. Plasmacytic transcription factor Blimp-1 is repressed by Bach2 in B cells. J. Biol. Chem. 281:38226–34 104. Cattoretti G, Chang CC, Cechova K, Zhang J, Ye BH, et al. 1995. BCL-6 protein is expressed in germinal-center B cells. Blood 86:45–53 105. Onizuka T, Moriyama M, Yamochi T, Kuroda T, Kazama A, et al. 1995. BCL-6 gene product, a 92- to 98-kD nuclear phosphoprotein, is highly expressed in germinal center B cells and their neoplastic counterparts. Blood 86:28–37 106. Lin L, Gerth AJ, Peng SL. 2004. Active inhibition of plasma cell development in resting B cells by microphthalmia-associated transcription factor. J. Exp. Med. 200:115– 22 107. O’Neill LA, Bowie AG. 2007. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat. Rev. Immunol. 7:353–64 108. Paus D, Phan TG, Chan TD, Gardam S, Basten A, Brink R. 2006. Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation. J. Exp. Med. 203:1081–91 109. Phan TG, Paus D, Chan TD, Turner ML, Nutt SL, et al. 2006. High affinity germinal center B cells are actively selected into the plasma cell compartment. J. Exp. Med. 203:2419–24 110. Kallies A, Hasbold J, Fairfax K, Pridans C, Emslie D, et al. 2007. Initiation of plasmacell differentiation is independent of the transcription factor Blimp-1. Immunity 26:555– 66 111. Bereshchenko OR, Gu W, Dalla-Favera R. 2002. Acetylation inactivates the transcriptional repressor BCL6. Nat. Genet. 32:606–13 112. Lee SC, Bottaro A, Chen L, Insel RA. 2006. Mad1 is a transcriptional repressor of Bcl-6. Mol. Immunol. 43:1965–71 113. Fernandez de Mattos S, Essafi A, Soeiro I, Pietersen AM, Birkenkamp KU, et al. 2004. FoxO3a and BCR-ABL regulate cyclin D2 transcription through a STAT5/BCL6dependent mechanism. Mol. Cell. Biol. 24:10058–71 114. Okkenhaug K, Ali K, Vanhaesebroeck B. 2007. Antigen receptor signalling: a distinctive role for the p110delta isoform of PI3K. Trends Immunol. 28:80–87 www.annualreviews.org • Blimp-1 in T and B Lymphocytes
97. This paper used microarray analyses to identify direct targets of Bcl-6 and was the first to show that Bcl-6 directly represses prdm1.
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125. The most complete study showing that PRDM1 is inactivated in one subset of DLBCL, implying a role for Blimp-1 as a tumor suppressor.
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115. Corcoran LM, Hasbold J, Dietrich W, Hawkins E, Kallies A, et al. 2005. Differential requirement for OBF-1 during antibody-secreting cell differentiation. J. Exp. Med. 201:1385–96 116. Stephenson LM, Miletic AV, Kloeppel T, Kusin S, Swat W. 2006. Vav proteins regulate the plasma cell program and secretory Ig production. J. Immunol. 177:8620– 25 117. Kearney JF, Cooper MD, Lawton AR. 1976. B lymphocyte differentiation induced by lipopolysaccharide. III. Suppression of B cell maturation by antimouse immunoglobulin antibodies. J. Immunol. 116:1664–68 118. de Gorter DJ, Vos JC, Pals ST, Spaargaren M. 2007. The B cell antigen receptor controls AP-1 and NFAT activity through Ras-mediated activation of Ral. J. Immunol. 178:1405–14 119. Rui L, Vinuesa CG, Blasioli J, Goodnow CC. 2003. Resistance to CpG DNA-induced autoimmunity through tolerogenic B cell antigen receptor ERK signaling. Nat. Immunol. 4:594–600 120. Rui L, Healy JI, Blasioli J, Goodnow CC. 2006. ERK signaling is a molecular switch integrating opposing inputs from B cell receptor and T cell cytokines to control TLR4driven plasma cell differentiation. J. Immunol. 177:5337–46 121. Vinuesa CG, Sunners Y, Pongracz J, Ball J, Toellner KM, et al. 2001. Tracking the response of Xid B cells in vivo: TI-2 antigen induces migration and proliferation but Btk is essential for terminal differentiation. Eur. J. Immunol. 31:1340– 50 122. Hoffman B, Amanullah A, Shafarenko M, Liebermann DA. 2002. The protooncogene c-myc in hematopoietic development and leukemogenesis. Oncogene 21:3414– 21 123. Tam W, Gomez M, Chadburn A, Lee JW, Chan WC, Knowles DM. 2006. Mutational analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell lymphomas. Blood 107:4090–100 124. Tate G, Hirayama-Ohashi Y, Kishimoto K, Mitsuya T. 2007. Novel BLIMP1/PRDM1 gene mutations in B-cell lymphoma. Cancer Genet. Cytogenet. 172:151–53 125. Pasqualucci L, Compagno M, Houldsworth J, Monti S, Grunn A, et al. 2006. Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma. J. Exp. Med. 203:311–17 126. Yoo NJ, Jeong EG, Lee SH, Lee SH. 2007. Absence of PRDM1 exon 2 mutation in acute leukemia. Eur. J. Haematol. 78:171–72 127. Garcia JF, Roncador G, Garcia JF, Sanz AI, Maestre L, et al. 2006. PRDM1/BLIMP-1 expression in multiple B and T-cell lymphoma. Haematologica 91:467–74 128. Buettner M, Greiner A, Avramidou A, Jack HM, Niedobitek G. 2005. Evidence of abortive plasma cell differentiation in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma. Hematol. Oncol. 23:127–32 129. Zhou X, Jiang H, Hou J. 2007. Coordination of upregulated XBP-1 and downregulated c-myc during myeloma cell differentiation induced by 2-methoxyestradiol. Leuk. Res. 31:1267–73 130. Ocana E, Gonzalez-Garcia I, Gutierrez NC, Mora-Lopez F, Brieva JA, Campos-Caro A. 2006. The expression of PRDI-BF1 beta isoform in multiple myeloma plasma cells. Haematologica 91:1579–80 131. Lee AH, Iwakoshi NN, Anderson KC, Glimcher LH. 2003. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc. Natl. Acad. Sci. USA 100:9946– 51 Martins
·
Calame
Annu. Rev. Immunol. 2008.26:133-169. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-05
ARI
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9:40
132. Santner-Nanan BB-SF, Xiao Z, Poser N, Sennefelder H, Rauthe S, et al. 2006. Blimp-1 is expressed in human and mouse T cell subsets and leads to loss of IL-2 production and to defective proliferation. Signal Transduct. 6:268–79 133. Tabrizifard SOA, Plotkin J, Fallahi-Sichani M, Livak F, Petrie HT. 2004. Analysis of transcription factor expression during discrete stages of postnatal thymocyte differentiation. J. Immunol. 173:1094–102 134. Okazaki T, Honjo T. 2006. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol. 27:195–201 135. Blumberg RSSL, Strober W. 1999. Animal models of mucosal inflammation and their relation to human inflammatory bowel disease. Curr. Opin. Immunol. 11:648–56 136. Bouma GSW. 2003. The immunological and genetic basis of inflammatory bowel disease. Nat. Rev. Immunol. 3:521–33 137. Asseman C, Read S, Powrie F. 2003. Colitogenic Th1 cells are present in the antigenexperienced T cell pool in normal mice: control by CD4+ regulatory T cells and IL-10. J. Immunol. 171:971–78 138. Walker LS, Abbas AK. 2002. The enemy within: keeping self-reactive T cells at bay in the periphery. Nat. Rev. Immunol. 2:11–19 139. Mathis DBC. 2004. Back to central tolerance. Immunity 20:509–16 140. Haks MCBS, Ciofani M, Rhodes M, Lefebvre JM, Trop S, et al. 2003. Low activation threshold as a mechanism for ligand-independent signaling in pre-T cells. J Immunol. 170:2853–61 141. Depper JM, Leonard WJ, Robb RJ, Waldmann TA, Greene WC. 1983. Blockade of the interleukin-2 receptor by anti-Tac antibody: inhibition of human lymphocyte activation. J. Immunol. 131:690–96 142. Malek TR, Bayer AL. 2004. Tolerance, not immunity, crucially depends on IL-2. Nat. Rev. Immunol. 4:665–74 143. Feh´ervari ZYT, Sakaguchi S. 2006. The dichotomous role of IL-2: tolerance vs immunity. Trends Immunol. 27:109–11 144. Villarino AV, Tato CM, Stumhofer JS, Yao Z, Cui YK, et al. 2007. Helper T cell IL2 production is limited by negative feedback and STAT-dependent cytokine signals. J. Exp. Med. 204:65–71 145. Kusam STL, Sato H, Dent AL. 2003. Inhibition of Th2 differentiation and GATA-3 expression by BCL-6. J. Immunol. 170:2435–41 146. Ansel KMLD, Rao A. 2003. An epigenetic view of helper T cell differentiation. Nat. Immunol. 4:616–23 147. Arima MTH, Ichii H, Kojima S, Okada S, Hatano M, et al. 2002. A putative silencer element in the IL-5 gene recognized by Bcl6. J. Immunol. 169:829–36 148. Ichii HSA, Hatano M, Okada S, Toyama H, Taki S, et al. 2002. Role for Bcl-6 in the generation and maintenance of memory CD8+ T cells. Nat. Immunol. 6:558–63 149. Ichii HSA, Kuroda Y, Tokuhisa T. 2004. Bcl6 acts as an amplifier for the generation and proliferative capacity of central memory CD8+ T cells. J. Immunol. 173:883–91 150. Ramakers JDVM, Thuijls G, Te Velde AA, Mensink RP, Plat J. 2007. The PPARgamma agonist rosiglitazone impairs colonic inflammation in mice with experimental colitis. J. Clin. Immunol. 3:275–83 151. Smith PMN, Walsh CM, Fallon RE, McKenzie AN, van Rooijen N, Fallon PG. 2007. Infection with a helminth parasite prevents experimental colitis via a macrophagemediated mechanism. J. Immunol. 178:4557–66 152. Maci´an FL-RC, Rao A. 2001. Partners in transcription: NFAT and AP-1. Oncogene 20:2476–89 www.annualreviews.org • Blimp-1 in T and B Lymphocytes
167
ARI
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9:40
153. Shaulian E, Karin M. 2002. AP-1 as a regulator of cell life and death. Nat. Cell Biol. 4:E131–36 154. Marsden VSSA. 2003. Control of apoptosis in the immune system: Bcl-2, BH3-only proteins and more. Annu. Rev. Immunol. 21:71–105 155. Knodel M, Kuss AW, Lindemann D, Berberich I, Schimpl A. 1999. Reversal of Blimp1-mediated apoptosis by A1, a member of the Bcl-2 family. Eur. J. Immunol. 29:2988–98 156. Tomayko MMPJ, Bolcavage JM, Levy SL, Allman DM, Cancro MP. 1999. Expression of the Bcl-2 family member A1 is developmentally regulated in T cells. Int. Immunol. 11:1753–61 157. Gonzalez JOA, Prystowsky MB. 2003. A1 is a growth-permissive antiapoptotic factor mediating postactivation survival in T cells. Blood 101:2679–85 158. Fontenot JDRJ, Gavin MA, Rudensky AY. 2005. A function for interleukin 2 in Foxp3expressing regulatory T cells. Nat. Immunol. 6:1142–51 159. Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA, Rudensky AY. 2007. Genomewide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445:936–40 160. Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan AD, et al. 2006. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126:375–87 160a. Spolski R, Leonard WJ. 2008. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu. Rev. Immunology 26:57–79 161. Peluso IFM, Fina D, Caruso R, Boirivant M, MacDonald TT, et al. 2007. IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes. J. Immunol. 178:732–39 162. Korn TBE, Gao W, Awasthi A, J¨ager A, Strom TB, et al. 2007. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448:484–87 162a. Magnusdottir E, Kalachikov S, Mizukoshi K, Savitsky D, Ishida-Yamamoto A, et al. 2007. Epidermal terminal differentiation depends on B lymphocyte induced maturation protein 1. Proc. Natl. Acad. Sci. USA 104:14988–93 163. Nutt SL, Heavey B, Rolink AG, Busslinger M. 1999. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature 401:556–62 164. Horcher M, Souabni A, Busslinger M. 2001. Pax5/BSAP maintains the identity of B cells in late B lymphopoiesis. Immunity 14:779–90 165. Taubenheim N, von Hornung M, Durandy A, Warnatz K, Corcoran L, et al. 2005. Defined blocks in terminal plasma cell differentiation of common variable immunodeficiency patients. J. Immunol. 175:5498–503 166. Ng T, Yu F, Roy S. 2006. A homologue of the vertebrate SET domain and zinc finger protein Blimp-1 regulates terminal differentiation of the tracheal system in the Drosophila embryo. Dev. Genes Evol. 216:243–52 167. de Souza FS, Gawantka V, Gomez AP, Delius H, Ang SL, Niehrs C. 1999. The zinc finger gene Xblimp1 controls anterior endomesodermal cell fate in Spemann’s organizer. EMBO J. 18:6062–72 168. Wilm TP, Solnica-Krezel L. 2005. Essential roles of a zebrafish prdm1/blimp1 homolog in embryo patterning and organogenesis. Development 132:393–404 169. Lee BC, Roy S. 2006. Blimp-1 is an essential component of the genetic program controlling development of the pectoral limb bud. Dev. Biol. 300:623–34 170. Mercader N, Fischer S, Neumann CJ. 2006. Prdm1 acts downstream of a sequential RA, Wnt and Fgf signaling cascade during zebrafish forelimb induction. Development 133:2805–15
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171. Baxendale S, Davison C, Muxworthy C, Wolff C, Ingham PW, Roy S. 2004. The Bcell maturation factor Blimp-1 specifies vertebrate slow-twitch muscle fiber identity in response to Hedgehog signaling. Nat. Genet. 36:88–93 172. Roy S, Ng T. 2004. Blimp-1 specifies neural crest and sensory neuron progenitors in the zebrafish embryo. Curr. Biol. 14:1772–77 173. Ohtani M, Miyadai T, Hiroishi S. 2006. B-lymphocyte-induced maturation protein-1 (Blimp-1) gene of torafugu (Takifugu rubripes). Fish Shellfish Immunol. 20:409–13 174. Ohinata Y, Payer B, O’Carroll D, Ancelin K, Ono Y, et al. 2005. Blimp1 is a critical determinant of the germ cell lineage in mice. Nature 436:207–13 175. Horsley V, O’Carroll D, Tooze R, Ohinata Y, Saitou M, et al. 2006. Blimp1 defines a progenitor population that governs cellular input to the sebaceous gland. Cell 126:597– 609
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:133-169. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack,1,2,3,4 James P. Scott-Browne,2 Shaodong Dai,1,2 Laurent Gapin,2 and John W. Kappler1,2,4,5,6 1
Howard Hughes Medical Institute, 2 Integrated Department of Immunology, National Jewish Medical and Research Center, 3 Department of Biochemistry and Molecular Genetics, 4 Department of Medicine, 5 Department of Pharmacology, and 6 Program in Biomolecular Structure, University of Colorado Denver Health Science Center, Denver, Colorado 80206; email:
[email protected],
[email protected],
[email protected],
[email protected],
[email protected] Annu. Rev. Immunol. 2008. 26:171–203
Key Words
First published online as a Review in Advance on January 22, 2008
T cell receptor, major histocompatibility complex, evolution, conserved interactions, tolerance, selection
The Annual Review of Immunology is online at immunol.annualreviews.org This article’s doi: 10.1146/annurev.immunol.26.021607.090421 c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0171$20.00
Abstract The rules for the conserved reaction of αβ T cell receptors (TCRs) with major histocompatibility complex (MHC) proteins plus peptides are poorly understood, probably because thymocytes bearing TCRs with the strongest MHC reactivity are lost by negative selection. Thus, only TCRs with an attenuated ability to react with MHC appear on mature T cells. Also, the interaction sites between TCRs and MHC may be inherently flexible and hence difficult to spot. We reevaluated contacts between TCRs and MHC in the solved structures of their complexes with these points in mind. Relatively conserved amino acids in the TCR complementarity-determining regions (CDR) 1 and CDR2 are often used to bind exposed areas of the MHC α-helices. These areas are exposed because of small amino acids that allow somewhat flexible binding of the TCRs. The TCR amino acids involved are specific to families of variable (V) regions and to some extent different rules may govern the recognition of MHCI versus MHCII.
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HISTORICAL INTRODUCTION MHC: major histocompatibility complex
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TCR: αβ T cell receptor
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Almost 50 years have elapsed since the discovery that the thymus is involved with immune responses. Shortly thereafter, cells derived from the thymus were found to improve the ability of B cells to make antibodies. This finding was followed by the discovery of the carrier effect, the observation that the antibody response to haptens requires simultaneous recognition of both the hapten and epitopes on the attached protein carrier. These findings dovetailed unexpectedly well to give rise to the idea that T cells created in the thymus react with one portion of the antigen and then help B cells produce antibody against a different determinant on the same molecule (1–4). This satisfying explanation for cell cooperation in immune responses left one key problem unresolved for immunologists: the major histocompatibility complex (MHC). Researchers studying the rejection of grafts and tumors (5, 6) recognized that the MHC represents a special case for immune responses. They found that differences at the MHC were recognized by the immune system extraordinarily rapidly. This phenomenon led Niels Jerne (7) to propose that lymphocyte receptors (by which he meant immunoglobulin proteins) had evolved to react with alleles of the MHC. In a groundbreaking theoretical paper, he suggested that lymphocytes developing in the thymus somatically mutate their evolutionarily generated receptors such that the receptors no longer react with the MHC of their host, but retain the ability to react well with the MHC of others. Meanwhile, others were beginning to realize that T and B cells do not react with the same determinants on antigens. Senyk and coworkers (8), for example, showed that after immunization with bovine glucagons, rabbits and guinea pigs make antibodies against a glucagon N-terminal peptide, whereas their lymphocytes divide in response to the Cterminal part of the protein. This seemed to be due to different reactivities of T and B cells because we showed (9) that mouse B and
Marrack et al.
T cells cross-react differently with red blood cells of different species. Furthermore, after immunization with sheep red blood cells, B cells can bind these cells directly and form rosettes but T cells cannot, even though the T cells are clearly able to respond to the antigen (9, 10). At approximately the same time, a number of experiments showed that T cells were geared toward recognition of antigens that were cell-associated rather than soluble. These kinds of experiments suggested that T and B cells recognize antigen in radically different ways and led to a lengthy search for the antigen receptor on T cells. The search was confused by reports that T cells secrete soluble factors that could bind antigen, by intermittent reports that T cells expressed immunoglobulin molecules, and by the idea that genes encoded by the MHC might be part of T cell antigen receptors. Conversely, a giant clue came from immune response (Ir) genes, which control the immune response against certain antigens and map to the MHC (reviewed in Reference 11). A shift in perspective led to the concept that resolved all these apparent contradictions, starting with the discovery by Zinkernagel & Doherty (12) that T cells must recognize not only antigen, but also products of the MHC. The issue of whether these were properties of a single receptor or two receptors, one specific for antigen and the other specific for MHC, was cleared up by the results of a dual TCR T cell hybrid experiment. This experiment showed that fused T cell hybrids able to react with two combinations of antigen and MHC (antigen a + MHC A and antigen b + MHC B) could not react with the mixed combinations (antigen a + MHC B and antigen b + MHC A) (13). Hence, a single receptor must react with a specific combination of antigen and MHC. This conclusion was confirmed by the discovery of the polypeptides and genes of the αβ T cell receptor (TCR) (14–20). TCRs are now known to comprise two chains, α and β, each composed of variable (Vα, Nα, Jα; Vβ, Dβ, Nβ, Jβ) and constant elements with all but the N regions
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encoded by the germ line (21). Biochemical, cellular immunological, and later, crystallography experiments showed that TCRs react usually with a complicated ligand composed of the α helices of MHC proteins and peptides derived from antigen, bound to specially designed grooves of MHC molecules (22–26). Investigators have reported a number of structures of TCRs bound to their MHC/peptide ligands (27–46). TCRs bind MHC/peptide via their complementaritydetermining region (CDR) loops: CDR1α, CDR2α, CDR1β, and CDR2β, encoded in the germ line, and CDR3α and CDR3β, made up at least partially of non–germ line encoded residues and the C-terminal and N-terminal ends of Vα or Vβ and Jα or Dβ/Jβ, respectively. In these structures, the TCRs often lie on a diagonal above the face of MHC/peptide (Figure 1). The six CDR loops of TCRs contact this face, to varying degrees, usually with CDR1α and CDR2α over the α2 helix of MHC class I (MHCI) or the β helix of MHC class II (MHCII), and CDR1β and CDR2β over the α1 helix of MHCI or the α helix of MHCII. Conversely, the interactions of CDR3α and CDR3β usually focus on amino acids of the peptide. We now know that in addition to αβ T cells an entirely different set of T cells exists, which bear receptors made up of γ and δ chains. Adams and coworkers (47) solved the structure of a γδ TCR bound to its ligand. Although the interactions of such receptors with their ligands are of great interest, these receptors are not the subject of this review and are not discussed further.
EVIDENCE THAT TCRs MAY NOT HAVE BEEN SELECTED EVOLUTIONARILY TO REACT WITH MHC All these wonderful discoveries left unresolved Jerne’s (7) original hypothesis: the idea that what are now known to be TCRs have evolved to react with MHC proteins. In fact the notion fell out of favor after
a
β2
MHC α1
Peptide α1
β1
α3
β3
MHC β1 or α2
α2 β3
b β2
α2
β1 α3 α1 Peptide
MHC α1
MHC β1 or α2
Figure 1 The TCR usually contacts MHC/peptide on a diagonal, via the loops of its CDRs. (a) A schematic of the contacts between the CDR1–3 loops of the α and β chains of a TCR and a space-filling surface of MHC and peptide. The example shown here is a mouse TCR bound to the MHCII protein, IAb , engaged by the peptide, 3K (FEAQKAKANKAVD) [Protein Data Bank (pdb) XXX]. Shown are the α1/α region of MHC (cyan), the α2/β region of MHC (magenta), the peptide ( yellow), as well as the CDR loops, color coded and labeled in their corresponding colors. (b) An elevation perspective of the interactions shown in a.
the discovery of positive selection, the phenomenon by which developing thymocytes are picked out to survive on the basis of the reaction between their receptors and self MHC + self peptides in the thymus (48, 49). The existence of positive selection allowed
www.annualreviews.org • The Interaction Between αβ TCRs and MHC
CDR: complementarity determining region
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immunologists to account for the obsession of T cells with MHC without proposing that evolution was responsible. Nevertheless, some still hoped that structures of TCRs bound to their MHC/peptide ligands would shore up the evolutionary hypothesis. They proposed that conserved amino acids in the MHC helices and TCR CDR loops would serve as lynchpins for the interaction and that other interactions among variable amino acids would determine specificity and affinity. However, the first few reported structures of TCRs bound to MHC/peptide failed to reveal any obvious rules governing their interaction, at least not at the fine structure level. There was no consistent pattern to the TCR amino acids that bound MHC or vice versa, thus suggesting that evolution had not selected TCRs that reacted in some predictable way with MHC. Other evidence weakens the evolutionary hypothesis. For example, TCR genes and MHC genes lie on different chromosomes; thus, there is no obvious genetic mechanism that will maintain coexpression of particular TCR variable (V) region alleles and particular versions of the rapidly evolving MHC genes. Although there are a few examples of TCR V region alleles or family members with a bias toward a particular MHC allele or class (50–52), in general most Vα and Vβ elements can be found in TCRs that recognize any of the extremely polymorphic alleles and isotypes of MHCI and MHCII. Worse still, in special cases, apparently quite conventional TCR α and β chains react with MHC-like proteins [such as the cluster of differentiation (CD1) proteins, for example CD1d] and their ligands, which are quite different stereochemically from classical MHCI and MHCII (53–60). How could evolution select for TCR V regions that could cope with all these differences? It is simplest to conclude that the somatic process of positive selection in the thymus must choose receptors that can react with MHC from an immense collection of receptors with random specificities.
V region: TCR variable region
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CD1: cluster of differentiation
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The CDR sequences of TCR V regions do not offer many clues to help us understand this problem. TCR genes do not usually mutate (61), a fact that weakens Jerne’s idea that somatic mutation might help solve the problem. If TCR CDR regions evolved to react with MHC, then one might expect their sequences to offer some clue as to how that has happened. Clearly the evolutionary secret cannot lie in the CDR3 regions of TCRs, because CDR3 regions are created somatically and are only partly encoded in the genome. The secret, if there is one, probably lies in the CDR1 and CDR2 sequences of the V regions of the α and β chains of the TCR. However, inspection of these sequences does not offer much hope. There are many different sequences for TCRα and β CDR1s and CDR2s, and although they can be, and have been, assigned to families on the basis of their amino acid contents and predicted structures, they are not particularly well conserved between mouse and human (62–64).
EVIDENCE FOR EVOLUTIONARY SELECTION FOR TCRs TO REACT WITH MHC Despite the lack of evidence for the evolutionary hypothesis based on the sequences of the TCR V genes or the initial structural data, several results suggest that Jerne might have been correct, in principle. First, in the solved structures TCRs usually bind MHC/peptide in approximately the same orientation (as mentioned above): angled across the MHC α-helices with the TCR α chain over the α2 helix of MHCI or the β helix of MHCII, and the TCR β chain CDR regions over the MHC helices α1/α (reviewed in References 65 and 66) (Figure 1). If MHC recognition is simply a matter of positive selection, why would the reverse orientation never occur? Mazza & Malissen (67) suggest that the accessory proteins CD4, CD8, or perhaps CD3 lock the TCR/MHC/peptide complex into the observed positions by binding
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simultaneously to both TCR and MHC; this remains an untested possibility. Second, the pivot point of the TCR on MHC is usually in approximately the same location: centered over peptide amino acids 4–6 in MHCI and peptide amino acid 5 (P5) in MHCII complexes. If TCR obsession with MHC is simply a matter of positive selection, why wouldn’t the TCR slide drastically to one end or the other of MHC, or even interact with the side of MHC? Actually a dramatic shift of this nature is seen in the reaction of a natural killer T cell (NKT) TCR with CD1d (see below) (68) but was observed only once for the reaction of TCR with classical MHC (38). Again, we can invoke the effects of CD4 and CD8 (see above) as an explanation. Third, although TCR CDR regions vary between species, they are better conserved evolutionarily in length and sequence than their counterparts in immunoglobulin (69, 70), a fact that suggests some required function. Finally, there is a small amount of direct experimental evidence that suggests evolution has played a role in the obsession of TCRs with MHC. For example, we showed that random combinations of TCR α and β chains react with MHC more frequently than expected (71), and others demonstrated that even before positive selection has had a chance to have an impact, TCRs react with surprising frequency with MHC (72, 73).
NEGATIVE SELECTION OBSCURES THE BIASES OF TCRs TO REACT WITH MHC The specificity of the TCRs on developing thymocytes is tested via both positive and negative selection. Positive selection allows the maturation of thymocytes bearing TCRs that react with self MHC + self peptides (48, 49), but negative selection deletes all thymocytes bearing TCRs that react too well (74, 75). We reasoned that if TCR V elements have been selected through evolution to react with MHC, this reactivity must be at-
tenuated in the thymus to allow escape from negative selection. Thus, whereas the CDR1s and CDR2s of most Vα/Vβ combinations can produce inherently MHC-reactive TCRs, CDR3s generated via somatic recombination will sterically interfere to varying degrees with this reactivity, producing a repertoire of TCRs with a wide range of affinities for MHC. Only T cells with TCRs that exhibit reactivity for self MHC/peptides in a narrow affinity window will pass the tests of both positive and negative selection. Thus, in the resulting mature TCR repertoire only a few of the germ line–encoded MHC interactions of the CDR1s and CDR2s may still be evident, although these interactions still contribute to the overall interaction of the TCRs for MHC, and their maintenance in the germ line is critical to provide a starting point for selection. The consequence of this line of reasoning is that the germ line–encoded MHC interactions may be difficult to identify structurally in T cells that have experienced normal negative selection. Thus, the best place to look for these interactions is in the window between positive and negative selection. We therefore examined the properties of TCRs in mice in which positive selection is relatively normal but negative selection is limited. Although several available mice fit the bill, we chose animals we had described previously, in which the MHCII protein has been replaced with an MHCII that is covalently bound to a single peptide (76). These animals are not ideal for the purposes of this experiment because they still express normal levels of MHCI, bound to the many different host peptides with which it normally engages, and they express one MHCII/peptide combination. Therefore, any thymocytes with TCRs that could react well with any of these combinations would still be deleted. However, these animals have two advantages for the planned studies: Previous characterization showed that they contain high frequencies of T cells that can react very well with MHC, and in fact the T cells cross-react with MHC of many different alleles (76), properties
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NKT cell: natural killer T cell
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Table 1 MHC
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T cells that have experienced only limited negative selection react frequently with
Mouse donor
Immunogen
C57BL/6 B6→MHCI+
MHCII−
Ii− IAb /Eα+a
MHCI+ MHCII− Ii− IAb /Eα+b a
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b
IAb /3K
5
IAb /3K
2
0
IAb /3K
19
40.4
4.4
The bone marrow–derived cells are B6, but the thymus epithelial cells are MHCI+ MHCII− Ii− IAb /Eα. Mice express a single MHCII protein, IAb , bound to the Eα peptide.
expected of TCRs manifesting their evolutionarily selected abilities to bind MHC. Secondly, the animals contain mature CD4+ T cells that could be primed with MHC/peptide, and therefore we could identify at least one target MHC/peptide combination for these cells. Mice that express a single class II protein, IAb , bound to a single peptide from Eα (MHCI+or− MHCII− Ii− IAb /Eα mice) and normal C57BL/6 (B6) animals were primed with IAb bound to another peptide, called 3K because it contains three lysine residues that point straight up out of the IAb groove. Thus, Table 2 The number of deleted MHC ligands controls T cell alloreactivity
Number of TCRs tested
Mouse donor
% of target MHC tested that stimulated hybridomas bearing the TCRs
C57BL/6
20
3.1
MHCI+ MHCII− Ii− IAb /Eα+a
19
44.1
MHCI+ MHCII− Ii− IEk /99A+b
8
52.2
MHCI+ MHCII− Ii−c
3
18.2
MHCI− MHCII− Ii− IAb /Eα+d
45
41.1
MHCI− MHCII− Ii−e
28
67.1
a
Mice express a single MHCII protein, IAb , bound to the Eα peptide. Mice express wild-type MHCI of the k allele and IEk bound to the 99A peptide (83). c Mice express MHCI of the b allele but no MHCII. d Mice express no MHCI and a single MHCII protein, IAb , bound to the Eα peptide. e Mice lack almost all MHC proteins. b
176
Number of TCRs tested
% of target MHC tested that stimulated hybridomas bearing the TCRs
Marrack et al.
these three lysines should bind to TCRs that reach with IAb /3K. We prepared T cell hybridomas specific for IAb /3K from the two sets of animals. Only one of the IAb /3K specific TCRs from B6 mice showed any alloreactivity, whereas many of the TCRs specific for the same MHC/peptide combination from MHCI+or− MHCII− Ii− IAb /Eα animals were extravagantly alloreactive (Table 1) (77). We tested two of these TCRs in detail and found that they react with both MHCI and MHCII. This phenomenon is not a special feature of TCRs from the MHCI+or− MHCII− Ii− IAb /Eα mice, because we obtained similar results with TCRs from other mice in which negative selection is limited (78–83). Also, the degree of MHC reactivity of the TCRs appeared to correlate with the degree to which negative selection was absent (Table 2). The few T cells in mice lacking almost all MHC proteins (MHCI− MHCII− Ii− in Table 2) reacted most frequently with allogeneic MHC proteins. To confirm that the ability to produce very MHC-reactive TCRs on mature T cells was due to lowered opportunities for negative selection in the MHCI+ MHCII− Ii− IAb /Eα mice, chimeras were examined in which the bone marrow–derived cells were B6 but the thymus epithelial cells were MHCI+ MHCII− Ii− IAb /Eα. In these animals, positive selection of most conventional T cells occurs on thymus epithelium, whereas negative selection occurs on both the epithelial and bone marrow–derived cells. IAb /3K-specific
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T cells from these chimeric mice were not MHC cross-reactive (Table 1) (77). Therefore, mature T cells bearing very MHCcross-reactive TCRs are allowed to appear in MHCI+ MHCII− Ii− IAb /Eα mice because of the limited opportunities for negative selection in these animals. Further studies showed that the MHCcross-reactive TCRs display several unexpected properties. Although the MHC-crossreactive TCRs react with their immunogen (IAb /3K) with the same kinetics, affinities, and footprints as normal TCRs do, they show less specificity for particular side chains of the amino acids of their ligand (77, 84). That is, the MHC-cross-reactive TCRs are more accepting of amino acid substitutions in both IAb and the 3K peptide than are normal TCRs. This result provides additional evidence that these TCRs are more cross-reactive. If the TCRs can accept amino acid substitutions, they are more likely to recognize different MHC alleles and classes than their wild-type counterparts. These results support the view that the T cell repertoire is intrinsically MHC reactive and that this reactivity is partially masked by negative selection in the thymus. To improve our understanding of the results, we recently solved the crystal structures of two TCRs, both bound to the IAb /3K complex (84a). One TCR (B3K506) came from a T cell developing in normal mice and was extremely peptide and MHC specific. The other TCR (YAe62) came from one of the very cross-reactive T cells described above. Both TCRs displayed approximately the same affinity for the IAb /3K ligand (84). The cross-reactive TCR showed a very concentrated footprint on IAb /3K with very strong contributions from several amino acids in Vα CDR1(Y31) and Vβ CDR2 (Y48 and E54). These amino acids also contributed to the binding of the specific TCR. However, in the peptide- and MHC-specific TCR these amino acids were less important in the overall footprint, which was distributed over a much wider area. These results further supported our view that germ line–encoded interactions
may best be revealed by these cross-reactive T cells that have avoided negative selection and that normally developing T cells may have attenuated forms of these interactions.
TCR VARIABLE REGIONS HAVE BUILT-IN BIASES FOR REACTION WITH MHC Investigators have inspected the increasing numbers of solved structures of TCRs bound to MHC/peptide many times in the hope that these structures will reveal the rules that govern the reactions between TCRs and MHC (27–46). Apart from the usual diagonal mode of interaction and the usual placement of the TCR V region loops over the α-helices of the MHC, a set of general rules is not apparent. However, some researchers noticed that particular TCR amino acids often make contact with MHC, and in the case of structures involving the same TCR Vβ region, bound to different ligands, some of the V region amino acids that bind MHC are identical and bind MHC in the same positions (42, 85). This observation gave hope that rules were present, although they may be difficult to make out. There are now more than 20 published structures of TCR/MHC complexes. This is both an advantage and a disadvantage for people who are searching for the rules that underlie the reactions. On the one hand, the increasing numbers of structures provide more data for analysis and a greater likelihood of spotting patterns. On the other hand, some of the new structures were chosen deliberately to illustrate unusual interactions, such as those with self antigens or with very large peptides. Therefore, these structures may not illustrate the general rules that guide the recognition of MHC by TCRs. Bearing these issues in mind, we revisited the published TCR/MHC structural information with new eyes and more flexible criteria for conserved interactions. We were guided by several thoughts: 1. Almost all the structures published so far involve TCRs that have undergone
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normal negative selection. Therefore, these TCRs are unlikely to demonstrate all their built-in abilities to react with MHC. Had the TCRs been able to react strongly with MHC, the cells that bear them would have been deleted in the thymus. Perhaps each TCR/MHC/peptide combination will manifest only a few of the evolutionarily selected interactions, and other interactions are prevented by the TCR CDR3 regions or the peptide. Thus, different TCR/MHC/peptide combinations will use different evolutionarily determined interactions, and some of the combinations may not use any at all. 2. Given the variability in TCR V region CDR1 and CDR2 sequences, the evolutionarily selected interactions may be distinct for different TCR V regions. 3. The angle and pitch with which TCRs settle onto MHC varies because of differences in peptide and CDR3 sequences. The evolutionarily selected interactions may therefore need a builtin flexibility to accommodate shifts in the relative positions of the amino acids involved. 4. The evolutionarily selected interactions may not be the same for MHCI and MHCII because some TCR V regions are used preferentially to react with one or the other MHC class (50–52). With these thoughts in mind, we have reexamined the contacts between the CDR1 and CDR2s of Vα and Vβ regions and MHC in
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ANRV338-IY26-06
all the published structures of TCRs bound to MHC/peptide ligands. The analyses also included data from two structures we solved recently, mentioned above. The only omissions from the analyses are TCR/MHC/peptide structures that are duplicates of particular TCR/MHC combinations and those well analyzed in this context in a recent publication (85). The results of these analyses are shown in Figure 2. The analyses are inherently incomplete because only a few structures of TCRs bound to their ligands are known, in comparison with the many existing TCR V region genes in human and mouse. The results are also distorted by the fact that TCRs containing some V regions are better behaved in crystallographic studies than others, perhaps because the V regions in question allow the TCRs to fold in a more stable fashion. Whatever the reason, the TCR/ligand structures reported so far are heavily biased in favor of TCRs using Vβ8 in the mouse or Vβ13 (a related Vβ) in human, and a few other Vβ regions related to these two. The Vα regions that have been crystallized show less bias. These caveats limit our ability to make predictions about the universe of human and mouse TCR V regions. However, the structures may help us see patterns of reactivity for those V regions that are overrepresented in the solved structures. Some patterns are evident from the limited numbers of structures available. As previously reported and mentioned above, Vα CDR amino acids usually contact amino acids
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→ Figure 2 Contacts between TCR CDR1 and CDR2 and MHC. (a) The cells contain the sequences of CDR1α of TCRs whose structure, bound to the MHC/peptide ligands, is known. In the same cell as each CDR amino acid are the MHC amino acids bound by that CDR residue, color coded ( pink or blue) to indicate the MHC region on which they lie. Amino acids from the α1/α regions of MHCI/MHCII are shaded blue, and those from the α2/β regions are shaded pink. Dashes indicate a gap in the CDR region, introduced according to References 63 and 64 to best align TCR sequences. TCR and MHC amino acids are numbered according to References 63 and 64. Structures are from References 27–46, 84a. (b-d ) As in a, except the sequences of TCR CDRα2, CDRβ1, and CDRβ2 and their contacts are displayed. PDB, Protein Data Bank; Pep, peptide. 178
Marrack et al.
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α1/α region of MHCI/II α2/β region of MHCI/II
Human TCRs binding MHCI
a
VαCDR1
Vα
PDB
TCR
MHC
Pep
10GA
JM-22
A2
MP
hVα10.1 S
–
–
V
1BD2
B7
A2
TAX
hVα21.1 N
S R170 –
M
S
A
2BNQ
1G4
A2
1AO7
A6
A2
1MI5
LC13
B8
2AK4
SB27
B35
2NX5
ELS4
B35
26
ESO-9C hVα23.1 D TAX
EBV
hVα2.1
hVα4.1
27
27a
W167
–
29
30
S Q155 S
F
D T163 Y Q155
I
Y Q155 N
G W167 S
Q Y159 S
E58 Y59
Q155
W167
T163 A150 R151
Q155
T R62 I
R
31
E154
F
K66
W167
D E58 R R170 –
13mer hVα12.1 T
28
S R62 G A158 T Y159 D
Y V152
D
Y
T
E154 Q155
T A158 Y L163
A158
EPLP hVα7.2
T
S E166 –
G E166
KK50.4 HLA-E Leader hVα4.2
T
I
S
G D162 N T163 E
–
G162 T163 Y E166 W167
F L163 N L163 G E154
2ESV
Y H155 A158
Mouse TCRs binding MHCI
1LP9
AHIII
A2
p1049 mVα8.5
S
T
Pkb1 mVα2.7
1FO0
BM3.3
Kb
Pbmi
mVα17.3 T
Q R62 D
S T163 S A158 Y
F R155
2OL3
BM3.3 Kbm8 pBM8 mVα17.3 T
Q R62 D
S T163 S
Y
F R155 Y R155
Kb
dEV8 mVα3.1
2OI9
2C
Ld
QL9
E58
E58
T W167 F
A158
Kb
2C
–
F Q155
1KJ2 KB5-C20
2CKB
D R62 S
E154
A158
S Y159 P
N T163 Y
Y R62 S R62 –
A
R62
T E166 P
Y
A E163
T Y159 P
A158
mVα3.1
S
–
Y155
Y A158
Human TCRs binding MHCII
E163
Mouse TCRs binding MHCII
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26 February 2008
1FYT
HA1.7
2IAM
1ZGL
DR1
flu HA hVα1.2
S
–
V
E8
DR1 mut TPI hVα13.1 D H81 –
–
S
3A6
DR2
T V85 –
G
MBP
S
hVα22.1 A
H81
H81
P
T77 H81
V
H81
Y159
P
Y T77
N T77 N D76 T77
Y R80 P
S
H81 D76
1YMM Ob.1A12 DR2
MBP
hVα3.1
Conalb mVα2.5
T
–
–
D
T77 S H81 –
S
I
T
T77 H81
F
N T77 N T77 H81 R70 D A73 Y R70 T77
1D9K
D10
IAk
1U3H
172.10
IAu
MBP
mVα2.3
N
S Y81 –
A
Y81
F
XXX
B3K506
IAb
3K
mVα4.1
A
S H81 –
G
T77 H81
Y T77 P
T77
D T77 Y D76
A
H81 D76
XXX
YAe62
IAb
3K
mVα4.6
T
T
–
G
Y T77 P
T
H81
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α1/α region of MHCI/II α2/β region of MHCI /II
b PDB 10GA
TCR JM-22
MHC A2
Pep MP
VαCDR2
Vα
48
S T hVα10.1
49
50
51
H151 V E154 T
V
E154
1BD2
B7
A2
TAX
hVα21.1 S
I
G A158
S Q155 S T163
Human TCRs binding MHCI
A158
Annu. Rev. Immunol. 2008.26:171-203. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
52
1G4
A2
ESO-9C hVα23.1 N
L
G
E
D
A6
A2
TAX
hVα2.1
S
1MI5
LC13
B8
EBV
hVα4.1
H R151 G
2AK4
SB27
B35
H151
Q155 Q155 E154 Y Q155 S A158 N E166 G A158
I
D
E154
A150
hVα12.1 13mer Y Y R
H151
Q H151 S Q155 S E154 Q E154 R
I
1AO7
54
R157 A158 I E161 K G162
A150
2BNQ
53
L Q155 T
S E154 N
V R151
A158
R
E154 R157
N E154 S
F A158 D
E
E161
2NX5 2ESV
ELS4
B35
EPLP hVα7.2 G
KK50.4 HLA-E Leader hVα4.2
R151
Y E154 N
V A158 L R157 D
H
G
L R157 K
S
F E154 T E154 D
G
L
N
N
E
N
K
R
I Q155 R E161 S E166 V G162 S
D
E154
H151
1LP9
Mouse TCRs binding MHCI
1KJ2 KB5-C20
p1049 mVα8.5
H151
Kb
Pkb1 mVα2.7
E154 Y R155 K E154 K A158 E154 Y R155 K E154 K A158
mVα17.3 R
Q
D
S
2OL3
BM3.3 Kbm8 pBM8 mVα17.3 R
Q
D
S
K
Y
Y A158 S G162 G
2C
Kb
Kb
2OI9
2C
Ld
1FYT
HA1.7
DR1
Pbmi
dEV8 mVα3.1
QL9
mVα3.1
flu HA hVα1.2
K A150 Y
K
I
P
S D76 G
T
K
K
A
D
K
G
L E69 I
R
S D76 N E69 E
R
3A6
DR2
MBP
hVα22.1 T
1YMM Ob.1A12 DR2
MBP
hVα3.1
D10
IAk
1U3H
172.10
IAu
Conalb mVα2.5 MBP
mVα2.3
P
S T77
D66 E69 Q70
E69 Q70 A73
A73
D
A73 T77
A
I
S
E69
L
S
I
L
E69 A73
S T77
E69 73 T77
E69 R72 A73 D76
XXX
B3K506
IAb
3K
mVα4.1
R E66 A
S
XXX
YAe62
IAb
3K
mVα4.6
Q
T
V
A E69 A
P
E69 A73 T77
1ZGL
1D9K
D
T163 A150 G151 E154 Y E154 S R157 G R155 D Y155 A158 Y159 E69
DR1 mut TPI hVα13.1 Y
Y
A158
R155
T
E8
Marrack et al.
E166
BM3.3
2IAM
(Continued )
A158
S
1FO0
2CKB
Mouse TCRs binding MHCII
Human TCRs binding MHCII
A2
Q155
Figure 2
180
AHIII
R
T
V
E69 R72 A73
T
S
N
V A73 S
D
D
K E69 E
A
N
N
E69
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α1/α region of MHCI/II α2/β region of MHCI/II
Human Vβ binding MHCI
c
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20:33
TCR
MHC
Pep
Vβ
10GA
JM-22
A2
MP
hVβ17.1
N
L
N
H
D
1BD2
B7
A2
TAX
hVβ13.1 D
M
N
H
E
2BNQ
1G4
A2
1AO7
A6
A2
TAX
1MI5
LC13
B8
EBV
2AK4
SB27
B35
2NX5 2ESV
Human V β binding MHCII
Mouse V β binding MHCI
1LP9
Mouse Vβ binding MHCII
Vβ CD R 1
PDB
ELS4
26
28
27
Q72 T73
29a
29
A
–
Y
–
Y
–
Y
–
D
M
N V76
H
E
hVβ13.1
D
M
N
H
E
hVβ6.2
I
S
G
H
V
N80
S
D
M
N
H
N
T69
S
T69 T73
13mer hVβ13.3
E76
– –
Q65 T69
T
E
N
H
R
KK50.4 HLA-E Leader hVβ16.1
I
S
G
H
D K146 N
T
N
N
H
D P
W
–
P
W V76
–
P
W
–
Q149 N K146 N A150
–
A2
EPLP
25
hVβ12.1
AHIII
B35
ESO-9C hVβ13.1
24
p1049 mVβ8.1
1KJ2
KB5-C20
Kb
Pkb1
mVβ2
N
S
K146 Q Q149 Y A150 A150
1FO0
BM3.3
Kb
Pbmi
mVβ2
N
S
Q
Kbm8 pBM8
Y
Q72
Y
Y
– –
T73
–
2OL3
BM3.3
mVβ2
N
S
Q K146 Y
2CKB
2C
Kb
dEV8
mVβ8.2
T
N
N K146 H
2OI9
2C
Ld
QL9
mVβ8.2
T
N
N
H
N
V76 N77
N
–
1FYT
HA1.7
DR1
D
M
D
H
E
A64 V65 A68
N
–
2IAM
E8
DR1 mut TPI hVβ13.6
D
M
N
H
E
A61 V65
Y
1ZGL
3A6
DR2
MBP
hVβ5.1
I
S
G
H
R W61 S
1YMM Ob.1A12 DR2
MBP
hVβ2.1
L
D
F
Q
A
T
E55 Q57
T
Conalb mVβ8.2
T
N
N
H
N
N Q61
–
flu HA hVβ3.1
G58
Y60
–
–
1D9K
D10
IAk
1U3H
172.10
IAu
MBP
mVβ8.2
T
N
N
H
N H68 N Q61
–
XXX
B3K506
IAb
3K
mVβ8.1
T
N
N
H
D
Y Q61
–
XXX
YAe62
IAb
3K
mVβ8.2
T
N
N
H
N H68 N Q61
–
E55
Figure 2 (Continued ) www.annualreviews.org • The Interaction Between αβ TCRs and MHC
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α1/α region of MHCI /II α2/β region of MHCI /II
d
VβCDR2
Human Vβ binding MHCI Mouse Vβ binding MHCI Human Vβ binding MHCII
TCR
MHC
Pep
Vβ
46
10GA
JM-22
A2
MP
hVβ17.1
1BD2
B7
A2
TAX
hVβ13.1 Y
2BNQ
ESO-9C hVβ13.1
Y
1G4
A2
1AO7
A6
A2
TAX
hVβ13.1
Y
1MI5
LC13
B8
EBV
hVβ6.2
Y
2AK4
SB27
B35
2NX5
ELS4
B35
2ESV
Mouse Vβ binding MHCII
Annu. Rev. Immunol. 2008.26:171-203. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
PDB
13mer hVβ13.3 EPLP
hVβ12.1
KK50.4 HLA-E Leader hVβ16.1
S
V
S
V
S
V
F
Q
S
A
Y Q65 S
Y
H
V
Q72 E76
Y
F
G
T
V
K
D K68
Q65
Q
D
K
T
D
K
T
D
K
Q72
V76 T80
E
R79
S R75 K
Q
V76
D69 Q72 I73
D
R65
E
R65
K V
mVβ2
T
L
R
S
V76 R79
P
G
D
K
E
V
mVβ2
T
L
R
S
R79
P
G
D
K
E
V
E
K
E
K
mVβ8.2
Y
S
DR1 mut TPI hVβ13.6
Y Q57 S
DR2
E
mVβ8.2
hVβ5.1
hVβ2.1
Conalb mVβ8.2
Y
Y
Y
F
Q57
Y
T
V76 R79 T30 V76 T80 S73 V76 G69 Q72 V76
G
R79
A
R79 R75 R79
G R79 S
V76 R79
T
G R75 S
Q72 R75
T
Q72
G
V76
A
Q57 G58 A61 A64
D
A64 K67
V
K
M L60
K
K39
E
K39 Q57
K
V
Q57 G58 A61
G
A
G
I
A61
T
Q57
D Q57
K
F
A61 V65
S
E
T A61 Q Q57
R
Q57 G58 A61
N
E55 Q57
K
S
N
Y Q57 S
Y
D10
IAk
1U3H
172.10
IAu
MBP
mVβ8.2
Y Q57 S
Y
XXX
B3K506
IAb
3K
mVβ8.1
Y
Q57 Q61
S
Y
XXX
YAe62
IAb
3K
mVβ8.2
Y Q57 S
Y
Marrack et al.
E
S
D Q72 R75
E
1D9K
182
L
K
S
(Continued )
T
Q
D Q72
flu HA hVβ3.1
Figure 2
I
R79
R65
G
R65
Y
MBP
D
P
Y
S
1YMM Ob.1A12 DR2
T
Q72
Kbm8 pBM8
MBP
K68
S
BM3.3
3A6
I
Q72 V76
2OL3
1ZGL
G
Q
R
Pbmi
E8
D
Q
E
K
T
A
R79
I73 V76
Q72
G
N
G
I
K
L
Kb
2IAM
A
G
R65
T
BM3.3
DR1
G
Q72
Q
E
1FO0
HA1.7
A
F
Q72 R75
T
mVβ2
1FYT
G Q72
D
N
55
S
Pkb1
QL9
A
54
D
Kb
Ld
Q72 R75 E76 Q65 Q65 K68 T69
G
Q72 V76
53
K68 A69 Q72
A
KB5-C20
2C
R65 K68 A69 Q72
V
52
Q72
1KJ2
2OI9
I
51
V
p1049 mVβ8.1
dEV8
Q
A69 Q72 T73 V76
50
R65 K68 A69
A2
Kb
S
49
Y
AHIII
2C
R65
48
S
1LP9
2CKB
Y
R65
47
Q57 G58 L60 Q61 A64 Q57 L60 Q61 A64 Q57 L60 Q61 Q57 L60 Q61 A64
A61 A64 V65
K39
L60 A64
E
G
S
K
A
G
A
G
S
T
K39
E
K39 Q57 L60
K
G
A
G
S
T
K39
E
K39 Q57 L60
K
V
A
D
S
T
E
Q57
K
G
A
G
S
T
E
K39 Q57 L60
K
K67
T
K39
Q57
Y
Q57
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in the α2 helix of MHCI or the β helix of MHCII. Conversely, Vβ CDR amino acids bind residues in the α1- or α-helices of MHCI or MHCII, respectively (Figures 2a–d ). However, the results also suggest that the contacts between TCRs and MHC might follow more rules than this one. For example, as previously noted, TCRs often bind MHC via the use of amino acids in positions 28, 29, and 31 of CDR1α; positions 50, 51, and 52 of CDR2α; positions 28 and 29 of CDR1β; and position 48 of CDR2β. (TCR V regions and their amino acids are numbered as listed in References 63 and 64. In all figures, MHC amino acids are from the MHC α chain unless specifically marked “β”.) This usage is to some extent independent of whether the target is MHCI or MHCII. We, among others, have discussed a number of these positions (αY29, βY46, and βY48) at length in previous publications, so in the discussion below we concentrate on positions that have not been covered as thoroughly.
Amino Acids Often Used by Vαs to Bind MHC Figure 2a and Figure 3 show that in VαCDR1, Y/F31 is very often bound to a site on MHC that includes amino acids around Q/H/R 155 of the α2 helix of MHCI or the equivalent position on MHCII, R70 on the β helix. Approximately 40% of human and mouse TCRαs have a Y or F at position 31, at the C-terminal end of their CDR1 regions (Figure 3a). So, if this is an interaction that routinely affects TCR/MHC binding, it may apply to many TCRs. Investigators have solved the structures of 13 TCRs that contain a VαY/F31, bound to different MHC ligands. Figure 3b–m shows the relative positions of VαY/F31 and MHC/peptide in 12 of these structures. (We omitted one structure, 2OL3, because it involves a TCR that was already included, bound to a closely related MHC.) VαY/F31 does not bind MHC in three of these structures (2AK4, 1KJ2, and 1U3H; Figure 3i, j,
and m). In one of these structures (2AK4), the entire TCR is lifted away from MHC by a very pronounced bulge in the engaged peptide, which correlates with an unusual 13mer in the structure. In another case (1KJ2), the TCR has a very long CDR3β, and the total number of interactions between this TCR and MHC is fewer than normal (Figure 2). The orientation of VαY/F31 is not identical in the nine structures shown in which it binds MHC; sometimes VαY/F31 adopts a vertical configuration, reacting with the C-terminal side of α2H/Q/R155 or βR70 (in 1LP9, 2ESV, 2CKB, 1FO0, and 1FYT; Figure 3c, d, f, h, and l ), and in other structures VαY/F31 reacts with the N-terminal side of the same amino acid or is oriented horizontally relative to the axis of the MHC α helix (in 1MI5, 1BD2, and 1DK9; Figure 3b, g, and k). For both MHCI and MHCII, the approach of VαCDR1 to the MHC in this region is often facilitated by the lack of a side chain on a highly conserved alanine on top of the MHC α helix (A158 for MHCI and βA73 for MHCII). This leads to the formation of a cup on the surface of the MHC α helix into which Y/F of TCR α31 can nestle in various orientations while still maintaining Van der Waals–like interactions with some portion of the exposed helix backbone and the surrounding amino acid side chains. The interaction is in a way analogous to a ball and socket structure. Almost as striking as the fact that VαY/F31 tends to bind to a particular site on MHC is the fact that other amino acids at this same position do not. Alternate amino acids in known structures at position 31α include G, A, S, N, and T. These amino acids engage MHC in only one of these structures (1YMM). In many cases, the VαY/F31 interaction seems to be replaced by binding between amino acid Vα29 or Vα30 and the ligand (Figure 2a). In human Vα22 and Vα4, VαY29 is a special case. In the three available structures, VαY29 interacts strongly with βH81 and βT77 of the MHCII β chain helix (84a). An adjacent proline at position 30
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a
20:33
31
hVα01.2, 3, 4 hVα02 hVα04.1 hVα04.2 hVα05.1 hVα08.1 hVα08.2 hVα12.1 hVα14.1 hVα14.2.1 hVα14.2.3 hVα15.1 hVα16.1 hVα17.1 hVα20.1 hVα21.1
SS - VPPY NS - A FQY T I SGT DY T I SGN E Y NY - SPAY DS - ASNY NS - ASDY T RD T T Y Y T SESDYY T S ENDY Y T SESNYY DS - SS T Y V S - GN P Y NT - A FDY N I A T NDY NS - MF DY
mVα1.1 mVα1.2, 8 mVα1.7 mVα2.1, 5, 9 mVα2.2, 4, 7 mVα2.3, 6 mVα3.1, 3, 9 mVα3.2, 5, 6 mVα3.4, 8 mVα3.7 mVα5.1 mVα5.3 mVα6.1 mVα8.1, 6 mVα8.3 mVα8.5 mVα8.13 mVα8.14 mVα9.1 mVα12.1 mVα13.1 mVα15.1 mVα16.1P mVα17.1 mVα17.3 mVα20.1
DS - A SQY DR - N FQY DR - NVDY DS - T FDY DS - T FNY NS - A FDY YS - ATPY Y F - GT PY YG - GS I Y SS - VTPY DP - NSYY DS - A T AY T I SGN E Y T I YSNP F TTYS - PF STYS - PF TAYS - TF T I YSNA F YS - AAPY N I ATSEY NS - ASNY DT - ASSY NA - A TNY RD - S S Y F QD - S S Y F ND - MF DY
b
c
hVα α4.1 (1MI5)
mVα8.5 (1LP9)
R151 Q155
Q155
mVα3.1 (2CKB)
Y155 R155
G151
βE69
HLA-E
g
Q155
H151
A158
A158
Ld
βR70 βT77 βA73
E154
Kb
i
hVα1.2 (1FYT)
βE69
E154
E154
IAk
l
hVα21.1 (1BD2)
G151
A158
mVα17.3 (1FO0)
βR70
S151
E154
HLA-A2
f
mVα3.1 (2OI9)
mVα2.5 (1LP9)
βT77 βA73
E154
HLA-B8
h
H155 A158
E154
e
k
hVα4.2 (2ESV)
H151
A158
A158
d
hVα12.1 (2AK4)
j
HLA-A2 mVα2.7 (1KJ2)
m
HLA-DR1 mVα2.3 (1U3H) βR70
R151 R155 A158
Q155
G151
R155
K
b
βT77 βA73
A158
A158 E154
G151
E154
HLA-B35
βE69 E154
K
b
IAu
Figure 3 TCRs often bind the same site in MHC via Y/F31 in TCRα CDR1α. (a) CDR1 sequences of the human (h) and mouse (m) Vα regions that contain an F or Y residue at position 31 (highlighted in salmon pink). V regions were omitted if the sequences of both their CDR1 and CDR2 regions were identical to one already displayed. V regions and their amino acids are numbered according to References 63 and 64. The sequences were selected from 48 human Vαs and 75 mouse Vαs. (b–j ) The arrangements of MHC amino acids around Y/F31α ( green with red hydroxyl groups) in nine of the solved structures of TCRs bound to MHCI, with the α2 helix of MHCI in magenta. Also indicated are the Vα region, MHC allele, and pdb number. The structures are arranged from b to j roughly according to the predicted strength of the interaction between Y/F31α and MHCI; there is no predicted contact for Y/F31α in 2AK4 (i ) and 1KJ2 ( j ). (k–m) As in b–j, but for TCRs bound to MHCII, with the β helix of MHCII in magenta. There is no predicted contact between Y/F31α and MHCII in 1U3H (m). Structures were selected from the references in Figure 2.
of these Vαs orients VαY29 to point straight out from the tip of CDR1, making VαY29 particularly available for interaction. In the other structures in which Vα contains a P30, the amino acid at p29 (P, T, or S) also interacts with the MHC helix in the same region (Figure 2a). This Vα29 interaction may be a conserved structural feature of Vαs with this proline. 184
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In VαCDR2, a serine at position 51 is the most conserved amino acid among the published structures (63, 64). In MHCI this serine most often interacts with the MHC helix slightly C-terminal to the site engaged by VαY/F31 (Figure 4b–g ). Only occasionally does VαS51 not engage MHC (2AK4 and 1FO0; Figure 4h,i ). The approach of αCDR2 to the MHCI α helix is again
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a hVα1.1, 2.1 hVα1.2.5 hVα1.3 hVα1.4 hVα1.5 hVα2.1.1 hVα2.1.2 hVα2.2 hVα2.3 hVα3.1 hVα6.1.1 hVα6.1.2 hVα6.1.1 hVα9.1 hVα12.1 hVα13.1 hVα15.1 hVα19.1 hVα21.1 hVα23.1 hVα27.1 hVα28.1 hVα30.1 mVα1.1, 7 mVα1.2, 8 mVα1.5 mVα2.2, 3, 4 mVα2.6 mVα2.7 mVα3.1, 5, 6, 7, 9 mVα3.4, 8 mVα5.1 mVα5.3 mVα7.1 mVα10.1 mVα10.2, 3, 6, 9 mVα10.5 mVα11.1, 6 mVα11.6 mVα13.1 mVα15.1 mVα16.1 mVα17.1, 3 mVα18.1, 2, 3 mVα20.1
20:33
51 K Y F SG D P K Y T SA A T K Y L SG S T K Y F SG D T K Y T SA A T F I Y SN G D S I Y SN G D Y T Y SSGN S VY SSGN L I R SN E R Y QG S Y D Q Y QG S Y D E D I R SN V G R H I SR E R RN S F D E Y I P SG T K Y I F SNM D M L S SG K K S I SS I KD L I Q SSQR V L L SN G A M L T SSG I T L Y SAG E S I F SN G E S I F SD G D S I F SN G N S I S SV S D S I L SV S N S I R SV S D K Y Y SG D P K Y Y SG N P K V F SS T E S V L SN V D R QT SS S T S N P SG T Y N P SG T Y S P SWA Y L A SG T Y L A SG T D I R SNM E D I R SN V D D I R SN V N R QD S Y K K L I R SN E R S V R SN V D
b
c
hVα α21.1 (1BD2)
hVα2.1 (1AO7)
Q155 T163 E154 A158 E166
E166 T163
HLA-A2
f
g
Q155 T163
A158
E154
R155
G162
hVα1.2 (1FYT)
βT77
βA73
E154
R157
k
βT77
h
L163 E166 A158
b
hVα13.1 (2IAM) βA73
Ld
i
Q155 E154
HLA-DR1
mVα17.3 (1FO0)
T163 E166
l
G162
R157
hVα3.1 (1YMM)
βD76
R157
m
βT77 βA73
Kb
mVα2.3 (1U3H)
βT77
βA73
βD76 HLA-DR1
HLA-DR2
IAk
Figure 4 S51 in TCRα CDR2α is often used in TCRs and often engages MHC at the same site. (a) The CDR2 sequences of the human (h) and mouse (m) Vα regions that contain an S at position 51 (highlighted in salmon pink). V regions were omitted and numbered as in Figure 3a. (b–i) The arrangements of MHC amino acids around αS51 (blue with red hydroxyl group) in eight of the solved structures of TCRs bound to MHCI, with the α2 helix of MHCI in magenta. Also indicated are the Vα region, MHC allele, and pdb number. The structures are arranged from b to i roughly according to the predicted strength of the interaction or alignment between S51α and MHCI; there is no predicted contact for S51α in 2AK4 (h) and 1FO0 (i ). ( j–m). As in b–i, but for TCRs bound to MHCII, with the β helix of MHCII in magenta. Structures were selected from the references in Figure 2.
facilitated by the conserved MHC A158, as well as G151. In a few cases the hydroxyl group of VαS51 hydrogen bonds to the backbone or amino acid side chains of the MHC helix; other Van der Waals interactions can involve the participation of the backbones of VαS51 and the MHC helix. On MHCII the binding site for VαS51 is similar to that of MHCI, but more fixed, and VαS51 engages MHCII βT77 in various orientations (Figure 4j–m). Particularly in the case of
R155 E154
A158
HLA-B35
βD76
βD76
R157
G162
hVα12.1 (2AK4)
G162
K
mVα3.1 (2OI9)
Kb
R157
HLA-A2
j
G162
mVα2.7 (1KJ2)
e
R155 Y155 E154 E166 E163 A158 A158 E154
E166 T163
R157
E166 T163 A158
R157
G162
E154
mVα3.1 (2CKB)
HLA-A2
hVα23.1 (2BNQ)
E166
A158
G162
R157
G162
Q155
d
MHCI, VαS51 binds at a region of the MHC α helix with some flexibility in its exact site and pitch on the MHC protein. Others have mentioned the involvement of VαY50 in the interaction of several TCRs with MHCI (86). Vαs with this amino acid are not abundant (present in 12%–16% of Vαs) (Figure 5b), but in the VαCDR2s of the published structures VαY50 and other amino acids at this position very often interact with MHC, using the same area of MHCI
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a
b Vα αs with a Y at aa29
Vαs with a Y at aa50
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29 hVα22.1 hVα31.1
Y T AT - - GYPS T ST - - GYP Y T
mVα4.1 mVα4.2 mVα4.3, 4 mVα4.5, 6 mVα4.7 mVα4.9 mVα4.10 mVα4.11 mVα4.12
Y S AS - - GYPA E TK - - QYP Y T S ATS I AYPN Y Y T S TT - - GYP S ATS I GYPN Y Y S AS - - GYPA S ATS I AYPN Y WYP S TT - - WY W Y T S TT - - GYP Y T
50 hVα 2.1. 1 hVα 2.1. 2, 3 hVα 2.2 hVα 2.3 hVα 20.1 hVα 25.1 hVα 30.1
F I YSNGD Y S I YSNGD Y Y T YSSGN Y SVY Y S SGN QGYK Y T KV A L YKAGE Y T L YSAGE Y
mVα3.1, 5, 6, 7, 9 mVα3.2 mVα3.4, 8 mVα12.1
KYYSGDP Y KYYPGDP Y K Y Y SGNP QGYKDYV Y
Figure 5 CDRα sequences that contain other amino acids that frequently bind MHC at the same position. Listed are the human and mouse V region CDR1α sequences that include a Y at position 29 (a), or the human and mouse V region CDR2α sequences that contain a Y at position 50 (b). The amino acid of interest is highlighted in salmon pink. Vαs that have been reported in structures of TCRs bound to MHC are highlighted in yellow or blue, if the structure involved binding to MHCI or MHCII respectively. The sequences were selected and numbered as in Figure 3a and structures were selected from those in Figure 2.
(around A158) and MHCII (around βA73) (Figure 2b). Perhaps these amino acids are evolutionarily selected to do this.
Amino Acids Often Used by Vβs to Bind MHC As pointed out above, the published TCR/MHC structures are dominated by TCRs that use mVβ8 family members or the related human Vβ elements (hVβ3, hVβ12, hVβ13, and hVβ17). With this large pool of data for a related set of Vβs, a number of studies have already revealed particular amino acids that interact with MHC in a similar way from structure to structure (42, 67, 85, 86). These include VβN/Y29 in CDR1 and VβY/F46, VβY48, and VβD/E54 in CDR2 of Vβ (Figure 2c,d ). In these Vβ families and a few others there is often a Y or N in position 29 of Vβ CDR1 (Figure 6). In the published structures these amino acids often make 186
Marrack et al.
contact with the α1 MHC helix, especially in the structures with MHCII in which there is often an H-bond to Q61. Thus, VβN/Y29 may be an amino acid selected by evolution to bind MHCα1. Also in VβCDR1, many different amino acids at position 28 often contact the MHC; however, there is no obvious conserved pattern of recognition for amino acids at this position. In fact, in some structures the rotation of the TCR has brought this amino acid over the peptide to contact the α2 helix of MHCI or the β1 helix of MHCII (Figure 2c); therefore, position 28 does not seem to be involved in an evolutionarily conserved interaction. The most striking example of a conserved point of interaction is position 48 of VβCDR2, which is a Y in the mVβ8 family. Originally, Maynard and coworkers (42) reported that this Y made very similar contacts with MHCII in the interactions of two different TCRs with two different MHC proteins (see 1U3H and 1D9K in Reference 42) and suggested that these residues might form an anchor point for TCRs that use mVβ8.2 to interact with MHCII. A recent paper from the Garcia group expanded on this idea (85). We subsequently found that in the B3K506 and YAe-62 TCRs (which use the closely related mVβs, 8.1 and 8.2) VβY48 binds to yet another MHCII molecule quite similarly. We and the Garcia group also pointed out a similar interaction in a human TCR that uses the related hVβ3 to bind to human HLADR1 and that when mVβ8-containing TCRs interact with MHCI, VβY48 also interacts with the MHCI α1 helix in a similar location (32, 84a, 85). The interaction of position 48 of VβCDR2 with MHC is similar to that discussed above for Vα, in that a conserved small amino acid on the top of the α1 helix at position 69 of MHCI and position 61 of MHCII creates an area for VβY48 to approach the helix. Mainly via Van der Waals interactions, VβY48 can pivot and slide somewhat on the helix without losing contact. In the Vβs of a number of structures, other amino acids (V, A, R, and Q) at Vβ48 contact
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a
b Vβ βs with an N/Y at aa29
c Vβs with a Y at aa48
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29 hVβ3.1 hVβ8.2 hVβ12.1 hVβ12.2 hVβ12.3 hVβ13.2 hVβ13.4, 7 hVβ13.6.1.6.4 hVβ14.1 hVβ16.1 hVβ20.1 hVβ22.1 hVβ25.1
D - MDHEN I - SGHDY T - ENHRY T - WNHNN T - WSHSY D - MNHEY D - MNHGY D - MNHNY N - MNHEY I - SGHDN EGT SNPN I - SNH L Y I - KGHSY
mVβ5.2 mVβ8.1 mVβ8.2a mVβ8.3 mVβ16 mVβ19a
I - SGHSN T - NNHDY T - NNHNN T - NSHNY V - SNH L Y I - NGHSY
Vβs with a D/E at aa54
48 hVβ1.1 hVβ1.2 hVβ3.1 hVβ5.2 hVβ5.3 hVβ5.6 hVβ11.1 hVβ12.1 hVβ12.2.1 hVβ12.2.2 hVβ12.2.3 hVβ22.1 hVβ23.1 hVβ24.1
QYY - NGEERA HYY - NGEERA F SY - DVKMKE QYY - EEEERQ QYY - EK E E RG QYY - R E E ENG YSY - GVNS T E YSY - GVKDTD YSY - GVQDTN YSY - GVKDTN YSY - GVHDTN S F Y - NN E I SE S F Y - EKMQSD HYYNKDF NN
mVβ5.1 mVβ5.2 mVβ7 mVβ8.1 mVβ8.2a mVβ8.3 mVβ9 mVβ16
QHY - - DKMER QHY - - EKVER I SY - DVDSNS YSY - VADS T E YSY - GAGS T E YSY - GAGN LQ F YYDK I L NRE NF Y - NGKVME
54 hVβ3.1 hVβ6.1 hVβ6.2 hVβ6.3 hVβ6.4 hVβ6.5 hVβ6.6 hVβ6.8 hVβ7.2 hVβ7.3 hVβ8.1, 2 hVβ8.3 hVβ11.1 hVβ12.1 hVβ12.3 hVβ13.1 hVβ13.3 hVβ13.4 hVβ13.6 hVβ13.7 hVβ14.1 hVβ16.1 hVβ18.1 hVβ21.1 hVβ21.2 hVβ21.3 hVβ22.1 hVβ23.1 hVβ25.1
F SY - DVKMKE Y FQ - GTGAAD Y FQ - NEAQL D Y FN - YEAQQD Y FQ - NEAQL E Y FQ - GNSAPD Y FN - YEAQPD YSQ - SDAQRD VYS - L EERVE VYN - F KEQT E Y FN - NNVP I D Y FR - NRAP L D YSY - GVNS T E YSY - GVKDTD YSA - AAD I TD YSV - GAG I TD YSA - SEGT TD YSV - AAG I TD YSV - GAG I TD YSA - AAGT TD YSM - NVEV TD HF V - KESKQD Y LQ - KEN I I D QFQ - DESVVD RYE - NEEAVD QFQ - NNGVVD S F Y - NNE I SE S F Y - EKMQSD S FQ - NENV FD
mVβ2a mVβ4 mVβ8.1 mVβ8.2a mVβ9 mVβ11 mVβ12 mVβ13 mVβ16 mVβ17a mVβ19a mVβ20
T L R - SPRDKE SYS - YQK LMD YSY - VADS T E YSY - GAGS T E F YYD K I L NRE Y FR - NQAP I D Y FR - SKS LME Y FR - DEAV I D NF Y - NGKVME NFR - NEE I ME Y FQ - NED I I D Y F Q - NQQP L D
Figure 6 TCR CDRβ sequences that contain amino acids that frequently bind to the same position of MHC. Listed are (a) the human and mouse V region CDR1β sequences that include an N/Y at position 29, (b) the human and mouse V region CDR2β sequences that contain a Y at position 48, and (c) the human and mouse V region CDR2β sequences that contain a D/E at position 54. Sequences are highlighted according to the criteria in Figure 5. The sequences were selected from 59 human Vβs and 23 mouse Vβs and were numbered as in Figure 3a.
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the MHC α1 helix in the same general area. Therefore, the amino acid at this position is a key determinant in anchoring the TCR to the MHC.
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a hVβ3.1 hVβ6.1 hVβ6.2 hVβ6.3 hVβ6.4 hVβ6.5 hVβ6.6 hVβ6.8 hVβ8.1, 2 hVβ8.3 hVβ11.1 hVβ12.1 hVβ12.2.1 hVβ12.2.2 hVβ12.2.3 hVβ12.3 hVβ13.1, 6 hVβ13.2 hVβ13.3 hVβ13.4 hVβ13.5 hVβ13.7 hVβ14.1 hVβ15.1 hVβ17.1 hVβ18.1 hVβ20.1.1 hVβ20.1.3 mVβ6a mVβ8.1 mVβ8.2 mVβ8.3 mVβ9 mVβ11 mVβ12 mVβ13 mVβ14 mVβ19a mVβ20
Another position in Vβ CDR2 worth consideration is Vβ46. As shown in Figure 7a, Vβ46 is a Y or F in a wide variety of Vβs, including 16 of the 22 structures analyzed
46 F S Y - D V KMK E Y FQ - GTGA A D Y FQ - NE AQL D Y F N - Y E A Q QD Y FQ - NE AQL E Y F Q - GN S A P D Y F N - Y E AQP D Y SQ - SDAQRD Y F N - NNV P I D Y F R - NRA P L D Y S Y - GVNS T E Y S Y - GV KD T D Y S Y - GVQD T N Y S Y - GV KD T N Y S Y - GVHD T N YSA - AAD I T D Y S V - GAG I T D Y S V - GEGT T A Y S A - S EGT T D Y S V - A AG I T D Y SN - T AGT T G Y S A - A AGT T D Y SM - N V E V T D YS F - DVKDI N Y SQ - I VND F Q Y LQ - KEN I I D Y S V - G I GQ I S Y S I - G I DQ I S Y S I - T END L Q YSY - VADS T E Y S Y - GAGS T E Y S Y - GAGN L Q F Y YDK I L N RE Y F R - NQA P I D Y F R - S K S L ME Y FR - DEAV I D Y S I - - - T V GQ Y FQ - NED I I D Y F Q - N QQ P L D
b
hVβ β12.1 (2NX5)
Q72
Q65
hVβ6.2 (1MI5)
Q72
hVβ13.1 (1BD2)
Q72
T69
HLA-B35
f
c
R65
A69
hVβ17.1 (1OGA)
hVβ13.1
Q72
(1AO7)
Q72
R65
A69
Q65 G69
R65
hVβ13.3 (2AK4)
Kb
l
mVβ8.2 (1D9K)
Q72 A69
T69
HLA-A2
n
mVβ8.2 (YAe62)
Q61
Q65
R65
HLA-B35
o
mVβ8.1 (B3K506)
Q61
Q57 A64
A64
IAb
A69
p
R65
HLA-A2 hVβ8.2 (2OI9)
Q65 Q72
m
G69
Kb mVβ8.2 (1U3H)
Q61
A64
Q57 A64
IAb
Q72
Q57
Q61 Q72
hVβ8.1 (1LP9)
i
hVβ8.2 (2CKB)
HLA-A2
k
e
HLA-A2
h
Q72 A69
HLA-B8
j
hVβ13.1 (2BNQ)
HLA-A2
g
Q65 T69
d
Q57
A64
IAk hVβ13.6 (2IAM)
A61
q
Q57
Q57 A64
HLA-DR1
IAu hVβ3.1 (1FTY)
A61
HLA-DR1
Figure 7 TCRβ Y/F46 in CDR2β is often used in TCRs and often engages MHC at the same site. (a) The CDR2 sequences of the human (h) and mouse (m) Vβ regions that contain a Y/F at position 46 (highlighted in salmon pink). V regions were omitted and numbered as in Figure 3a. (b–k) The arrangements of MHC amino acids around Y46β (orange with red hydroxyl group) in ten of the solved structures of TCRs bound to MHCI, with the α1 helix of MHCI in cyan. Also indicated are the Vβ region, MHC allele, and pdb number. The structures are arranged from b to k roughly according to the predicted strength of the interaction or alignment between S51α and MHCI; there is no predicted contact for Y46β in g–k. (l–q) Structures are shown as in b–k, but for TCRs bound to MHCII, with the α helix of MHCII in cyan. Structures were selected from the references in Figure 2. 188
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in Figure 2d. In 5 of the MHCI structures, VβY/F46 contacts the MHC α1 helix, usually via α65 (Figure 7b–f ). In the other 5 MHCI structures VβY/F46 is too far away to bind MHC, but it lies in roughly the same position (Figure 7g–k ). In all 6 VβY/F46-containing TCR/MHCII structures, this amino acid contacts Q57 of the α1 helix (Figure 7l–q). Finally, Vβ CDR2 very frequently has an acidic D or E at position 54 (Figure 6). Four of the 14 TCR structures with MHCI have VβD/E54 in contact with R65 of the α1 MHC helix. Because so many different mouse and human Vβs have D/E54, this residue is a candidate for a conserved and sometimesused interaction site. Six of the eight TCR structures with MHCII contain VβD/E54; in all cases D/E54 contacts Q57 of the MHCII α1 helix (Figure 2d ). As pointed out previously, in the five cases with an E at Vβ54, there is a salt bridge to αK39 of MHCII. αK39 is not on the α helix of MHCII, but rather lies on one of the β strands of MHCII as it protrudes beyond the peptide-binding site. This solvent-exposed amino acid is highly conserved in MHCII, although it is not involved in the structural integrity of MHCII or in peptide binding. Thus, D/E54 may represent a TCR CDR2 amino acid that has been evolutionarily selected to react with MHCI and MHCII (in this case in different ways).
The Biases for MHC Reaction Built into TCR Vαs and Vβs May Control the Orientation of TCRs on MHC Our purpose in this analysis was to determine whether the existing TCR/MHC structures could be used to make a case for germ line– encoded features of TCR Vα and Vβ elements that account for the obsession of TCRs with MHC ligands. Any analysis should account for both the conserved general diagonal orientation of the TCR on the MHC ligand as well as the considerable variation in angle and pitch of the TCR on the MHC sur-
face. We were guided in this analysis by the idea that the need to avoid negative selection in the thymus might select for TCR CDR3s that attenuated these germ line interactions and that in mice with limited negative selection highly MHC-cross-reactive T cells were common. Therefore, in examining the structures we looked for sites of interaction in which particular TCR amino acids were often but not always found and for interactions that might be flexible and not necessarily lost by small shifts in orientation position. We conclude that such interactions can be identified. Our overall conclusions are summarized schematically in Figure 8. We propose that the anchor points on MHC molecules are not particular amino acid side chains, but rather two exposed areas on the tops of the MHC α-helices, centered about α169 and α2158 for MHCI and α1 64 and β173 for MHCII. These amino acids are highly conserved (mostly A and G) and contribute to dish-like areas that expose the backbones of the helices. The flanking amino acids on the helices determine the size of this area. In the majority of the TCR/MHC structures, these exposed areas are major sites of interaction with specific amino acids in TCR CDR1 and CDR2 regions. Because these areas occur diagonally opposite one another on the helices, we propose that these exposed areas determine the general diagonal orientation of the TCR on the MHC. The TCR amino acids involved in these interactions are often, as previously noted (85), tyrosines that make many Van der Waals contacts with the backbones of helices and the amino acid side chains that flank these areas. These types of interactions do not require a precise geometry and thus allow considerable flexibility in the orientation and exact position of the TCR amino acid in question along the MHC helices, from one TCR/MHC combination to another. This may account for the ability of TCRs to bind MHCs in different structures with similar but not identical docking angles.
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b
a α2
β1 Vβ28 Vβ29
Vβ28 Vβ29
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Vβ46 Vβ48
69 158
Vα50 Vα51
Vβ46 Vβ48 Vβ54
64
73
Vα29 Vα31
Vα29 Vα31
α1
α1
MHC I
MHC II
Figure 8 The amino acids in Vα and Vβ that frequently contact the same areas of MHC can determine the diagonal aspect of the binding of the TCR to MHC. Ribbon representations of HLA-A2/Tax peptide (pdb 1BD2) and IAb /3K (pdb 1LNU) are shown as examples of MHCI and MHCII molecules, respectively, showing the α1/α domains (cyan), the MHCI α2 domain and the MHCII β1 domains (magenta), and the peptide ( yellow). The positions of two amino acids on the helices of each MHC molecule are labeled: α69 and α158 on MHC1 and α64 and β73 on MHCII. An area around each of these amino acids is circled. TCR amino acids most often found in contact with the MHC within these areas are listed next to each circle.
Interestingly, tyrosines are also often involved in these kinds of interactions between antibodies and protein antigens (87).
Why Are Not All the Evolutionarily Selected Rules Apparent in All TCR/MHC Complexes? If there are rules that govern the interactions between TCR V regions and MHC, then one might expect that these rules would always be manifest, particularly when the V region is involved in recognition of the same MHC allele, regardless of the peptide. However, this is not always observed. For example, investigators have reported the structures of three human TCRs containing Vβ13.1, bound to the class I protein, HLA-A2 (28, 29, 35). One TCR (1G4 190
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Vα50 Vα51
in 2BNQ) has many contacts between Vβ13.1 and HLA-A2, another (B7 in 1BD2) has a few, and the last (A6 in 1AO7) has none (Figure 2). These differences are due to changes in the CDR3 regions of the TCR. A6 has a very long CDR3β that lifts the TCR away from the MHC, so that contacts are not possible. We hypothesize that this ability of CDR3s to attenuate the evolutionarily selected ability of V regions to interact with MHC is needed for TCRs and the cells bearing them to escape negative selection in the thymus. The intrinsic reactivity of TCR V regions with MHC may then be even further obscured when the TCR binds MHC bound to foreign peptides, since, although these foreign peptides may provide additional positive interactions with TCRs, they may also interfere with the
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built-in TCR/MHC interactions. Such may be illustrated by the 2AK4 structure, in which TCR contacts with MHC were limited by a very pronounced bulge in the surface of MHC, caused by the extraordinary length of the engaged peptide (Figure 2). Thus, the CDR3 regions of the TCR and/or the peptide amino acids projecting out of the MHC groove determine whether or not the TCR will be lifted away from MHC or pitched such that it can contact only a portion of the MHC amino acids.
Do the Evolutionarily Selected Interactions Operate for Both MHCI and MHCII Recognition? Our analysis of highly cross-reactive T cells, such as YAe62, suggested that the same conserved MHC-reactive features of a particular CDR1 and CDR2 might apply to both MHCI and MHCII recognition. In general, we found evidence for this in our analysis, but there seem to be some differences. The rules seem somewhat more apparent with MHCII than with MHCI. For example, in TCRs with mVβ8.2, the limits of the area of contact between VβCDR2 Y48 and the α1 MHC helix appear to be more restricted on MHCII than on MHCI. Also, the MHC αK39 that forms a unique salt bridge with VβCDR2 E54 does not exist in MHCI. One factor might be that a number of the TCR/MHCI structures involve MHC alloantigens, and therefore the TCRs did not come from a repertoire shaped by negative selection by that particular MHC during development. Thus, as more TCR/MHCI structures that involve conventional peptide antigens appear, some of these differences may fade.
A Caveat TCR amino acid engagement of a particular site on MHC does not necessarily mean that the reaction is predetermined by the sequences of TCR and MHC. Instead, the reaction may be forced by other elements, such
as the docking sites of CD4 and CD8 or other phenomena (67). Another possibility is that there are limited numbers of amino acids in the CDR1 and CDR2 regions of TCRs and on the α helices of MHC, so some common reactions are bound to occur. We believe that these possibilities are unlikely for two reasons: First, the interactions are determined by the nature, not the position, of the TCR amino acid (Figure 2). Second, as proposed in Figure 8, the prominent availability of particular TCR amino acids does not in itself predict a particular area of MHC contact. Moreover, differences exist between MHCI and MHCII engagement (see above), which suggests that the system is built more subtly than suggested by the forced position argument. Ultimately, the hypothesis we propose simply focuses attention on particular amino acids whose function must be confirmed in proper experiments, for example, by changing the relevant TCR amino acids in the mouse germ line and observing the effects of the changes on TCR selection and function.
DO THE BIASES OF TCRs FOR RECOGNITION OF MHC APPLY TO NONCLASSICAL MHC MOLECULES? In addition to the classical polymorphic MHC molecules, mammalian species express other relatively nonpolymorphic MHCIb and MHC-like molecules, such as HLA-E, H2M3, MR1, and members of the CD1 family (39, 88, 89). These molecules are also recognized by αβTCR-bearing T cells and are important in fending off infectious diseases. For example, HLA-E-restricted T cells have been identified in responses to bacteria and viruses, including Mycobacterium tuberculosis (Mtb) and cytomegalovirus (CMV) (90, 91). In mice, H2-M3-restricted T cells have a characteristic preactivated phenotype and mediate early T cell responses against Listeria monocytogenes (92). Similarly, T cells that recognize lipid antigens in the context of the CD1 family have been implicated in
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responses to Sphingomonas, Borrelia burgdorferi, and Mtb (93–98). One feature of this family of MHC-like proteins is that they often present nonpeptide antigens, such as glycolipids. The question then arises how TCRs that may have evolved to react with classical MHC/peptide cope with these nonconventional MHCs and their bound ligands. The nonpolymorphic MHCIb molecule, HLA-E, presents peptides from the leader sequences of conventional MHCIa molecules (99). These MHC/self-peptide complexes are recognized by inhibitory natural killer (NK) receptors as surrogate markers for MHCI fidelity when MHCI expression is altered by specific pathogens (100, 101). Inhibitory NK receptors are quite tolerant of amino acid changes in HLA-E-presented peptides (39), whereas αβTCRs have conventional specificities both for HLA-E and its engaged peptides. This is exemplified by the recent solution of the structure of a TCR, KK50.4, bound to HLA-E plus a CMV-encoded mimic of an MHCI leader peptide (39). The overall recognition of HLA-E by the KK50.4 TCR has the same topology as that of T cells reacting with conventional MHC, a similar diagonal binding mode, and the same TCR amino acids are used to dock with HLA-E (Figure 2). Thus, the proposed evolutionary biases of TCRs for MHC apply to reactions with both classical MHC and HLA-E. H2-M3 was originally identified as a minor histocompatibility molecule that presents a maternally linked factor (102). Like HLAE, H2-M3 is relatively nonpolymorphic but is unique to murine species. The peptidebinding groove of H2-M3 is unlike that of conventional MHCI molecules; it accommodates a formylmethionine moiety at the N terminus of the peptide that facilitates the presentation of bacterial- and mitochondrialproduced proteins (103, 104). The overall dimensions of the groove between the α-helices of H2-M3 are similar to those of conventional MHCI molecules, but the amino acids that line this pocket are primarily nonpolar, which facilitates the presentation of hy-
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drophobic peptides. The molecular basis for TCR recognition of H2-M3 remains undetermined, but the overall similarities to MHCIa suggest it may be receptive to conserved TCR interactions. MHC-related protein 1 (MR1) is another β2 m-associated, MHCIb molecule that is evolutionarily conserved among mammals (105). MR1 is associated with stimulation of, and is required for the development of, mucosal-associated invariant T (MAIT) cells. This population of T cells expresses a TCR with an invariant Vα19-Jα33 TCRα (Vα19i) in mice; in humans MAIT cells express the highly similar combination of Vα7.2 and Jα19 (Vα7.2i) (106). The natural antigens presented by MR1 in vivo are largely unknown, although researchers have suggested a role for gut flora in the activation of these MAIT cells. Surprisingly, although the amino acid composition of the MR1 groove is not especially suited for glycolipid presentation [unlike that of CD1 molecules (see below)], αmannosylceramide stimulates Vα19i T cells in a MR1-dependent manner (107). The structure of MR1 is currently unknown, but, on the basis of the overall similarity to MHCIa and MHCIb, a computational analysis suggested an MHC-like fold and allowed a mutational analysis of the α-helices and the putative antigen-binding groove. The response of several T cell hybridomas to these mutants suggested both an antigen presentation function as well as a diagonal TCR docking mode similar to that of conventional T cells (108).
TCR Recognition of CD1d Molecules The human CD1 family and mouse CD1d are nonpolymorphic, β2 m-associated, MHCIlike molecules expressed predominately on hematopoetic cells. Compared with classical MHCI and MHCII molecules, the antigenbinding groove of CD1 family members is narrower, has a more pronounced bulge in its α2 helix, and is composed primarily of nonpolar amino acids to facilitate the presentation of
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diverse hydrophobic ligands, including lipids, glycolipids, and lipopeptides. Whereas the lipid tails serve to anchor these antigens in the groove, the polar head groups extend out of the groove for recognition by T cells (reviewed in Reference 58). Group I CD1 isoforms (CD1a, b, and c) present many different antigens, including lipids and lipopeptides that vary in size and shape (58, 109–113). Most human T cells reactive to CD1a, CD1b, and CD1c express diverse Vα and Vβ gene segments (110, 111, 113), which suggests that group I CD1reactive T cells may have a broad range of unique antigen specificities. Indeed, CD1aand CD1b-reactive T cell lines are highly specific for particular peptide moieties on didehydroxymycobactin antigens (for CD1a) and for carbohydrate moieties of mycolyl lipid antigens (for CD1b) (114, 115). Although the precise molecular basis for αβTCR recognition of CD1a, CD1b, or CD1c has not yet been resolved by crystallography, results from mutational analysis of the TCR-interacting face of CD1b suggest a diagonal orientation of TCR contacts, similar to the binding mode observed in conventional T cells (116). The interesting question remains how TCRs with apparently normal geometry can contact the group I CD1 proteins and classical MHC proteins in the same way, given the quite different geometry of the two types of MHC molecules. The situation is entirely different for the group II isoform of CD1d, the only CD1 isoform conserved between mouse and human (58). In contrast to the highly diverse TCR repertoire expressed by T cells reactive to other MHC molecules and group I CD1s, most CD1d-reactive cells in humans and mice are NKT cells (117, 118). NKT cells express an invariant TCRα composed of Vα24-Jα18 (Vα24i TCRα) in humans and the nearly identical Vα14-Jα18 (Vα14i TCRα) in mice (119, 120). The peripheral NKT population uses a diverse but limited number of TCRβ gene segments; the majority of the population expresses Vβ11 in humans and Vβs 2, 7, and
8.2 in mice (117, 118). The invariant TCRα chain and the complete lack of NKT cells in Jα18-deficient mice strongly suggest a critical role for the TCRα in the recognition of glycolipid/CD1d complexes (121). Conversely, the role of the more diverse TCRβ is less clear. NKT cells react with a number of glycolipid antigens (118). Perhaps different TCRβs allow reaction with different glycolipids. We recently used mutagenesis analysis to assess the role of the mouse Vα14i TCRα and TCRβ chains in the recognition of different glycolipid/CD1d complexes (122). We showed that mouse Vα14i TCRα recognition of multiple α-linked glycolipids is conferred by a functional hot spot composed of germ line–encoded amino acids within CDR3α, CDR1α, and CDR2β. This functional hot spot does not differ between structurally distinct antigens, which suggests that the Vα14i TCRα functions as a pattern-recognition receptor. Results from the mutagenesis studies highlighted the critical role of germ line–encoded residues in the Vα14i TCRα,
CD1 α1
α1
β2
Glycolipid α3 α2 β1 β3 CD1 α2 Figure 9 TCRs bind CD1d/glycolipid in an orientation that is completely different from that used to bind classical MHC/peptide. Shown is a plan of the contacts between the CDR1–3 loops of the α and β chains of the hVα24i TCR and a space-filling surface of CD1d and α-galactosylceramide (data taken from Reference 68, pdb 2PO6). Shown are the α1 region of CD1d (cyan), the α2 region of CD1d (magenta), the glycolipid ( yellow), as well as the CDR loops, color coded and labeled in their corresponding colors.
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CDR2β residue Mouse Vβ8.1
46 47 48 49 50 51 52 53 54 Y S Y V A D S T E
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506-IA (3K)
Mouse Vβ8.2
1LP9 Y
S
Y
G
A
G
S
T
E
b
###
YAe62-IA (3K) k
D10-IA (Conalb)
1D9K
u
1U3H
172.10-IA (MBP) d
2OI9
2C-L (QL9) b
2CKB
b
1G6R
2C-K (dev8)
Mutational
Structural
Mutational
2C-K (SIYR)
NKT TCR recognition of CD1d
PDB ###
AHIII-A2 (p1049) Structural
Mouse TCR recognition of MHCI/II
b
2C-Ld (QL9)
A
A
2C-Kb (SIYR)
A
A
A
W
A
Human Vβ11
Y
Y
G
V
N
S
S
A
A
A
A
T
E
hNKT-hCD1d (αGC) Mouse Vβ8.2
2PO6 Y
S
Y
G
mNKT-mCD1d (αGC)
A
A
mNKT-hCD1d (αGC)
A
A
A
G
S
A
A
A
A
A
A
T
E
Figure 10 Some of the CDR2β amino acids used to contact classical MHCI/MHCII and CD1d are identical. The amino acid sequences of mVβ8.1 and mVβ8.2 are shown in bold. Amino acids that have been shown to bind MHC in solved structures are indicated by blue squares, along with the names of the TCRs and pdb files used. White squares indicate amino acids that do not contact MHC in the indicated structure. Also shown are the results of mutational analyses, in which the amino acid in question was mutated as shown in each square. The influence of each mutation is indicated: red-filled squares indicate >1 log change in reactivity, whereas white squares indicate a 50% loss in tetramer mean fluorescent intensity (MFI), pink indicates a change between 10% and 50% in tetramer MFI, and white indicates a 60%) of T cells in the asthmatic BAL as compared to healthy controls or subjects with sarcoidosis (64). However, although CD1d-restricted NKT cells were significantly enriched in the BAL as compared to blood, we have found that they made up only 1000-fold enrichment compared to peripheral blood NKT concentrations, as suggested by Akbari et al. (64). More recent data are consistent with the conclusion that the frequency of CD1drestricted NKT cells in the BAL may have been substantially overestimated, possibly for technical reasons (95). A number of other groups have also observed low numbers of BAL NKT cells in persons with mild, moderate, and severe asthma, subjects with chronic obstructive pulmonary disease (COPD), and healthy controls (95–99), in contrast to the findings of Akbari et al. (64). In mouse models of asthma, CD1drestricted NKT cells have also been shown to be critical for generating the allergic airway response through production of IL-4 and
214
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Thomas
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IL-13 (65, 100). However, the requirement for CD1d-restricted NKT cells (and CD8 T cells) in the development of T cell–dependent airway inflammation has been called into question by a recent study that shows that CD4+ T cells, but not CD1d-restricted NKT or CD8 T cells, are sufficient to induce allergic airway inflammation (68). Thus, although CD1d-restricted NKT cells likely contribute to the asthmatic response through secretion of Th2 cytokines, we believe that conventional T cells make up the predominant T cell population in the asthmatic BAL and play the predominant role in promoting the allergic asthmatic response.
CHEMOKINES AND CHEMOATTRACTANT RECEPTORS IN THE ALLERGIC ASTHMATIC RESPONSE Although the recruitment of eosinophils into the airways is an important component in the pathogenesis of asthma (see the sidebar, Eosinophil Recruitment into the Lung During Allergic Inflammation), the trafficking of activated T lymphocytes into the airways clearly orchestrates the asthmatic inflammatory response (101). Consistent with this, after exposure to allergen, there is a dramatic increase in the number of T cells in the airways of humans and in murine models of asthma (1, 21, 22, 41, 71, 102, 103). In a murine model of asthma, we determined that the trafficking of Th2 cells into the airway both before and following allergen challenge is controlled by G protein–coupled chemoattractant receptors (104). Although CCR4 and CCR8 are expressed on Th2 cells, deletion of these receptors in mouse models of asthma has yielded conflicting results (105–110). The preservation of Th2 cell trafficking in the absence of individual chemoattractants or their receptors has led us to hypothesize that multiple pathways, acting through multiple chemoattractants and their receptors, direct Th2 cell trafficking into the airways.
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Comparisons between normal controls and human asthmatics, as well as human segmental allergen challenge studies, have yielded information about T cell trafficking and chemoattractant receptor expression. At baseline, healthy controls and asthmatic subjects express similar chemokine receptors on BAL T cells (31, 84, 86, 111, 112). BAL T cells were enriched in expression of specific receptors as compared to peripheral blood T cells and expressed high levels of CCR5, CXCR3, and CXCR4; intermediate levels of CCR4, CCR6, CCR7, and CXCR6; and low levels of BLT1, CCR1, CCR2, CCR3, and CXCR1 along with other chemoattractant receptors. The increased expression of specific chemoattractant receptors on BAL T cells as compared to peripheral blood T cells may be related to the larger memory T cell population in the BAL and to the requirement for specific chemokine receptors in trafficking to tissue sites. Following allergic stimulus, a number of chemokines are produced and lead to recruitment of T cells along with other leukocytes to the allergic lung. Human CCR2, CCR3, CCR4, CCR5, CCR6, CXCR1/2, CXCR3, CRTH2, but not CCR8 or CXCR6 ligands were increased following segmental allergen challenge (22, 102, 113–118). Similarly, in the mouse models of asthma, ligands of the chemoattractant receptors, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CXCR1, CXCR3, and BLT1 were induced in the lung at early time points (119–122). These data suggest that a number of chemokine receptors play a role in recruitment of T cells and other allergic mediators. We and others have examined the profiles of chemoattractant receptor expression on T cells before and after segmental allergen challenge to determine whether specific chemoattractant receptors were preferentially utilized in T cell recruitment (22, 31). We hypothesized that the Th2-associated receptors CCR3, CCR4, and CCR8 would be increased following allergen challenge, whereas the Th1-associated receptors CCR5,
EOSINOPHIL RECRUITMENT INTO THE LUNG DURING ALLERGIC INFLAMMATION Although T cells likely orchestrate allergic asthmatic inflammation, it is the eosinophil that remains the primary leukocyte recruited into the airway during allergic inflammation. Recent data indicate that eosinophils are necessary for the full manifestations of the asthma phenotype (17, 18), and thus the mechanisms that control their recruitment into the airway are important for asthma pathogenesis. Eosinophils express the chemokine receptor CCR3 and are likely recruited via production of the STAT6-dependent chemokines CCL11 and CCL24 (in both mice and humans) and CCL26 (in humans only), all of which are upregulated in the airways of asthmatics (117, 173–175). Data in animal models indicate that both CCL11 and CCL24 contribute to eosinophil recruitment, with CCL24 likely being the dominant eosinophilactive chemokine (176). STAT6 expression in a lung cell is necessary for eosinophil recruitment (41), and recent data (159) suggest that alternatively activated macrophages may mediate eosinophil recruitment. We also have data suggesting that myeloid DCs can express CCL24 and may also help mediate eosinophil recruitment (unpublished observation). These data demonstrate that eosinophil recruitment into the airway in allergic inflammation is largely controlled by myeloid cells in the lung via a STAT6-dependent mechanism.
CXCR3, and CXCR6 would be decreased following challenge. Although total numbers of T cells were increased following allergen challenge, we did not observe an increase in the percentage of CD4+ or CD8+ T cells expressing any chemoattractant receptor (22). Instead, we noted a statistically significant decrease in CCR6 and CXCR3 expression on CD4+ and CD8+ BAL T cells 24 h following allergen challenge. We believe that CCR6 and CXCR3 were downregulated following encounter with cognate ligand, indicating that these two receptors might play an underappreciated role in T cell recruitment to the asthmatic airway. However, we would also argue that these data have not ruled out the significance of other chemoattractant receptors in the recruitment of T cells to the allergic lung. www.annualreviews.org • T Cell Trafficking in Asthma
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Overall, these data suggest that T cells are recruited to the asthmatic BAL through a number of different chemoattractant receptors. Because the chemokines expressed following the asthmatic response can recruit a variety of T cells, it is important to understand the role of different T cell subsets in the asthmatic response.
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THE PHASES OF T CELL TRAFFICKING IN ALLERGIC ASTHMA: A NEW PARADIGM In the past few years, we and others have made considerable progress in delineating the mechanisms that control T cell trafficking in asthma. These data have led us to the central hypothesis of this review: T cell trafficking into the allergic lung is controlled by several discrete regulatory pathways that involve the collaboration of innate and acquired immune cells. We propose a four-step model that includes an initiation phase, a propagation phase, an amplification phase, and a resolution phase (Figure 5). The first two phases of T cell recruitment into the airways are mediated by chemoattractants produced by innate immune cells stimulated by the direct interactions of inhaled allergens. Binding and cross-linking of mast cell–associated IgE by allergens lead to mast cell activation, resulting in the release of a first set of chemoattractants that initiate T cell recruitment (phase I). We propose that early T cell recruitment is then propagated by the recognition of allergen by PAMP (pathogen-associated molecular pattern) receptors on innate immune cells in the lung, which leads to the release of chemokines (phase II). The third phase of T cell recruitment is mediated by chemoattractants produced in response to the interactions of resident airway cells with the Th2 cells arriving in the initiation and propagation phases of recruitment. These early recruited Th2 cells elaborate Th2-type cytokines that stimulate resident innate immune cells of the airways to release this third set of STAT6inducible chemoattractants that dramatically 216
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amplify Th2 cell recruitment (phase III), and also mediate eosinophil recruitment. Finally, a subset of T cells leaves the airways and enters the lymphatics during a resolution phase (phase IV) that we believe may be involved in both attenuating allergic pulmonary inflammation and in establishing immunologic memory. In this review, we present data that support this paradigm for the control of T cell migration into and out of the lung.
PHASE I: INITIATION—MAST CELL–DEPENDENT TH2 CELL RECRUITMENT Within minutes of inhaling allergen, IgE on mast cells binds the foreign substance, leading to cross-linking of mast cell IgE Fc receptors (Figure 5a). This cross-linking stimulates the mast cells to release preformed inflammatory mediators, such as histamine, and also stimulates the cells to produce and release other mediators, including leukotrienes, TNF-α, chemokines, and Th2-type cytokines. These mediators start the development of mucosal edema, mucus secretion, and airway reactivity. In addition, some of these mediators initiate the recruitment of T cells into the airways (123, 124). We have recently shown that one of these mediators, LTB4 , is a potent chemoattractant for Th2 and Th1 cells (125– 127). Furthermore, we have demonstrated that deletion of the LTB4 receptor, BLT1, leads to an early defect in T cell accumulation in the airways in a model of allergic pulmonary inflammation that involves active immunization to a foreign antigen (chicken egg albumin or OVA) with IgE formation. However, this defect was not seen when OVA-specific Th2 cells were adoptively transferred into unimmunized mice, which do not form OVAspecific IgE (127). Because one of the important differences between these two models is the formation of IgE and mast cell stimulation with OVA challenge, these results led us to hypothesize that in response to allergen challenge, IgE-activated mast cells release LTB4 into the airway, which mediates the
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Figure 5 Proposed multiphase model of T cell trafficking into the asthmatic airway. (a) Phase I: initial T cell recruitment into the airways. Antigen-IgE complexes stimulate airway mast cells to release various mediators, such as leukotriene B4 (LTB4 ) and CCL1, which leads to Th2 cell recruitment through BLT1 and CCR8. (b) Phase II: propagation of T cell recruitment into the airways. Antigen directly interacts with innate immune cells, such as macrophages via TLRs, to stimulate the release of chemokines, such as CXCL10 and CCL20. These chemokines then recruit more T cells into the airways via their receptors CXCR3 and CCR6. (c) Phase III: proposed mechanism for amplification of T cell recruitment into the airways. IL-4 and IL-13 produced by Th2 cells already recruited into the airways stimulate innate immune cells, such as myeloid DCs, to release the STAT6-dependent chemokines CCL17 and CCL22. These chemokines amplify Th2 cell recruitment into the airways through their receptor CCR4. (d ) Phase IV: proposed mechanism for resolution of T cell accumulation in the airways. Th2 cells in the airways that express CCR7 are recruited into the lymphatics through the action of CCL21. This then leads to efflux of the Th2 cells out of the lung and into the lymph node.
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initial recruitment of Th2 cells into the lung (126). Mast cells also produce and release the chemokines CCL1, CCL17, CCL22, and the chemical histamine, all of which are chemotactic for Th2 cells through interactions with their G protein–coupled receptors CCR8 (CCL1), CCR4 (CCL17, CCL22), and H1R (histamine) (123, 128–130). CCL1 release may be particularly important for early Th2 cell recruitment, as recently demonstrated in a murine model of mast cell-dependent allergic airway inflammation (130). Mast cell stimulation by allergen-IgE complexes thus leads to the release of multiple chemoattractants able to initiate the recruitment of T lymphocytes into the airways. The sequential release of LTB4 and chemokines from mast cells is consistent with the differing time courses of the generation of these chemoattractants: LTB4 is rapidly generated enzymatically from membrane lipids within minutes, whereas the release of chemokines may require transcription and translation and consequently take several hours. In addition to generating leukotrienes, activated mast cells also generate prostaglandins, including PGD2 , which could lead to Th2 cell recruitment through the CRTH2 receptor (131–133). In addition to preformed IgE antibodies, IgG antibodies to allergens can also stimulate mast cells and macrophages to release inflammatory mediators (134–136). These mediators, which include LTB4 , can further enhance the recruitment of T cells into the airways following allergen exposure. The initial recruitment of T cells in the airways allows the immune system to respond to a perceived threat within minutes as opposed to the hours it would take to mount an adaptive immune response. DC maturation and function may also depend on an initial interaction with memory T cells in the airways (8). Thus, the almost immediate recruitment of memory T cells into the airways following allergen challenge may also help prime the adaptive immune response by increasing potential DC–T cell interactions. Furthermore,
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mast cell degranulation may contribute to the efficiency and intensity of the LAR by enhancing T cell recruitment into the airways (124, 127). In summary, soon after the inhalation of allergen, antigen interaction with preformed IgE and IgG antibodies leads to early mediator release, including chemoattractants. These chemoattractants then rapidly induce the initial recruitment of T cells into the airways.
PHASE II: PROPAGATION—INNATE IMMUNE-DEPENDENT TH2 CELL RECRUITMENT In addition to binding to antigen-specific antibodies, components in allergens, or associated viral infections or particles in the air, can stimulate innate immune cells in the airways through interactions with PAMP receptors, such as the TLRs (Figure 5b). TLR stimulation in asthma exacerbations may occur through LPS (lipopolysaccharide) found in antigens. In addition, viral infections (a common cause of asthma exacerbations) can stimulate innate immune cells as well as epithelial cells via TLR stimulation (137– 140). We have previously shown that most Th2 cell recruitment into the lung following allergen challenge is dependent on tissuederived STAT6-induced chemokines, such as CCL22 and CCL17. Although STAT6 plays a significant role in the regulation of antigen-specific Th2 cell trafficking, there is evidence that STAT6-independent pathways contribute to T cell trafficking into the allergic lung. Namely, after the adoptive transfer of antigen-specific Th2 cells and antigen challenge, a small number of antigen-specific Th2 cells do enter the lung of STAT6−/− mice (41, 104). We hypothesize that PAMP receptorinducible chemokines and their corresponding chemokine receptors represent a STAT6independent pathway of antigen-specific Th2 cell and Th1 cell trafficking. This could have direct relevance to upper respiratory viral
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infections, such as the influenza virus (141) or respiratory syncytial virus (142), which can activate TLR7 and TLR3. In addition, aeroallergens, like animal dander and house dust mites, contain LPS. The importance of TLRs in asthma is indicated by studies demonstrating that the inflammatory response in a murine model of asthma is partially dependent on the adaptor molecule, MyD88, a downstream mediator of TLR signaling (12). In addition, LPS in allergens can stimulate antigen-presenting cells in the lung and may play role in Th2 cell polarization (143). Recently, Jung et al. (144) have shown that TLR4 stimulation in an animal model of allergic airway inflammation enhances both Th1 and Th2 cell recruitment into the lung. Consistent with this, there is evidence in the published literature that TLR activation leads to CXCL10 and CCL20 expression (145, 146) and that CXCL10 and CCL20 are increased in the context of allergen exposure (22, 102, 121, 122, 147, 148). CXCR3 and CCR6, the receptors recognizing CXCL10 and CCL20, are expressed on T cells that infiltrate the lung during allergic inflammation (22, 31, 111). Furthermore, CCR6-deficient mice have decreased airway resistance, fewer lung eosinophils, and reduced lung IL-5 levels compared with their wild-type counterparts (121, 149), and the transfer of CCR6+/+ T cells from sensitized wild-type mice into CCR6−/− mice results in an increase in airway eosinophilia and IL5 levels (149). In addition, studies with the CXCL10 knockout and transgenic mice suggest that recruitment of CXCR3+ T cells exacerbates the allergic asthmatic response (122). These data are also consistent with some of our recent findings suggesting that CXCR3 and CCR6 are mediators of T cell recruitment into the airways of asthmatics following allergen challenge (22). Although Th2 and Th1 cells are likely the primary mediators of allergic airway inflammation, some data suggest that other T cell subsets may also be involved in asthma pathogenesis. These include Th17 cells, NKT cells,
CD8+ T cells, and γδ T cells. Th17 cells express CCR6, for which the ligand (CCL20) is made in this phase (44, 150, 151). In addition, NKT cells, CD8+ T cells, and γδ T cells may all be recruited by similar mechanisms as Th1 cells in this phase, with CXCL10 and CCL20 both potentially mediating the recruitment of these cells (22, 94, 152). Allergen deposition in the lung may also interact with other inflammatory pathways, such as the complement cascade, and enzymes in the airways, such as chitinases, which could then influence the production of chemokines (153, 154). For example, the activation of the C5a receptor following allergen challenge increases the secretion of the CCL17 and CCL22 by airway DCs in a murine model of asthma. These data suggest that allergen-induced pattern recognition receptor stimulation on innate immune cells in the lung may contribute to T cell recruitment. We hypothesize that allergen or viral components directly stimulate innate immune cells, activating these cells to present antigen and to produce chemokines and other inflammatory cytokines. These mediators then propagate the inflammatory response and enhance the recruitment of Th2 cells into the lung. In addition, these mediators may also initiate the recruitment of Th1 cells and other T cell subsets into the lung, which could further enhance the homing of Th2 cells into the lung (58, 59, 144).
PHASE III: AMPLIFICATION— STAT6-DEPENDENT TH2 CELL RECRUITMENT Following the early trafficking of Th2 cells into the airways, there is a dramatic amplification of Th2 cell recruitment (Figure 5c). Previous research by our group has shown that deletion of STAT6 in the lung eliminates more than 80% of Th2 cell trafficking following allergen (41, 42). These studies also demonstrated that STAT6 expression in a resident lung cell is necessary for effective www.annualreviews.org • T Cell Trafficking in Asthma
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Th2 cell and eosinophil recruitment into the airways. Consistent with this finding, STAT6−/− mice had significantly lower production of the Th2-active chemokines CCL17 and CCL22 and the eosinophil-active chemokines CCL11 and CCL24. Using a model of pulmonary Th2 inflammation induced by infection by Nippostrongylus brasiliensis, Voehringer et al. (19, 20) demonstrated that STAT6 expression in a bone marrow– derived myeloid cell is necessary for Th2 cell trafficking into the lung. These data suggest that the critical cellular mediator of Th2 cell recruitment is a bone marrow–derived nonlymphocyte cell in the lung, possibly a myeloid-derived cell such as a pulmonary macrophage or DC. We hypothesize that Th2 cells recruited into the lung in the initial and propagation phases produce IL-4 and IL-13 (155), which stimulate myeloid-derived cells in the lung, such as pulmonary macrophages and/or DCs, to produce STAT6-dependent chemokines. These chemokines then serve to amplify the recruitment of Th2 cells and initiate eosinophil trafficking into the lung. Previous work by others has demonstrated that depletion of CD11c+ cells in the lung after sensitization to OVA but prior to challenge prevents the development of allergic airway inflammation, suggesting that airway DCs and/or alveolar macrophages (both are CD11c+ ) control key aspects in the pathogenesis of the inflammatory response (156). When alveolar macrophages or DCs were added back to the lung in those experiments, the phenotype was restored only with DC transfer, suggesting that DCs were necessary for allergic inflammation. In addition, pulmonary DCs accumulate around the airways during allergic inflammation and produce CCL17 and CCL22 (9, 153, 156, 157, 158). We have recently found that selective depletion of a population of CD11b+ /CD11c+ myeloid DCs in the lung significantly impairs Th2 cell trafficking into the lung following Th2 cell transfer and antigen challenge (B.D. Medoff and A.D. Luster, unpublished observation). Our data demonstrate that myeloid
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DCs in the lung are both necessary and sufficient for Th2 cell trafficking in this model. Based on these data, we propose that Th2 cells recruited into the airways in the initiation and propagation phase produce cytokines that stimulate pulmonary myeloid DCs to make CCL17 and CCL22, which amplifies Th2 cell recruitment into the airways. In addition, these cells, as well as alternatively activated pulmonary macrophages (159), produce CCL24, which stimulates eosinophil recruitment into the airways. Tregs likely are involved in the control of airway inflammation and have been shown to accumulate in the airway during the development of allergic inflammation in an animal model of asthma (62). Tregs express the chemokine receptors CCR4 and CCR8 (56) and thus may be recruited by the release of CCL1 during phase I, and CCL17 and CCL22 during phase III of the paradigm.
PHASE IV: RESOLUTION/ MEMORY—CCR7-DEPENDENT TH2 CELL EXIT In murine models of asthma, intense airway inflammation produced by sensitization and challenge with allergen decreases over time following the cessation of allergen exposure (160–162) (Figure 5d ). The resolution of airway inflammation following allergen challenge is clearly an important process for limiting the allergic response and may prevent complications of inflammation. For example, deletion of matrix metalloproteinase2 expression in a murine model of asthma reduced the efflux of inflammatory cells out of the lung, which slowed the resolution of airway inflammation and was associated with increased mortality from asphyxiation (163). Despite its potential importance in asthma, the mechanisms of Th2 cell clearance from the lung are poorly understood. Some cells may become apoptotic (160), and others are likely cleared with expectoration (163). Recently, we have demonstrated that a subset of Th2 effector cells express CCR7 and migrate
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into the lymphatics under the guidance of CCL21 expression (33). Although the exact contribution of this CCR7-directed migration for Th2 cell egress from the lung remains to be determined, this may be one of several mechanisms involved in the resolution of allergic airway inflammation. In addition, migration of Th2 cells from the lung into the lymphatics may help establish immunologic memory and, importantly, contribute to future exacerbations following allergen reexposure. We propose that CCR7-mediated T cell egress from the asthmatic lung contributes to both the resolution of a primary allergic response as well as to the establishment of T cell memory and generation of local lung recall immune responses.
EXPANSION OF THE PARADIGM FOR OTHER LUNG CELL TYPES The contributions of structural lung cells, such as epithelial cells, endothelial cells, fibroblasts, and smooth muscle cells, in asthma pathogenesis remain less well defined than other innate immune cells in the lung. All these cell types produce chemokines when properly stimulated (164–173) and thus may
also contribute to T cell recruitment into the lung in asthma. However, our data and data from others indicate that mast cells and myeloid cells in the lung are likely the primary mediators of T cell recruitment (19, 20, 156)
CONCLUSIONS In this review, we have tried to identify the critical mediators of T cell migration into and out of the lung during the development and resolution of allergic airway inflammation. On the basis these data, we propose a new paradigm in T cell trafficking in asthma, involving three phases of chemoattractant-directed T cell recruitment into the lung, followed by a resolution phase of chemoattractant-directed T cell exit (Figure 5). This paradigm involves extensive interactions between the innate immune cells in the lung and T cells. In addition, each phase is regulated by distinct mechanisms, providing an overlapping network of pathways involved in T cell recruitment. This new paradigm may help provide novel insights into the pathogenesis of asthma and identify potential therapeutic targets to treat this common disorder.
SUMMARY POINTS 1. Asthma is a chronic inflammatory disease of the airways that is often caused by an allergic-type reaction to antigen. 2. In most cases the inflammatory reaction is orchestrated by CD4+ T cells that are recruited into the airways. 3. Recruitment of T cells into the lung is orchestrated by secretion of chemokines and chemoattractants in response to allergen exposure. 4. IgE-stimulated mast cells mediate early T cell recruitment through the secretion of leukotriene B4 and the chemokines CCL1, CCL17, and CCL22. 5. Allergen may also directly stimulate early T cell recruitment into the airway through interaction with PAMP receptors on macrophages, leading to secretion of chemokines, such as CXCL10 and CCL20. 6. The great majority of T cell recruitment is mediated by exposure of mucosal DCs to the cytokines IL-4 and IL-13, which leads to STAT6-mediated secretion of CCL17 and CCL22. www.annualreviews.org • T Cell Trafficking in Asthma
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7. Tregs may also be recruited into the airways via the action of chemokines. 8. Some T cells in the airways express CCR7 and are recruited out of the lung back into lymphoid tissue, which may reduce airway inflammation but may also provide a mechanism for memory responses to allergens.
DISCLOSURE STATEMENT
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The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS This work was supported by the National Institutes of Health grants K08 HL072775 to B.D. Medoff and R01 AI40618 and T32 AI060548 to A.D. Luster and a Dana Foundation Award in Human Immunology to A.D. Luster.
LITERATURE CITED
7. Established that specialized DCs lie beneath the airway epithelium and provide a sampling network for the airway that serves as the basis for allergen sensitization. 8. Demonstrated that airway DCs interact with airway T cells following antigen uptake, which helps stimulate DC maturation.
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1. Busse WW, Lemanske RF Jr. 2001. Asthma. N. Engl. J. Med. 344:350–62 2. Weiss S. 1998. Asthma: epidemiology. In Fishman’s Pulmonary Diseases and Disorders, ed. J Fishman, J Elias, M Fishman, L Grippi, L Kaiser, R Senior, pp. 735–43. New York: McGraw-Hill 3. Wardlaw TJ, Guillen C, Morgan A. 2005. Mechanisms of T cell migration to the lung. Clin. Exp. Allergy 35:4–7 4. D’Ambrosio D, Mariani M, Panina-Bordignon P, Sinigaglia F. 2001. Chemokines and their receptors guiding T lymphocyte recruitment in lung inflammation. Am. J. Respir. Crit. Care Med. 164:1266–75 5. Herrick CA, Bottomly K. 2003. To respond or not to respond: T cells in allergic asthma. Nat. Rev. Immunol. 3:405–12 6. Haldar P, Pavord ID. 2007. Noneosinophilic asthma: a distinct clinical and pathologic phenotype. J. Allergy Clin. Immunol. 119:1043–52 7. Holt PG, Schon-Hegrad MA, Oliver J, Holt BJ, McMenamin PG. 1990. A contiguous network of dendritic antigen-presenting cells within the respiratory epithelium. Int. Arch. Allergy Appl. Immunol. 91:155–59 8. Huh JC, Strickland DH, Jahnsen FL, Turner DJ, Thomas JA, et al. 2003. Bidirectional interactions between antigen-bearing respiratory tract dendritic cells (DCs) and T cells precede the late phase reaction in experimental asthma: DC activation occurs in the airway mucosa but not in the lung parenchyma. J. Exp. Med. 198:19–30 9. van Rijt LS, Lambrecht BN. 2005. Dendritic cells in asthma: a function beyond sensitization. Clin. Exp. Allergy 35:1125–34 10. Eisenbarth SC, Cassel S, Bottomly K. 2004. Understanding asthma pathogenesis: linking innate and adaptive immunity. Curr. Opin. Pediatr. 16:659–66 11. Eisenbarth SC, Piggott DA, Bottomly K. 2003. The master regulators of allergic inflammation: dendritic cells in Th2 sensitization. Curr. Opin. Immunol. 15:620–26 Medoff
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12. Piggott DA, Eisenbarth SC, Xu L, Constant SL, Huleatt JW, et al. 2005. MyD88dependent induction of allergic Th2 responses to intranasal antigen. J. Clin. Invest. 115:459–67 13. Marathias KP, Preffer FI, Pinto C, Kradin RL. 1991. Most human pulmonary infiltrating lymphocytes display the surface immune phenotype and functional responses of sensitized T cells. Am. J. Respir. Cell Mol. Biol. 5:470–76 14. Medoff BD, Thomas SY, Banerji A, Wain JC, Zhang H, et al. 2005. Pathogenic T-cell recruitment into the airway in human disease. Ann. NY Acad. Sci. 1062:220–41 15. Strickland D, Kees UR, Holt PG. 1996. Regulation of T-cell activation in the lung: isolated lung T cells exhibit surface phenotypic characteristics of recent activation including down-modulated T-cell receptors, but are locked into the G0/G1 phase of the cell cycle. Immunology 87:242–49 16. Upham JW, McMenamin C, Schon-Hegrad MA, Robinson BW, Holt PG. 1994. Functional analysis of human bronchial mucosal T cells extracted with interleukin-2. Am. J. Respir. Crit. Care Med. 149:1608–13 17. Humbles AA, Lloyd CM, McMillan SJ, Friend DS, Xanthou G, et al. 2004. A critical role for eosinophils in allergic airways remodeling. Science 305:1776–79 18. Lee JJ, Dimina D, Macias MP, Ochkur SI, McGarry MP, et al. 2004. Defining a link with asthma in mice congenitally deficient in eosinophils. Science 305:1773–76 19. Voehringer D, Reese TA, Huang X, Shinkai K, Locksley RM. 2006. Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic noneosinophil cells of the innate immune system. J. Exp. Med. 203:1435–46 20. Voehringer D, Shinkai K, Locksley RM. 2004. Type 2 immunity reflects orchestrated recruitment of cells committed to IL-4 production. Immunity 20:267–77 21. Lommatzsch M, Julius P, Kuepper M, Garn H, Bratke K, et al. 2006. The course of allergen-induced leukocyte infiltration in human and experimental asthma. J. Allergy Clin. Immunol. 118:91–97 22. Thomas SY, Banerji A, Medoff BD, Lilly CM, Luster AD. 2007. Multiple chemokine receptors, including CCR6 and CXCR3, regulate antigen-induced T cell homing to the human asthmatic airway. J. Immunol. 179:1901–12 23. Harris NL, Watt V, Ronchese F, Le Gros G. 2002. Differential T cell function and fate in lymph node and nonlymphoid tissues. J. Exp. Med. 195:317–26 24. D’Ambrosio D, Iellem A, Colantonio L, Clissi B, Pardi R, Sinigaglia F. 2000. Localization of Th-cell subsets in inflammation: differential thresholds for extravasation of Th1 and Th2 cells. Immunol. Today 21:183–86 25. Lukacs NW. 2001. Role of chemokines in the pathogenesis of asthma. Nat. Rev. Immunol. 1:108–16 26. von Andrian UH, Mackay CR. 2000. T-cell function and migration. Two sides of the same coin. N. Engl. J. Med. 343:1020–34 27. Campbell DJ, Kim CH, Butcher EC. 2003. Chemokines in the systemic organization of immunity. Immunol. Rev. 195:58–71 28. Schaerli P, Ebert L, Willimann K, Blaser A, Roos RS, Loetscher P, Moser B. 2004. A skin-selective homing mechanism for human immune surveillance T cells. J. Exp. Med. 199:1265–75 29. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. 1999. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401:708–12 30. Campbell JJ, Murphy KE, Kunkel EJ, Brightling CE, Soler D, et al. 2001. CCR7 expression and memory T cell diversity in humans. J. Immunol. 166:877–84 www.annualreviews.org • T Cell Trafficking in Asthma
19 and 20. These two papers demonstrated that bone marrow–derived myeloid cells control Th2 cell recruitment into the lung during the establishment of a type 2 immune response.
22. Found that multiple chemokine receptors are expressed on T cells recruited into the airway of allergic asthmatic individuals following allergen challenge, including chemokine receptors associated with Th1 cells. 23. Demonstrated that adoptively transferred Th2 cell effectors migrated into the lymph node and lung parenchyma. Following allergen challenge, lymph node T cells proliferated and migrated into lung tissue; T cells in the lung did not proliferate but produced cytokines.
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31. Kallinich T, Schmidt S, Hamelmann E, Fischer A, Qin S, et al. 2005. Chemokine-receptor expression on T cells in lung compartments of challenged asthmatic patients. Clin. Exp. Allergy 35:26–33 32. Kim CH, Rott L, Kunkel EJ, Genovese MC, Andrew DP, et al. 2001. Rules of chemokine receptor association with T cell polarization in vivo. J. Clin. Invest. 108:1331–39 33. Bromley SK, Thomas SY, Luster AD. 2005. Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nat. Immunol. 6:895–901 34. Debes GF, Arnold CN, Young AJ, Krautwald S, Lipp M, et al. 2005. Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Nat. Immunol. 6:889–94 35. Homey B, Alenius H, Muller A, Soto H, Bowman EP, et al. 2002. CCL27-CCR10 interactions regulate T cell-mediated skin inflammation. Nat. Med. 8:157–65 36. Campbell JJ, Haraldsen G, Pan J, Rottman J, Qin S, et al. 1999. The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature 400:776–80 37. Hudak S, Hagen M, Liu Y, Catron D, Oldham E, et al. 2002. Immune surveillance and effector functions of CCR10+ skin homing T cells. J. Immunol. 169:1189–96 38. Clark RA, Chong B, Mirchandani N, Brinster NK, Yamanaka K, et al. 2006. The vast majority of CLA+ T cells are resident in normal skin. J. Immunol. 176:4431–39 39. Kunkel EJ, Campbell JJ, Haraldsen G, Pan J, Boisvert J, et al. 2000. Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity. J. Exp. Med. 192:761–68 40. Papadakis KA, Prehn J, Nelson V, Cheng L, Binder SW, et al. 2000. The role of thymusexpressed chemokine and its receptor CCR9 on lymphocytes in the regional specialization of the mucosal immune system. J. Immunol. 165:5069–76 41. Mathew A, MacLean JA, DeHaan E, Tager AM, Green FH, Luster AD. 2001. Signal transducer and activator of transcription 6 controls chemokine production and T helper cell type 2 cell trafficking in allergic pulmonary inflammation. J. Exp. Med. 193:1087–96 42. Mikhak Z, Fleming CM, Medoff BD, Thomas SY, Tager AM, et al. 2006. STAT1 in peripheral tissue differentially regulates homing of antigen-specific Th1 and Th2 cells. J. Immunol. 176:4959–67 43. Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, et al. 2006. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc. Natl. Acad. Sci. USA 103:8137–42 44. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, et al. 2007. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat. Immunol. 8:639–46 45. Dieu MC, Vanbervliet B, Vicari A, Bridon JM, Oldham E, et al. 1998. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J. Exp. Med. 188:373–86 46. Liao F, Rabin RL, Smith CS, Sharma G, Nutman TB, Farber JM. 1999. CC-chemokine receptor 6 is expressed on diverse memory subsets of T cells and determines responsiveness to macrophage inflammatory protein 3α. J. Immunol. 162:186–94 47. Charbonnier AS, Kohrgruber N, Kriehuber E, Stingl G, Rot A, Maurer D. 1999. Macrophage inflammatory protein 3α is involved in the constitutive trafficking of epidermal langerhans cells. J. Exp. Med. 190:1755–68 Medoff
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ANRV338-IY26-07
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48. Dieu-Nosjean MC, Massacrier C, Homey B, Vanbervliet B, Pin JJ, et al. 2000. Macrophage inflammatory protein 3α is expressed at inflamed epithelial surfaces and is the most potent chemokine known in attracting Langerhans cell precursors. J. Exp. Med. 192:705–18 49. Sato W, Aranami T, Yamamura T. 2007. Cutting edge: Human Th17 cells are identified as bearing CCR2+ CCR5− phenotype. J. Immunol. 178:7525–29 50. Kocks JR, Davalos-Misslitz AC, Hintzen G, Ohl L, Forster R. 2007. Regulatory T cells interfere with the development of bronchus-associated lymphoid tissue. J. Exp. Med. 204:723–34 51. Schneider MA, Meingassner JG, Lipp M, Moore HD, Rot A. 2007. CCR7 is required for the in vivo function of CD4+ CD25+ regulatory T cells. J. Exp. Med. 204:735–45 52. Yuan Q, Bromley SK, Means TK, Jones KJ, Hayashi F, et al. 2007. CCR4-dependent regulatory T cell function in inflammatory bowel disease. J. Exp. Med. 204:1327–34 53. Kang SG, Piniecki RJ, Hogenesch H, Lim HW, Wiebke E, et al. 2007. Identification of a chemokine network that recruits FoxP3+ regulatory T cells into chronically inflamed intestine. Gastroenterology 132:966–81 54. Yurchenko E, Tritt M, Hay V, Shevach EM, Belkaid Y, Piccirillo CA. 2006. CCR5dependent homing of naturally occurring CD4+ regulatory T cells to sites of Leishmania major infection favors pathogen persistence. J. Exp. Med. 203:2451–60 55. Soler D, Chapman TR, Poisson LR, Wang L, Cote-Sierra J, et al. 2006. CCR8 expression identifies CD4 memory T cells enriched for FOXP3+ regulatory and Th2 effector lymphocytes. J. Immunol. 177:6940–51 56. Iellem A, Mariani M, Lang R, Recalde H, Panina-Bordignon P, et al. 2001. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4+ CD25+ regulatory T cells. J. Exp. Med. 194:847–53 57. Huang TJ, MacAry PA, Eynott P, Moussavi A, Daniel KC, et al. 2001. Allergen-specific Th1 cells counteract efferent Th2 cell-dependent bronchial hyperresponsiveness and eosinophilic inflammation partly via IFN-γ. J. Immunol. 166:207–17 58. Randolph DA, Carruthers CJ, Szabo SJ, Murphy KM, Chaplin DD. 1999. Modulation of airway inflammation by passive transfer of allergen-specific Th1 and Th2 cells in a mouse model of asthma. J. Immunol. 162:2375–83 59. Randolph DA, Stephens R, Carruthers CJ, Chaplin DD. 1999. Cooperation between Th1 and Th2 cells in a murine model of eosinophilic airway inflammation. J. Clin. Invest. 104:1021–29 60. Schnyder-Candrian S, Togbe D, Couillin I, Mercier I, Brombacher F, et al. 2006. Interleukin-17 is a negative regulator of established allergic asthma. J. Exp. Med. 203:2715–25 61. Lewkowich IP, Herman NS, Schleifer KW, Dance MP, Chen BL, et al. 2005. CD4+ CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J. Exp. Med. 202:1549–61 62. Strickland DH, Stumbles PA, Zosky GR, Subrata LS, Thomas JA, et al. 2006. Reversal of airway hyperresponsiveness by induction of airway mucosal CD4+ CD25+ regulatory T cells. J. Exp. Med. 203:2649–60 63. Kearley J, Barker JE, Robinson DS, Lloyd CM. 2005. Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+ CD25+ regulatory T cells is interleukin 10 dependent. J. Exp. Med. 202:1539–47 64. Akbari O, Faul JL, Hoyte EG, Berry GJ, Wahlstrom J, et al. 2006. CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N. Engl. J. Med. 354:1117–29 www.annualreviews.org • T Cell Trafficking in Asthma
62. Demonstrated significant recruitment of Tregs into the airway after induction of allergic inflammation.
225
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65. Akbari O, Stock P, Meyer E, Kronenberg M, Sidobre S, et al. 2003. Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat. Med. 9:582–88 66. Krug N, Erpenbeck VJ, Balke K, Petschallies J, Tschernig T, et al. 2001. Cytokine profile of bronchoalveolar lavage-derived CD4+ , CD8+ , and γδ T cells in people with asthma after segmental allergen challenge. Am. J. Respir. Cell Mol. Biol. 25:125–31 67. Miyahara N, Swanson BJ, Takeda K, Taube C, Miyahara S, et al. 2004. Effector CD8+ T cells mediate inflammation and airway hyper-responsiveness. Nat. Med. 10:865–69 68. Das J, Eynott P, Jupp R, Bothwell A, Van Kaer L, et al. 2006. Natural killer T cells and CD8+ T cells are dispensable for T cell-dependent allergic airway inflammation. Nat. Med. 12:1345–46 69. Lahn M, Kanehio A, Takeda K, Joetham A, Schwarze J, et al. 1999. Negative regulation of airway responsiveness that is dependent on γδ T cells and independent of αβ T cells. Nat. Med. 5:1150–56 70. Zuany-Amorim C, Ruffie C, Haile S, Vargaftig BB, Pereira P, Pretolani M. 1998. Requirement for γδ T cells in allergic airway inflammation. Science 280:1265–67 71. Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, et al. 1992. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N. Engl. J. Med. 326:298–304 72. Walker C, Bode E, Boer L, Hansel TT, Blaser K, Virchow JC Jr. 1992. Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am. Rev. Respir. Dis. 146:109–15 73. Batra V, Musani AI, Hastie AT, Khurana S, Carpenter KA, et al. 2004. Bronchoalveolar lavage fluid concentrations of transforming growth factor (TGF)-β1, TGF-β2, interleukin (IL)-4 and IL-13 after segmental allergen challenge and their effects on alphasmooth muscle actin and collagen III synthesis by primary human lung fibroblasts. Clin. Exp. Allergy 34:437–44 74. Kroegel C, Julius P, Matthys H, Virchow JC Jr, Luttmann W. 1996. Endobronchial secretion of interleukin-13 following local allergen challenge in atopic asthma: relationship to interleukin-4 and eosinophil counts. Eur. Respir. J. 9:899–904 75. Liu L, Jarjour NN, Busse WW, Kelly EA. 2004. Enhanced generation of helper T type 1 and 2 chemokines in allergen-induced asthma. Am. J. Respir. Crit. Care Med. 169:1118–24 76. Virchow JC Jr, Walker C, Hafner D, Kortsik C, Werner P, et al. 1995. T cells and cytokines in bronchoalveolar lavage fluid after segmental allergen provocation in atopic asthma. Am. J. Respir. Crit. Care Med. 151:960–68 77. Brusselle G, Kips J, Joos G, Bluethmann H, Pauwels R. 1995. Allergen-induced airway inflammation and bronchial responsiveness in wild-type and interleukin-4-deficient mice. Am. J. Respir. Cell Mol. Biol. 12:254–59 78. Foster PS, Hogan SP, Ramsay AJ, Matthaei KI, Young IG. 1996. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J. Exp. Med. 183:195–201 79. Grunig G, Warnock M, Wakil AE, Venkayya R, Brombacher F, et al. 1998. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282:2261–63 80. Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, et al. 1998. Interleukin-13: central mediator of allergic asthma. Science 282:2258–61 81. Cohn L, Homer RJ, Marinov A, Rankin J, Bottomly K. 1997. Induction of airway mucus production By T helper 2 (Th2) cells: a critical role for interleukin 4 in cell recruitment but not mucus production. J. Exp. Med. 186:1737–47
Annu. Rev. Immunol. 2008.26:205-232. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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·
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ANRV338-IY26-07
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9:43
82. Li L, Xia Y, Nguyen A, Feng L, Lo D. 1998. Th2-induced eotaxin expression and eosinophilia coexist with Th1 responses at the effector stage of lung inflammation. J. Immunol. 161:3128–35 83. Li XM, Schofield BH, Wang QF, Kim KH, Huang SK. 1998. Induction of pulmonary allergic responses by antigen-specific Th2 cells. J. Immunol. 160:1378–84 84. Brightling CE, Symon FA, Birring SS, Bradding P, Pavord ID, Wardlaw AJ. 2002. TH2 cytokine expression in bronchoalveolar lavage fluid T lymphocytes and bronchial submucosa is a feature of asthma and eosinophilic bronchitis. J. Allergy Clin. Immunol. 110:899– 905 85. Krug N, Madden J, Redington AE, Lackie P, Djukanovic R, et al. 1996. T-cell cytokine profile evaluated at the single cell level in BAL and blood in allergic asthma. Am. J. Respir. Cell Mol. Biol. 14:319–26 86. Morgan AJ, Symon FA, Berry MA, Pavord ID, Corrigan CJ, Wardlaw AJ. 2005. IL-4expressing bronchoalveolar T cells from asthmatic and healthy subjects preferentially express CCR 3 and CCR 4. J. Allergy Clin. Immunol. 116:594–600 87. Martin RJ, Boguniewicz M, Henson JE, Celniker AC, Williams M, et al. 1993. The effects of inhaled interferon γ in normal human airways. Am. Rev. Respir. Dis. 148:1677–82 88. Barczyk A, Pierzchala W, Sozanska E. 2003. Interleukin-17 in sputum correlates with airway hyperresponsiveness to methacholine. Respir. Med. 97:726–33 89. Hashimoto T, Akiyama K, Kobayashi N, Mori A. 2005. Comparison of IL-17 production by helper T cells among atopic and nonatopic asthmatics and control subjects. Int. Arch. Allergy Immunol. 137(Suppl. 1):51–54 90. Molet S, Hamid Q, Davoine F, Nutku E, Taha R, et al. 2001. IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J. Allergy Clin. Immunol. 108:430–38 91. Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, et al. 2004. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J. Exp. Med. 199:1567–75 92. Hartl D, Koller B, Mehlhorn AT, Reinhardt D, Nicolai T, et al. 2007. Quantitative and functional impairment of pulmonary CD4+ CD25hi regulatory T cells in pediatric asthma. J. Allergy Clin. Immunol. 119:1258–66 93. Thomas SY, Lilly CM, Luster AD. 2006. Invariant natural killer T cells in bronchial asthma. N. Engl. J. Med. 354:2613–16 94. Thomas SY, Hou R, Boyson JE, Means TK, Hess C, et al. 2003. CD1d-restricted NKT cells express a chemokine receptor profile indicative of Th1-type inflammatory homing cells. J. Immunol. 171:2571–80 95. Vijayanand P, Seumois G, Pickard C, Powell RM, Angco G, et al. 2007. Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease. N. Engl. J. Med. 356:1410–22 96. Bratke K, Julius P, Virchow JC. 2007. Invariant natural killer T cells in obstructive pulmonary diseases. N. Engl. J. Med. 357:194 97. Heron M, Claessen AM, Grutters JC. 2007. Invariant natural killer T cells in obstructive pulmonary diseases. N. Engl. J. Med. 357:194 98. Mutalithas K, Croudace J, Guillen C, Siddiqui S, Thickett D, et al. 2007. Bronchoalveolar lavage invariant natural killer T cells are not increased in asthma. J. Allergy Clin. Immunol. 119:1274–76 99. Pham-Thi N, de Blic J, Leite-de-Moraes MC. 2006. Invariant natural killer T cells in bronchial asthma. N. Engl. J. Med. 354:2613–16 www.annualreviews.org • T Cell Trafficking in Asthma
227
ARI
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100. Lisbonne M, Diem S, de Castro Keller A, Lefort J, Araujo LM, et al. 2003. Cutting edge: invariant Vα14 NKT cells are required for allergen-induced airway inflammation and hyperreactivity in an experimental asthma model. J. Immunol. 171:1637–41 101. Larche M, Robinson DS, Kay AB. 2003. The role of T lymphocytes in the pathogenesis of asthma. J. Allergy Clin. Immunol. 111:450–63 102. Bochner BS, Hudson SA, Xiao HQ, Liu MC. 2003. Release of both CCR4-active and CXCR3-active chemokines during human allergic pulmonary late-phase reactions. J. Allergy Clin. Immunol. 112:930–34 103. Pilette C, Francis JN, Till SJ, Durham SR. 2004. CCR4 ligands are up-regulated in the airways of atopic asthmatics after segmental allergen challenge. Eur. Respir. J. 23:876–84 104. Mathew A, Medoff BD, Carafone AD, Luster AD. 2002. Cutting edge: Th2 cell trafficking into the allergic lung is dependent on chemoattractant receptor signaling. J. Immunol. 169:651–55 105. Chung CD, Kuo F, Kumer J, Motani AS, Lawrence CE, et al. 2003. CCR8 is not essential for the development of inflammation in a mouse model of allergic airway disease. J. Immunol. 170:581–87 106. Chvatchko Y, Hoogewerf AJ, Meyer A, Alouani S, Juillard P, et al. 2000. A key role for CC chemokine receptor 4 in lipopolysaccharide-induced endotoxic shock. J. Exp. Med. 191:1755–64 107. Gonzalo JA, Pan Y, Lloyd CM, Jia GQ, Yu G, et al. 1999. Mouse monocyte-derived chemokine is involved in airway hyperreactivity and lung inflammation. J. Immunol. 163:403–11 108. Goya I, Villares R, Zaballos A, Gutierrez J, Kremer L, et al. 2003. Absence of CCR8 does not impair the response to ovalbumin-induced allergic airway disease. J. Immunol. 170:2138–46 109. Lloyd CM, Delaney T, Nguyen T, Tian J, Martinez AC, et al. 2000. CC chemokine receptor (CCR)3/eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo. J. Exp. Med. 191:265–74 110. Chensue SW, Lukacs NW, Yang TY, Shang X, Frait KA, et al. 2001. Aberrant in vivo T helper type 2 cell response and impaired eosinophil recruitment in CC chemokine receptor 8 knockout mice. J. Exp. Med. 193:573–84 111. Campbell JJ, Brightling CE, Symon FA, Qin S, Murphy KE, et al. 2001. Expression of chemokine receptors by lung T cells from normal and asthmatic subjects. J. Immunol. 166:2842–48 112. Morgan AJ, Guillen C, Symon FA, Huynh TT, Berry MA, et al. 2005. Expression of CXCR6 and its ligand CXCL16 in the lung in health and disease. Clin. Exp. Allergy 35:1572–80 113. Murray JJ, Tonnel AB, Brash AR, Roberts LJ 2nd, Gosset P, et al. 1986. Release of prostaglandin D2 into human airways during acute antigen challenge. N. Engl. J. Med. 315:800–4 114. Berkman N, Ohnona S, Chung FK, Breuer R. 2001. Eotaxin-3 but not eotaxin gene expression is upregulated in asthmatics 24 hours after allergen challenge. Am. J. Respir. Cell Mol. Biol. 24:682–87 115. Brown JR, Kleimberg J, Marini M, Sun G, Bellini A, Mattoli S. 1998. Kinetics of eotaxin expression and its relationship to eosinophil accumulation and activation in bronchial biopsies and bronchoalveolar lavage (BAL) of asthmatic patients after allergen inhalation. Clin. Exp. Immunol. 114:137–46
Annu. Rev. Immunol. 2008.26:205-232. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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ANRV338-IY26-07
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9:43
116. Holgate ST, Bodey KS, Janezic A, Frew AJ, Kaplan AP, Teran LM. 1997. Release of RANTES, MIP-1α, and MCP-1 into asthmatic airways following endobronchial allergen challenge. Am. J. Respir. Crit. Care Med. 156:1377–83 117. Lilly CM, Nakamura H, Belostotsky OI, Haley KJ, Garcia-Zepeda EA, et al. 2001. Eotaxin expression after segmental allergen challenge in subjects with atopic asthma. Am. J. Respir. Crit. Care Med. 163:1669–75 118. Sur S, Kita H, Gleich GJ, Chenier TC, Hunt LW. 1996. Eosinophil recruitment is associated with IL-5, but not with RANTES, twenty-four hours after allergen challenge. J. Allergy Clin. Immunol. 97:1272–78 119. Henderson WR Jr, Lewis DB, Albert RK, Zhang Y, Lamm WJ, et al. 1996. The importance of leukotrienes in airway inflammation in a mouse model of asthma. J. Exp. Med. 184:1483–94 120. Fulkerson PC, Zimmermann N, Hassman LM, Finkelman FD, Rothenberg ME. 2004. Pulmonary chemokine expression is coordinately regulated by STAT1, STAT6, and IFNγ. J. Immunol. 173:7565–74 121. Lukacs NW, Prosser DM, Wiekowski M, Lira SA, Cook DN. 2001. Requirement for the chemokine receptor CCR6 in allergic pulmonary inflammation. J. Exp. Med. 194:551–55 122. Medoff BD, Sauty A, Tager AM, Maclean JA, Smith RN, et al. 2002. IFN-γ-inducible protein 10 (CXCL10) contributes to airway hyperreactivity and airway inflammation in a mouse model of asthma. J. Immunol. 168:5278–86 123. Bryce PJ, Mathias CB, Harrison KL, Watanabe T, Geha RS, Oettgen HC. 2006. The H1 histamine receptor regulates allergic lung responses. J. Clin. Invest. 116:1624–32 124. Stephens R, Chaplin DD. 2002. IgE cross-linking or lipopolysaccharide treatment induces recruitment of Th2 cells to the lung in the absence of specific antigen. J. Immunol. 169:5468–76 125. Goodarzi K, Goodarzi M, Tager AM, Luster AD, von Andrian UH. 2003. Leukotriene B4 and BLT1 control cytotoxic effector T cell recruitment to inflamed tissues. Nat. Immunol. 4:965–73 126. Luster AD, Tager AM. 2004. T-cell trafficking in asthma: lipid mediators grease the way. Nat. Rev. Immunol. 4:711–24 127. Tager AM, Bromley SK, Medoff BD, Islam SA, Bercury SD, et al. 2003. Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment. Nat. Immunol. 4:982–90 128. Gombert M, Dieu-Nosjean MC, Winterberg F, Bunemann E, Kubitza RC, et al. 2005. CCL1-CCR8 interactions: an axis mediating the recruitment of T cells and Langerhanstype dendritic cells to sites of atopic skin inflammation. J. Immunol. 174:5082–91 129. Oliveira SH, Lukacs NW. 2001. Stem cell factor and IgE-stimulated murine mast cells produce chemokines (CCL2, CCL17, CCL22) and express chemokine receptors. Inflamm. Res. 50:168–74 130. Gonzalo JA, Qiu Y, Lora JM, Al-Garawi A, Villeval JL, et al. 2007. Coordinated involvement of mast cells and T cells in allergic mucosal inflammation: critical role of the CC chemokine ligand 1:CCR8 axis. J. Immunol. 179:1740–50 131. Hirai H, Tanaka K, Yoshie O, Ogawa K, Kenmotsu K, et al. 2001. Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J. Exp. Med. 193:255–61 132. Nagata K, Hirai H, Tanaka K, Ogawa K, Aso T, et al. 1999. CRTH2, an orphan receptor of T-helper-2-cells, is expressed on basophils and eosinophils and responds to mast cellderived factor(s). FEBS Lett. 459:195–99 www.annualreviews.org • T Cell Trafficking in Asthma
127. Established leukotriene B4 as a potent chemoattractant for effector T cells and as a mediator of early T cell recruitment following allergen challenge in sensitized mice.
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133. Nagata K, Tanaka K, Ogawa K, Kemmotsu K, Imai T, et al. 1999. Selective expression of a novel surface molecule by human Th2 cells in vivo. J. Immunol. 162:1278–86 134. DuBourdieu DJ, Morgan DW. 1990. Multiple pathways for signal transduction in the regulation of arachidonic acid metabolism in rat peritoneal macrophages. Biochim. Biophys. Acta 1054:326–32 135. Hsueh W, Gonzalez-Crussi F, Henderson S. 1987. LTB4 production and lysosomal enzyme release by rat alveolar macrophages: effects of phagocytosis, receptor binding, and ionophore stimulation. Exp. Lung Res. 13:385–99 136. Rankin JA, Schrader CE, Smith SM, Lewis RA. 1989. Recombinant interferon-γ primes alveolar macrophages cultured in vitro for the release of leukotriene B4 in response to IgG stimulation. J. Clin. Invest. 83:1691–700 137. Everard ML. 2006. The relationship between respiratory syncytial virus infections and the development of wheezing and asthma in children. Curr. Opin. Allergy Clin. Immunol. 6:56–61 138. Heymann PW, Platts-Mills TA, Johnston SL. 2005. Role of viral infections, atopy and antiviral immunity in the etiology of wheezing exacerbations among children and young adults. Pediatr. Infect. Dis. J. 24:S217–22, discussion S220–21 139. Platts-Mills TA, Erwin EA, Woodfolk JA, Heymann PW. 2006. Environmental factors influencing allergy and asthma. Chem. Immunol. Allergy 91:3–15 140. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, et al. 2006. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–5 141. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. 2004. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–31 142. Rudd BD, Smit JJ, Flavell RA, Alexopoulou L, Schaller MA, et al. 2006. Deletion of TLR3 alters the pulmonary immune environment and mucus production during respiratory syncytial virus infection. J. Immunol. 176:1937–42 143. Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K. 2002. Lipopolysaccharide-enhanced, Toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J. Exp. Med. 196:1645–51 144. Jung YW, Schoeb TR, Weaver CT, Chaplin DD. 2006. Antigen and lipopolysaccharide play synergistic roles in the effector phase of airway inflammation in mice. Am. J. Pathol. 168:1425–34 145. Kawai T, Takeuchi O, Fujita T, Inoue J, Muhlradt PF, et al. 2001. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J. Immunol. 167:5887–94 146. Reibman J, Hsu Y, Chen LC, Bleck B, Gordon T. 2003. Airway epithelial cells release MIP-3α/CCL20 in response to cytokines and ambient particulate matter. Am. J. Respir. Cell Mol. Biol. 28:648–54 147. Pichavant M, Charbonnier AS, Taront S, Brichet A, Wallaert B, et al. 2005. Asthmatic bronchial epithelium activated by the proteolytic allergen Der p 1 increases selective dendritic cell recruitment. J. Allergy Clin. Immunol. 115:771–78 148. Thomas MS, Kunkel SL, Lukacs NW. 2002. Differential role of IFN-γ-inducible protein 10 kDa in a cockroach antigen-induced model of allergic airway hyperreactivity: systemic vs local effects. J. Immunol. 169:7045–53 149. Lundy SK, Lira SA, Smit JJ, Cook DN, Berlin AA, Lukacs NW. 2005. Attenuation of allergen-induced responses in CCR6−/− mice is dependent upon altered pulmonary T lymphocyte activation. J. Immunol. 174:2054–60
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150. Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, et al. 2007. Phenotypic and functional features of human Th17 cells. J. Exp. Med. 204:1849–61 151. Kao CY, Huang F, Chen Y, Thai P, Wachi S, et al. 2005. Up-regulation of CC chemokine ligand 20 expression in human airway epithelium by IL-17 through a JAK-independent but MEK/NF-κB-dependent signaling pathway. J. Immunol. 175:6676–85 152. Glatzel A, Wesch D, Schiemann F, Brandt E, Janssen O, Kabelitz D. 2002. Patterns of chemokine receptor expression on peripheral blood γδ T lymphocytes: strong expression of CCR5 is a selective feature of Vδ2/Vγ9 γδ T cells. J. Immunol. 168:4920–29 153. Kohl J, Baelder R, Lewkowich IP, Pandey MK, Hawlisch H, et al. 2006. A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma. J. Clin. Invest. 116:783–96 154. Zhu Z, Zheng T, Homer RJ, Kim YK, Chen NY, et al. 2004. Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science 304:1678–82 155. Venkayya R, Lam M, Willkom M, Grunig G, Corry DB, Erle DJ. 2002. The Th2 lymphocyte products IL-4 and IL-13 rapidly induce airway hyperresponsiveness through direct effects on resident airway cells. Am. J. Respir. Cell Mol. Biol. 26:202–8 156. van Rijt LS, Jung S, Kleinjan A, Vos N, Willart M, et al. 2005. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J. Exp. Med. 201:981–91 157. Hammad H, Smits HH, Ratajczak C, Nithiananthan A, Wierenga EA, et al. 2003. Monocyte-derived dendritic cells exposed to Der p 1 allergen enhance the recruitment of Th2 cells: major involvement of the chemokines TARC/CCL17 and MDC/CCL22. Eur. Cytokine Netw. 14:219–28 158. Beaty SR, Rose CE, Sung SJ. 2007. Diverse and potent chemokine production by lung CD11bhigh dendritic cells in homeostasis and in allergic lung inflammation. J. Immunol. 178:1882–95 159. Voehringer D, van Rooijen N, Locksley RM. 2007. Eosinophils develop in distinct stages and are recruited to peripheral sites by alternatively activated macrophages. J. Leukoc. Biol. 81:1434–44 160. Duez C, Tomkinson A, Shultz LD, Bratton DL, Gelfand EW. 2001. Fas deficiency delays the resolution of airway hyperresponsiveness after allergen sensitization and challenge. J. Allergy Clin. Immunol. 108:547–56 161. Mojtabavi N, Dekan G, Stingl G, Epstein MM. 2002. Long-lived Th2 memory in experimental allergic asthma. J. Immunol. 169:4788–96 162. Tomkinson A, Cieslewicz G, Duez C, Larson KA, Lee JJ, Gelfand EW. 2001. Temporal association between airway hyperresponsiveness and airway eosinophilia in ovalbuminsensitized mice. Am. J. Respir. Crit. Care Med. 163:721–30 163. Corry DB, Rishi K, Kanellis J, Kiss A, Song LZ, et al. 2002. Decreased allergic lung inflammatory cell egression and increased susceptibility to asphyxiation in MMP2-deficiency. Nat. Immunol. 3:347–53 164. Gounni AS, Hamid Q, Rahman SM, Hoeck J, Yang J, Shan L. 2004. IL-9-mediated induction of eotaxin1/CCL11 in human airway smooth muscle cells. J. Immunol. 173:2771–79 165. Kumagai N, Fukuda K, Nishida T. 2000. Synergistic effect of TNF-α and IL-4 on the expression of thymus- and activation-regulated chemokine in human corneal fibroblasts. Biochem. Biophys. Res. Commun. 279:1–5 166. Li L, Xia Y, Nguyen A, Lai YH, Feng L, et al. 1999. Effects of Th2 cytokines on chemokine expression in the lung: IL-13 potently induces eotaxin expression by airway epithelial cells. J. Immunol. 162:2477–87 www.annualreviews.org • T Cell Trafficking in Asthma
156. Suggests that CD11c+ DCs in the airway control Th2 cell recruitment into the lung during allergic inflammation.
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167. Lilly CM, Nakamura H, Kesselman H, Nagler-Anderson C, Asano K, et al. 1997. Expression of eotaxin by human lung epithelial cells: induction by cytokines and inhibition by glucocorticoids. J. Clin. Invest. 99:1767–73 168. Matsukura S, Stellato C, Plitt JR, Bickel C, Miura K, et al. 1999. Activation of eotaxin gene transcription by NF-κB and STAT6 in human airway epithelial cells. J. Immunol. 163:6876–83 169. Miyamasu M, Misaki Y, Yamaguchi M, Yamamoto K, Morita Y, et al. 2000. Regulation of human eotaxin generation by Th1-/Th2-derived cytokines. Int. Arch. Allergy Immunol. 122(Suppl. 1):54–58 170. Rothenberg ME, Luster AD, Leder P. 1995. Murine eotaxin: an eosinophil chemoattractant inducible in endothelial cells and in interleukin 4-induced tumor suppression. Proc. Natl. Acad. Sci. USA 92:8960–64 171. Sekiya T, Miyamasu M, Imanishi M, Yamada H, Nakajima T, et al. 2000. Inducible expression of a Th2-type CC chemokine thymus- and activation-regulated chemokine by human bronchial epithelial cells. J. Immunol. 165:2205–13 172. Shore SA. 2004. Direct effects of Th2 cytokines on airway smooth muscle. Curr. Opin. Pharmacol. 4:235–40 173. Ying S, Meng Q, Zeibecoglou K, Robinson DS, Macfarlane A, et al. 1999. Eosinophil chemotactic chemokines (eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein-3 (MCP-3), and MCP-4), and C-C chemokine receptor 3 expression in bronchial biopsies from atopic and nonatopic (Intrinsic) asthmatics. J. Immunol. 163:6321–29 174. Lilly CM, Woodruff PG, Camargo CA Jr, Nakamura H, Drazen JM, et al. 1999. Elevated plasma eotaxin levels in patients with acute asthma. J. Allergy Clin. Immunol. 104:786–90 175. Yuan Q, Campanella GS, Colvin RA, Hamilos DL, Jones KJ, et al. 2006. Membranebound eotaxin-3 mediates eosinophil transepithelial migration in IL-4-stimulated epithelial cells. Eur. J. Immunol. 36:2700–14 176. Pope SM, Zimmermann N, Stringer KF, Karow ML, Rothenberg ME. 2005. The eotaxin chemokines and CCR3 are fundamental regulators of allergen-induced pulmonary eosinophilia. J. Immunol. 175:5341–50
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:205-232. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania 19104; email:
[email protected],
[email protected],
[email protected] Annu. Rev. Immunol. 2008. 26:233–59
Key Words
First published online as a Review in Advance on November 19, 2007
immunological synapse, distal pole complex, signaling, lymphocyte
The Annual Review of Immunology is online at immunol.annualreviews.org This article’s doi: 10.1146/annurev.immunol.26.021607.090347 c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0233$20.00
Abstract T cell cytoarchitecture differs dramatically depending on whether the cell is circulating within the bloodstream, migrating through tissues, or interacting with antigen-presenting cells. The transition between these states requires important signaling-dependent changes in actin cytoskeletal dynamics. Recently, analysis of actin-regulatory proteins associated with T cell activation has provided new insights into how T cells control actin dynamics in response to external stimuli and how actin facilitates downstream signaling events and effector functions. Among the actin-regulatory proteins that have been identified are nucleation-promoting factors such as WASp, WAVE2, and HS1; severing proteins such as cofilin; motor proteins such as myosin II; and linker proteins such as ezrin and moesin. We review the current literature on how signaling pathways leading from diverse cell surface receptors regulate the coordinated activity of these and other actin-regulatory proteins and how these proteins control T cell function.
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INTRODUCTION APC: antigen-presenting cell IL-2: interleukin-2
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TCR: T cell receptor
Regulated reorganization of the actin cytoskeleton is important for multiple aspects of T cell function, including signaling and differentiation along discrete developmental lineages, migration through tissues, and execution of effector functions. Early studies testing the role of actin in T cell activation were based on the use of actin-disrupting agents such as cytochalasin D (CytoD) (see sidebar: Actin Depolymerizing Agents). These studies showed that actin is required for adherence to target cells and cytotoxic activity (1), as well as for signaling events associated with Ca2+ flux and downstream changes in gene expression (2). However, these studies revealed a complex role for actin. For example, in T cells stimulated with superantigen-pulsed antigenpresenting cells (APCs), CytoD treatment results in diminished Ca2+ flux, but stimulation with anti-CD3 antibodies results in a prolonged Ca2+ response (2). Similarly, although one study showed that CytoD treatment impairs the activation of the interleukin-2 (IL-2) promoter (3), another found that at low doses of CytoD, Ca2+ signaling is prolonged and IL2 production increases (4). These findings and more recent data described below suggest that actin filaments play a dual role, enhancing T cell activation by promoting conjugate formation and the assembly of signaling complexes, but also downregulating activation, perhaps by facilitating molecular movements that culminate in the internalization of the T cell receptor (TCR).
ACTIN DEPOLYMERIZING AGENTS The two most commonly used pharmacological agents to perturb actin dynamics are cytochalasin D and latrunculin A. Neither inhibitor actually disassembles polymerized actin filaments. Instead, they induce net actin depolymerization by preventing new actin polymerization. Latrunculin A sequesters actin monomers, whereas cytochalasin D binds to the fast-growing (barbed) ends of actin filaments, preventing monomer addition.
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Recent studies focusing on individual actin-regulatory proteins have greatly advanced our understanding of how actin dynamics are regulated and have provided new insights into how actin functions to facilitate or terminate T cell activation. This review focuses on the roles of those proteins in T cell function and on the interplay between cytoskeletal changes and the signaling events associated with T cell activation.
T CELL MOVEMENTS AND SHAPE CHANGES The actin cytoskeleton controls T cell shape, which changes dramatically depending on whether the cell is circulating in the bloodstream, migrating through tissues, or interacting with APCs (Figure 1).
Microvillar Dynamics in Circulating T Cells Circulating T cells are covered in short microvilli containing parallel bundles of highly dynamic actin filaments (Figure 1, cell 1) (5). Low-affinity adhesion molecules such as Lselectin and α4β7 integrin (VLA-4) are concentrated at the tips of the microvilli (6), whereas molecules involved in tight adhesion, e.g., leukocyte function–associated antigen 1 (LFA-1, αLβ2), are distributed randomly or excluded from microvilli (7, 8). This segregation is thought to facilitate tethering and rolling along vessel walls and to minimize nonspecific adhesion (Figure 1, cell 2) (9). Interaction of T cells with soluble and endothelium-displayed chemokines triggers rapid microvillar collapse as well as upregulation of integrin avidity through a process involving release of integrins from the cortical actin cytoskeleton (9, 10). This leads to the arrest of the lymphocyte on the endothelium and, ultimately, to transmigration across the endothelial wall (Figure 1, cells 3 and 4). The mechanisms that control microvillar formation and collapse in T cells are not fully understood. Several studies point to a key role
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5 3
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Target cell
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Figure 1 Actin remodeling in response to environmental cues. 1. Circulating T cells are decorated with microvilli containing parallel actin bundles anchored in cortical actin filaments. 2. Segregation of adhesion molecules with respect to microvilli facilitates tethering and rolling along the vascular endothelium. 3. Chemokine stimulation induces microvillar collapse and a switch from tethering and rolling to tight adhesion mediated by high-affinity integrin interactions. 4. The T cell must then squeeze between endothelial junctions to enter the underlying tissue. 5. As the T cell migrates through tissues, a leading edge rich in branched actin filaments pushes the cell forward, while the uropod trails behind. 6. Upon recognizing an APC, the T cell forms a tight contact rich in branched actin filaments. This contact leads to the formation of the immunological synapse (IS), where active actin polymerization is associated with formation and inward movement of TCR microclusters. Cortical actin, most likely comprised of linear filaments, remains at sites peripheral to the IS, forming a scaffold for protein sequestration at the distal pole complex (DPC).
for proteins of the ezrin, radixin, and moesin (ERM) family, which link plasma membrane proteins to cortical actin filaments. Treatment of T cells with antisense oligonucleotides to both ezrin and moesin results in dramatic loss of microvilli (11). Similarly, T cells expressing a dominant-negative ERM mutant are devoid of microvilli, whereas cells expressing a constitutively active form exhibit enhanced microvillar structures (9). Chemokine-induced microvillar loss is accompanied by dephosphorylation of ERM proteins at a regulatory C-terminal threonine (see below), an event that inhibits their linker function (9). In addition to ezrin and moesin, WASp may contribute to microvillar structure, as T cells
from patients with mutations in WASp exhibit defective microvilli (12–14). However, a recent study by Higgs and coworkers failed to find microvillar abnormalities in WASpdeficient T cells, when analyzed immediately ex vivo (5). Because WASp promotes the formation of branched actin filaments rather than the linear filaments found in microvilli, WASp may affect microvillar dynamics only indirectly.
Migration Within Tissues Once a T cell receives the appropriate cues to cross the vascular wall, it begins to migrate within tissues. Migrating T cells exhibit a www.annualreviews.org • Actin in T Cell Activation
ERM: ezrin, radixin, moesin
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Inside-out signaling: cytoplasmic signaling pathways (typically downstream of TCR or chemokine receptors) leading to conformational changes that enhance integrin affinity
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“hand mirror” morphology, with a large cell body comprised of the nucleus and a thin band of cytoplasm, and a narrow trailing uropod that projects above the substrate surface (Figure 1, cell 5). The leading edge is enriched in chemokine receptors and is sensitized for antigen recognition (15, 16). The uropod contains a meshwork of cytoskeletal elements, including the microtubule organizing center (MTOC), vimentin filaments, actin filaments, ERM proteins, and the cytoskeletal linker protein plectin (17). Within tissues, T cells can be highly motile, sampling multiple APCs, or can pause to engage in more prolonged interactions. Transition between these states is controlled in part by the presence of antigen, but also involves the activation state of both the T cell and the APC, as well as the three-dimensional nature of the matrix (18). Motile T cells move much faster than most nonhematopoietic cells, averaging 10 μm/min, and reaching rates of 25 μm/min (19). T cell movement is essentially amoeboid in nature, and is driven by protrusion of actin-rich pseudopodia at the leading edge, working in concert with contractile forces at the rear of the cell (19). A fundamental feature of this mechanism is the ability to form protrusions at the leading edge, and not at the uropod. As in other cell types, it is thought that Rho GTPases control this cycle (20–26). Leading edge protrusion is controlled largely by Rac1, whereas the lack of protrusion within the uropod is controlled by Rho. Cdc42 serves as a “compass” controlling overall cell polarity. Myosins, in particular MyH9, the heavy chain of nonmuscle myosin IIA, are also required for uropod formation and crawling (19). Using video analysis, Krummel and coworkers (19) have shown that MyH9 moves in clusters toward the uropod of crawling T cells. Thus, as in other amoeboid cells, it appears that actomyosin-based contraction within the uropod generates an extrusive force that propels the bulk of the T cell cytoplasm forward. Burkhardt
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Interaction with APCs and Immunological Synapse Formation Upon interaction with an APC bearing appropriate MHC-peptide complexes, the T cell rounds up, draws in its uropod, and extends large pseudopodia and lamellipodia toward the APC. This process results in the formation of a flattened, F-actin-rich interface with the APC. In parallel with these shape changes, the MTOC and associated secretory organelles reorient within the T cell cytoplasm and come to lie just beneath the plasma membrane, near the center of the APC contact site. This reorientation of T cell cytoskeletal elements was observed by several investigators in the early 1980s and was recognized as a hallmark of productive T cell engagement and a prerequisite for directed cytolysis and T cell help (27–29). The morphological transition induced by interaction with an APC is associated with several changes in cytoskeletal proteins. Myosin IIA heavy chain is phosphorylated at a site known to lead to downregulation of motor function (19). This event is thought to be a key factor in controlling uropod resorption. Indeed, the idea that myosin II activity is “switched off” upon TCR engagement is consistent with the finding that this protein is dispensable for organizing signaling molecules at the T cell–APC contact site. TCR crosslinking also leads to the transient dephosphorylation of ERM proteins, an event that is proposed to facilitate membrane protrusion and receptor clustering at the site of TCR engagement by increasing the fluidity of the plasma membrane (9, 30–32). Ca2+ -dependent cleavage of actin-binding proteins and severing of actin filaments by proteins such as calpain and gelsolin probably also contribute to this process (33–35). TCR-induced “inside-out signaling” leads to conformational changes in T cell integrins, particularly LFA-1 (reviewed in 36, 37). This process, which results in high-affinity binding to ligands such as ICAM-1 (intercellular adhesion molecule-1) on the APC, is controlled in part by regulated interactions of the β integrin
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cytoplasmic tail with actin-binding proteins such as filamin and talin (38–40). Once integrins have undergone this conformational change, these proteins cluster as a result of binding to multivalent ligands on the APC, resulting in strengthening of adhesion between the T cell and APC (41). This latter facet of integrin function is closely tied to the increased membrane fluidity that results from the release of cortical cytoskeletal tethers. LFA-1 clustering is largely ligand-driven, although there is also evidence for the active involvement of talin in this process (40). In concert with all these changes, TCR cross-linking leads to localized activation of actin polymerizing proteins and actin-binding proteins at the site of TCR engagement, resulting in lamellipodial protrusion toward the APC and the formation of a dense actin network at the cell-cell contact site (see below). Actin responses at the T cell–APC contact site are important for the organization of signaling molecules at this site, to form the immunological synapse (IS) (42–45). IS organization and function has been an area of intense study (reviewed in 46–48). Protein segregation within the IS was initially described as forming a “supramolecular activation cluster (SMAC)” comprised of a central region (cSMAC) containing TCR and associated signaling proteins within a peripheral ring (pSMAC) containing LFA-1 and associated adhesion molecules (49). Recent studies have shown, however, that IS architecture and dynamics vary greatly depending on several variables, including the nature of the T cell and the APC, agonist strength, costimulatory interactions, and the tissue context in which the interaction is taking place (48, 50). Our understanding of IS function has evolved considerably over the past decade. Once thought to facilitate TCR signaling by bringing interacting molecules together, the c-SMAC was subsequently shown to be a site where signaling is terminated by internalization of TCR signaling complexes (51, 52). The role of the c-SMAC in downregulating T cell signaling is supported by studies in which signaling is en-
hanced under conditions where c-SMAC formation is blocked and inhibited under conditions where c-SMAC formation is induced. (51–53). Recently, an interesting study combining empirical analysis with mathematical modeling has shown that the IS probably both augments and downregulates TCR cell signaling and that parameters such as peptideMHC half-life determine the balance between these two interrelated facets of IS function (52). Video analysis of molecular movements during IS formation shows that the TCR and associated signaling molecules form microclusters around the periphery of the cell-cell contact site and converge to form the cSMAC (43, 54–56). Sustained signaling occurs in the peripheral clusters, while central clusters are destined for degradation, at least in the context of a strong signal. Microcluster formation and centripetal movement are actin-dependent processes, controlled in part by Cdc42 (42, 43, 56). Once formed, however, these signaling complexes are highly stable and are largely unaffected by actindepolymerizing agents. It will be interesting to learn how specific actin regulatory molecules work to orchestrate microcluster formation and movement, especially as this relates to parameters such as peptide-MHC half-life and T cell subset.
Immunological synapse (IS): specialized membrane domain enriched in signaling molecules formed at the T cell–APC contact site SMAC: supramolecular activation cluster Guanine nucleotide exchange factor (GEF): protein that activates small GTPases by catalyzing the exchange of GDP for GTP
CONTROL OF ACTIN DYNAMICS AT THE IMMUNOLOGICAL SYNAPSE Engagement of the TCR activates multiple actin-regulatory proteins that work in concert to drive actin polymerization at the IS. The best understood of these molecules function downstream of Vav1 and other guanine nucleotide exchange factors (GEFs), which activate the Rho GTPases Rac1 and Cdc42 at sites of TCR engagement (Figure 2). The signaling pathways linking TCR ligation to Rho GTPase activation are addressed in a later section. Here, we focus on molecules that directly influence actin dynamics at the IS. www.annualreviews.org • Actin in T Cell Activation
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CD4 TCR LFA-1
Actin
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HS 1
Costimulation (e.g., CD28)
L Lck Zap70 A T WASp Nck Slp76 WIP Vav Itk
PP2A Cofilin
Cdc42 Rac1 WAVE2 complex
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ER
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Transmembrane DPC proteins (e.g., CD43)
Figure 2 Simplified model of signaling pathways linking TCR signaling to actin remodeling. Encounter of an APC induces a signaling cascade comprised of tyrosine kinases (dark green), adaptor proteins (light green), and immediate upstream actin-regulatory proteins (dark blue). The latter transduce signals to several nucleation-promoting factors (red ) that direct the polymerization of branched actin filaments at sites of TCR engagement. Engagement of costimulatory molecules leads to activation of proteins that sever actin filaments (dark brown), creating new barbed ends as substrates for filament growth. Signals emanating from the TCR also lead to transient dephosphorylation and rephosphorylation of ERM proteins (orange), which direct the localization of transmembrane and cytoplasmic proteins (light blue) to cortical actin filaments at the distal pole complex (DPC). Also localized to the DPC are proteins containing PDZ (PSD-95/Discs large/ZO-1) domains ( purple), which form a network at this site. Question marks indicate the unknown mechanisms by which actin remodeling leads to IL-2 promoter activation and other changes in gene expression.
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Arp2/3 Complex–Dependent Actin-Regulatory Proteins The initiation of actin filament formation is a kinetically unfavorable process, requiring the action of nucleation-promoting factors (NPFs) to generate a “seed” from which a filament can elongate. Many of the bestunderstood NPFs work in concert with the seven-subunit Arp2/3 complex to form new actin branches on the sides of existing actin filaments (reviewed in 57). This complex, which contains two actin-related proteins, Arp2 and Arp3, binds to the side of an existing actin filament, where Arp2 and Arp3 mimic two actin monomers as part of the core nucleus. NPFs such as WASp and WAVE2 then bind to the Arp2/3 complex and present an actin monomer, allowing elongation to take place. Using an RNAi-based strategy, the Billadeau group showed that suppression of either Arp2 or Arp3 in Jurkat T cells results in degradation of other complex components (58). Arp2/3-deficient cells fail both to polymerize F-actin at the IS and to form lamellipodia in spreading assays using anti-TCR-coated coverslips. These cells generate highly dynamic F-actin-rich filopodia in response to either APCs or anti-TCR-coated surfaces, a finding that points toward additional Arp2/3 complex–independent actin regulatory pathways. Nonetheless, this study demonstrates that the Arp2/3 complex and its upstream activators are central effectors of actin polymerization at the IS. The best-characterized activator of the Arp2/3 complex is WASp, named for its causative role in Wiskott Aldrich syndrome (WAS), a severe immune deficiency disorder. The domain structure of WASp is shown in Figure 3. The N-terminal WASp-homology region (WH1) binds constitutively to WASp interacting protein (WIP). Disruption of this interaction results in degradation of WASp (59, 60). Most mutations associated with WAS are found in this region and interfere with WIP binding (61). WIP is almost certainly an important actin-regulatory protein in its own
right, but WIP function per se has not been tested, presumably because of the challenges associated with constructing WIP-deficient cells that express normal amounts of WASp. However, evidence that WIP and WASp play nonredundant roles comes from analysis of WIP/WASp double-knockout mice; T cells lacking both proteins migrate less well than T cells from either of the single knockouts (62). WASp recruitment and activation at the IS are relatively well understood. Recruitment occurs through an interaction between the WASp proline-rich domain (PRD) and the SH3 domains of the adaptors Nck and PSTPIP (63, 64). Localization to the IS facilitates WASp contact with Cdc42-GTP, which binds to the GTPase-binding domain (GBD) (63), leading to a conformational change in WASp. In resting cells, WASp exists in a closed, inactive state in which the GBD contacts the verprolin, cofilin, acidic (VCA) region. Cdc42 binding releases the VCA domain, allowing the VCA to interact with the Arp2/3 complex (65). Phosphorylation of WASp at tyrosine 291 by the Src family kinase Fyn, and subsequent binding of the SH2-SH3 domain module of Src kinases to WASp, works in a synergistic manner with Cdc42 binding to induce optimal WASp activity (66–68). WASp-deficient T cells from both mice and humans exhibit consistent defects in signaling pathways leading to IL-2 production, but the literature is divided about the importance of WASp for controlling actin polymerization at the IS. Although there are numerous reports that T cells from WAS patients exhibit defective actin responses (reviewed in 61), Jurkat cells depleted of WASp using RNAi polymerize actin normally (69). Moreover, T cells from two different WASp-knockout mice behave differently with respect to their ability to polymerize actin in response to TCR engagement (67, 70, 71). A possible explanation for these discrepancies is that other proteins (including the close homolog N-WASp, as well as less closely related proteins such as WAVE2 and HS1) have partially overlapping functions. Recent work from the Dustin lab www.annualreviews.org • Actin in T Cell Activation
Nucleationpromoting factor (NPF): protein that promotes the nucleation of actin filaments, either alone or by activating Arp2/3 complex Arp2/3 complex: seven subunit complex that nucleates the formation of new actin filaments on the sides of preexisting filaments Wiskott Aldrich syndrome (WAS): X-linked immunodeficiency disorder characterized by eczema, recurring infections, and thrombocytopenia. WAS results from mutations in WASp
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YY NTA
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Ezrin
p38 MAPK
SH3
I3
MAGUK
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LRR
PDZ
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Figure 3 Structure of proteins involved in regulating actin dynamics and T cell polarity. The domain structure of the indicated molecules is shown, with related regions colored similarly. Important binding partners are indicated below the domains to which they bind. Total amino acid number is shown at the upper right of each protein. Important phosphorylation sites are indicated (Y, T, S). NTA, N-terminal acidic region; HTH, helix-turn-helix repeats; CC, coiled-coil; PRD, proline-rich domain; SH3, Src homology 3; WH1, WASp homology 1; GBD, GTPase-binding domain; VCA, verprolin homology, cofilin homology, acidic region; WHD, WAVE homology domain; WH2, WASp homology 2; FERM, Band 4.1, ezrin, radixin, and moesin; ABD, actin-binding domain; PDZ, PSD-95/Discs large/ZO-1; I3, splice insert 3; MAGUK, membrane-associated guanylate kinase; LRR, leucine-rich repeats.
supports the idea that WASp-dependent actin polymerization is indispensable for T cell activation (44). This study shows that naive T cells contacting APCs or lipid bilayers con240
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taining MHC-peptide complexes and ICAM1 form a short-lived IS, then migrate some distance before generating a second, more stable contact. Although WASp−/− T cells form
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an initial contact in this assay, they continue to migrate and fail to re-form and maintain a long-lived IS. Another important activator of the Arp2/3 complex is the WAVE/SCAR family member WAVE2, an NPF that functions as an effector for Rac1. RNAi-mediated suppression of WAVE2 in Jurkat T cells results in loss of actin polymerization at the IS (69, 72). In addition, WAVE2 suppression perturbs conjugate formation, suggesting a role in integrin function. WAVE2 resembles WASp in that it binds the Arp2/3 complex via a C-terminal VCA domain (Figure 3), but WAVE2 lacks a GBD and does not bind Rac1 directly (73). WAVE2 exists as part of a constitutive complex containing Abi1/2, Sra1/PIR121, Hspc300, IRSp53, and HEM1 (reviewed in 37). WAVE complex components stabilize one another against degradation, and suppression of Abi1/2 or HEM-1 also results in actin defects (69, 72, 74, 75). WAVE complex components also function in WAVE2 targeting and activation. IRSp53 acts as an adaptor between Rac1 and WAVE2, and this interaction leads to the recruitment of WAVE2 to the membrane (75). Abi1/2 can mediate an interaction between Abl kinase and WAVE2, resulting in phosphorylation at Y150, which increases the actin polymerization activity of WAVE2 (76). A third activator of the Arp2/3 complex is HS1, the hematopoietic lineage–restricted homolog of the actin-binding protein cortactin (Figure 3). Like WASp and WAVE, HS1 contains an acidic region (NTA) that binds the Arp2/3 complex, and HS1 can modestly activate Arp2/3-dependent actin polymerization (Figure 3). However, HS1 also binds to F-actin directly through its helixturn-helix (HTH) repeats and coiled-coil (CC) domain (77). It is therefore thought that HS1 functions primarily to stabilize existing branched actin filaments by bridging the Arp2/3 complex with F-actin (78–80). In keeping with this idea, HS1-suppressed T cells extend unstable lamellipodia on antiTCR-coated coverslips and exhibit short-
lived actin responses at the IS (81). TCR engagement induces ZAP-70-dependent phosphorylation of HS1 at Y378 and Y397, an event that is required for HS1 function at the IS. WASp, WAVE2, and HS1 are highly modular in structure and can interact with multiple signaling molecules at the IS. The adapter properties of these proteins undoubtedly facilitate coordination of actin polymerization. For example, phosphorylation of HS1 creates binding sites for Vav1, such that HS1 contributes to Cdc42 and Rac1 activation upstream of WASp and WAVE2. It is also likely that these proteins facilitate T cell activation by coordinating other signaling molecules independent of their role in actin polymerization.
Arp2/3 Complex–Independent Actin-Regulatory Proteins In other cell types, the function of Arp2/3 complex–dependent NPFs is complemented by proteins that drive actin polymerization independently of Arp2/3 complex, as well as by proteins that cap, sever, cross-link, and bundle actin filaments. Only a few of these proteins have been analyzed in T cells. One actinsevering protein, cofilin, has been shown to play an important role in controlling actin responses at the IS (82). Cofilin is a small (19-kDa) protein that severs actin filaments, promoting depolymerization but also generating fresh barbed ends that serve as substrates for elongation factors. Because of its requirement for cell viability, cofilin has been difficult to study. However, the Samstag group has used cell-permeant peptides that compete with actin for cofilin binding to approximate a loss-of-function phenotype. Cells treated with these peptides form conjugates inefficiently, polarize CD2 and cofilin to the IS poorly, and exhibit severe defects in proliferation and cytokine secretion (82). Phosphorylation at serine 3 negatively regulates cofilin activity by antagonizing its capacity to bind actin (83). Cofilin is phosphorylated in resting www.annualreviews.org • Actin in T Cell Activation
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normal human T cells, but upon accessory receptor (CD2, CD4, CD8, or CD28) ligation, the serine phosphatases PP1 and PP2a can dephosphorylate and activate it (84, 85). Regulation of cofilin activity is likely to be an important control point for actin dynamics at the IS because cofilin can either promote lamellar growth or collapse, depending on whether Arp2/3-dependent NPFs are activated in parallel. Among the other Arp2/3-independent actin-regulatory proteins that have been studied in T cells are members of two important families, formins and Ena/VASP proteins. Members of both families localize to sites of TCR engagement (86, 87); however, their role in controlling actin responses at the IS is not clear. Formins are NPFs that promote the formation of long, linear actin filaments (87). So far, two formins have been found at significant levels in T cells, FMNL1 and Dia1 (58). Jurkat T cells suppressed for these proteins (alone or together) polymerize F-actin at the IS normally. Ena/VASP proteins bind to the barbed ends of actin filaments and promote filament growth by antagonizing the binding of capping proteins (88). The predominant Ena/VASP protein expressed in T cells is EVL. Overexpression of sequences derived from the protein ActA in Listeria monocytogenes competes for binding of EVL to other proteins. This treatment displaces EVL from sites of TCR engagement and disrupts actin responses at the IS. However, it is not clear that the effects of this construct are specific, as suppression of EVL (alone or together with the related protein VASP) has no effect on T cell spreading or actin responses at the IS (58). One possibility is that the activity of formins and Ena/VASP proteins, which can work together to generate filopodia, is masked by the broader lamellipodia generated by Arp2/3-dependent NPFs. However, even the fine filopodia generated in Arp2/3-deficient cells do not depend on the expression of formins or Ena/VASP proteins (58). Thus, it appears that the presence of these proteins at the IS reflects a role
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in processes other than control of actin polymerization. Formins are crucial for polarization of the MTOC and directed cytolysis (58), whereas EVL, which binds to the adaptor protein ADAP and the Rap1 activator RIAM, is likely to function in integrin-based adhesion (reviewed in 37).
Proteins that Affect IS Actin Dynamics by Unknown Mechanisms Among the many proteins required for efficient actin polymerization at the IS are the immediate regulators of actin dynamics described above and several well-understood signaling molecules that function upstream of these proteins. However, some proteins affect actin dynamics in ways that are not yet understood. One such protein is the methyltransferase Ezh2. Better known as a nuclear protein that methylates histones on lysine residues, Ezh2 is also found in the cytoplasm of T cells in a complex containing Vav1 (89). Recently, the Tarakhovsky group has made the unexpected observation that mature T cells deficient for Ezh2 completely fail to polymerize actin at the IS (89). Cytoplasmic Ezh2 possesses methyltransferase activity, but cytoplasmic substrates have not yet been identified. Indeed, it is not known if Ezh2 requires its methyltransferase activity to control actin responses; it could play an adaptor function by binding Vav1 and stabilizing its open active conformation (90). The position of Ezh2 within the TCR signaling pathway appears to be upstream of Cdc42 function, as Ezh2−/− T cells activate Cdc42 inefficiently, and constitutively active Cdc42 rescues TCR signaling–dependent actin polymerization in these cells (89). The large GTPase dynamin2 is also required for actin polymerization at the IS (91). Dynamin2 interacts directly with Vav1, and requires the presence of Vav1 for its localization to the IS. Although dynamin has been shown to interact with several actin-binding proteins and to affect actin dynamics in many cell types, its mechanism of action is not
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understood (92). Because dynamin plays a critical role in endocytosis, it is interesting to speculate that it functions at a point of crosstalk between actin regulatory and endocytic machinery.
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ORGANIZATION OF THE DISTAL POLE COMPLEX BY ACTIN LINKER PROTEINS In addition to organizing signaling proteins at the IS, actin and actin-binding proteins organize a second protein complex at the opposite face of the T cell, termed the distal pole complex (DPC) (93). The DPC was initially discovered based on the localization of CD43 and ERM proteins to a region that was clearly outside the IS, and in many cases distributed in a tight cap opposite the IS (30, 94). Further study showed that basic residues within the cytoplasmic tail of CD43 are required for its localization and function in T cell activation (30, 95). These residues bind to the ERM proteins ezrin and moesin (T cells Table 1
express low levels of the third family member, radixin). As detailed below, these ERM proteins bind through their N-terminal FERM (Band 4.1, ezrin, radixin, and moesin) domain to CD43 and other cargo molecules, linking them to the actin cytoskeleton in a regulated fashion. Localization of CD43 and other ERM binding proteins (e.g., RhoGDI and DLG1) to the DPC is ERM dependent because mutation of interacting residues or overexpression of a dominant-negative ERM mutant disrupts their distribution (93–95). A survey of the literature reveals that many proteins exhibit an antipodal distribution during at least some phases of the T cell response (Table 1). It is not known if ERM proteins control the localization of all of these; some may prove to lie upstream of ERM proteins in assembly of the protein network. For example, the polarity protein scribble, recently found to be required for DPC formation, T cell conjugation, and activation, is required to generate a polarized ERM protein response (96).
Distal pole complex (DPC): specialized membrane domain formed at the T cell pole distal to the site of TCR engagement DLG1: discs large; also known as SAP97
Molecules displaying patterns of localization corresponding to the DPC
DPC component
Proposed function in T cells
References
Ezrin/moesin
Linker of molecules to actin; required for localization of multiple DPC proteins and T cell activation
30, 94, 95, 97
CD43
Highly glycosylated transmembrane protein (mucin); regulator of T cell proliferation, adhesion, and migration
30, 94, 95
DLG1
PDZ domain–containing polarity protein; regulator of actin polymerization, NFAT, alternate p38 pathway
93, 98, 99
Scribble
PDZ domain–containing polarity protein; required for uropod and IS formation, migration, T cell activation
96
CD148
Tyrosine phosphatase; negative regulator of TCR-dependent NFAT activation
100
PDE4B2
Cyclic nucleotide phosphodiesterase; antagonizes PKA; associates with TCRζ and enhances IL-2 production
101
PKCζ
Atypical protein kinase C; positive regulator of NF-κB and JAK/STAT signaling
102
PtIns(3,4,5)P3
Phospholipid; required for the localization and activation of PH domain–containing proteins
103
RhoGDI
Rho GTPase guanine dissociation inhibitor; inhibits Rho GTPases; regulator of T cell development and migration
25, 94
SHP-1
Tyrosine phosphatase; negative regulator of early T cell activation signaling events
104a
EBP50
Adaptor protein; links CBP to actin through ERM proteins
105a
PTP-BL
Tyrosine phosphatase; downregulator of STAT activity and TH cell differentiation
106a
a
Localization to the DPC was ascertained by P. Cullinan, R.S. Dupree, M.H. Shaffer & J.K. Burkhardt, unpublished data.
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Although there is good evidence that the DPC is important for T cell activation, the function of this complex is still not well understood. Based on the proteins that have been identified in the DPC to date, three models have emerged. First, the DPC may modulate signaling events at the IS by serving as a sink for negative regulators of T cell activation. It is sensible that the sequestration of SHP1, CD148, PTP-BL, CD43, RhoGDI, and DLG1 away from the IS enhances T cell function because each of these molecules can antagonize events occurring at the IS (Table 1). ERM proteins also interact via EBP50 with CBP/PAG, a negative regulator of Src kinases (105), although the role of ERM proteins in regulation of CBP/PAG activity has not been established. However, some DPC proteins are not negative regulatory molecules (or play dual roles), suggesting that DPC function is more complex than simple protein sequestration. A second model is that the DPC serves as an active signaling complex, separate from the IS. In support of this idea, cross-linking CD43 with certain antibodies leads to MAP (mitogen-activated protein) kinase and NFAT (nuclear factor of activated T cells) activation (107), and coligation with TCR enhances T cell signaling (108). Cross-linking CD46 (using antibodies or by binding to measles virus) inhibits T cell activation and drives T cells to a regulatory fate (109, 110). Finally, crosslinking ICAM-2, an ERM binding protein, can activate PI3K-dependent survival signaling (111). A third model for DPC function is that it establishes overall T cell polarity, as discussed below. These models are not mutually exclusive; resolution of their relative importance will require functional analysis of individual DPC proteins.
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functions ranging from maintenance of microvilli, TCR-induced signaling events leading to cytokine production, and regulation of CD95-induced cell death (9, 30, 32, 94, 97, 112, 113). ERM proteins are present in two conformations. In the inactive form, the N-terminal FERM domain (equivalent to the N-terminal ERM-association domain, NERMAD) interacts with a C-terminal region (C-ERMAD), which encompasses the actinbinding region. This intramolecular interaction masks both the actin and cargo binding sites (Figure 3) (114, 115). In the active conformation, this intramolecular interaction is relieved, allowing linkage of cargo proteins to actin filaments. Conversion to the activated state is regulated by phosphorylation of a conserved threonine (T558 in moesin, T567 in ezrin) in the C terminus. In response to TCR engagement, active ERM proteins undergo transient dephosphorylation, temporarily relaxing their constraint of cortical protein mobility. Reactivation is then achieved by concerted binding of PtIns(4,5)P2 to the FERM domain and phosphorylation of the regulatory threonine. In parallel with rephosphorylation, ERM proteins move away from the site of TCR engagement by an unknown mechanism. The inactivation/reactivation of ERM proteins is associated with changes in cellular morphology, including the collapse of microvilli and the flattening of the T cell against an APC (9, 32). So far, neither the relevant kinase nor the phosphatase in T cells has been identified. ERM dephosphorylation requires Vav1-dependent activation of Rac1, independently of Rho and Cdc42 (Figure 2) (116). ERM proteins may use this transient dephosphorylation to alter cargo binding patterns and therefore change the localization of a subset of binding proteins, but this idea has not been tested. Prolonged ERM threonine dephosphorylation is associated with unresponsiveness induced by measles virus binding to CD46 (117). In addition to on/off regulation by phosphorylation at T567, ezrin is tyrosine phosphorylated in response to cross-linking of
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TCR, CD4, or ICAM-2 (111, 118, 119). Tyrosine phosphorylation of ezrin downstream of TCR or CD4 is dependent on the Src family kinase Lck, which can phosphorylate ezrin at Y146 in vitro (118, 120). The significance of ezrin tyrosine phosphorylation in T cells is unknown. In nonhematopoietic cells, ezrin tyrosine phosphorylation leads to activation of the PI3K/Akt pathway and enhanced cell survival (121). In T cells, ezrin phosphorylation in response to ICAM-2 cross-linking may play a similar role (111). Although the dogma in the field has been that ezrin and moesin are functionally redundant, two of the known tyrosine phosphorylation sites in ezrin are not conserved in moesin and differences in cargo binding have been described. In lymphocytes, l-selectin and CD95/Fas bind ezrin and moesin differentially (113, 122). Thus, ezrin and moesin may play unique roles in DPC function.
The DPC in T Cell Polarity Several DPC proteins (PKCζ, DLG1, and scribble) control cell polarity in epithelial cells, neurons, and developing organisms (123). These proteins, many of which contain PDZ domains, function in complex networks (124). Analysis of polarity proteins in T cells is still in its infancy, but it is already clear that they play key roles. Scribble appears to be important for polarity per se; T cells in which scribble is suppressed using RNAi fail both to form a uropod and to segregate IS and DPC proteins in response to contact with APCs (96). DLG1 is required for TCR-induced actin polymerization and regulates p38 and NFAT activation (98, 99, 125). PKCζ, an initiator of polarity cascades in other systems, has been implicated in Rap1-induced T cell polarization and chemokineinduced migration (126), as well as NF-κB and JAK/STAT activation (102). Recently, a role for polarity proteins has been established in T cell responses in vivo. Reiner and colleagues showed that during the first cell division after stimulation, PKCζ and scribble, as well as sig-
naling proteins such as CD3, IFN-γR, CD8, LFA-1, and Numb, segregate asymmetrically to the two daughter cells (127). This segregation leads to functionally distinct daughter cells; the “proximal” daughter takes on an effector phenotype, whereas the “distal” daughter is more memory-like. Many DPC proteins also localize to the uropod in migrating T cells (31). Both the uropod and DPC sequester proteins away from the site of active actin polymerization (leading edge or IS, respectively), reflecting the fundamental role of cytoskeletal architecture in dictating intrinsic cell polarity, as well as regulating signaling complexes.
INTERPLAY BETWEEN T CELL SIGNALING AND ACTIN DYNAMICS The actin cytoskeleton functions as a key intermediate in diverse signaling pathways downstream of the TCR, chemokines, death receptors, and integrins. The role of actin in integrin function is complex and has been recently reviewed elsewhere (36, 37). Here, we summarize briefly the literature regarding TCR signaling pathways, and review what is known about signaling downstream of chemokines and death receptors.
TCR Signaling To and Through the Actin Cytoskeleton Signaling pathways leading from TCR engagement to actin remodeling have been reviewed elsewhere (128). Briefly, the primary pathway involves signaling through Lck and ZAP-70, leading to the formation of a signaling complex at the IS containing the adaptor proteins LAT and SLP-76, the Tec family kinase Itk, and the Rho GEF Vav1 (diagrammed in Figure 2) (128). These proteins stabilize one another at sites of TCR engagement, and loss of any of these molecules results in disruption of actin polymerization at the IS. Interaction with complex components promotes the activation of Vav1 by phosphorylation and www.annualreviews.org • Actin in T Cell Activation
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phosphoinositide-dependent engagement of its PH domain (129). Vav1 then generates localized pools of active Cdc42 and Rac1, promoting actin polymerization by WASp and WAVE2, respectively (130, 131). As discussed above, other events also contribute to WASp and WAVE2 activation; however, Vav1 function is clearly critical (3, 132). Importantly, Vav1 binds to multiple actin regulatory molecules, suggesting that its central role in controlling actin dynamics involves adaptor functions as well as GEF activity. Costimulatory signaling also controls actin responses at the IS (42). A major consequence of costimulation via CD28 is the activation of PI3K. Through the production of PtIns(3,4,5)P3, PI3K can influence the localization and activation of PH domain–containing signaling molecules including Vav1 and Itk, leading to enhanced and/or sustained activation of the pathways described above (133–135). CD28 can also signal through a PI3K-Ras pathway to dephosphorylate and activate cofilin (136). Though less well studied, costimulatory signaling via other molecules such as CD2, CD82, CD46, and ICOS also affects TCRinduced actin responses (137–140). Thus, one way that costimulation promotes full T cell activation is by augmenting actin-dependent signaling events at the IS. Despite significant progress in determining the upstream events linking TCR engagement to actin remodeling, our understanding of how actin contributes to downstream signaling events is largely restricted to activation of the IL-2 promoter. Disruption of the actin network perturbs the activation of each of the three key elements within the IL2 promoter (NFAT, NF-κB, and AP-1). Virtually every condition that affects actin dynamics also affects Ca2+ signaling pathways leading to NFAT activation. Treatment of T cells with CytoD affects Ca2+ flux and NFAT activation, although, as noted above, the effects vary depending on the time of treatment and dose of inhibitor (2–4). Diminished Ca2+ influx and inefficient NFAT activation
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CRAC: calcium release–activated calcium
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have also been observed in T cells deficient for Vav1, WASp, WAVE2, and HS1 (3, 69, 71, 81, 132, 141, 142). However, the requirement is not simply for actin per se, because individual actin-regulatory proteins facilitate Ca2+ signaling in distinct ways. For example, WAVE2-deficient T cells exhibit defects in coupling store release to calcium release– activated calcium (CRAC) channel activation (69), whereas HS1-deficient T cells exhibit a defect at the level of release from stores (81). The defect in release from stores presumably reflects defects in PLCγ1 activation, but this has not been demonstrated. T cells deficient for Vav1 and WASp also fail to activate AP1, likely stemming from upstream defects in ERK activation (142, 143). Activation of NFκB is defective in T cells lacking Vav1 or HS1 (81, 143). The molecular basis for this defect has not been established, but it may reflect defects in PKCθ signaling. Additional analysis of signaling events in T cells lacking actin-regulatory proteins will be required to fill in the “black box” linking actin polymerization and changes in T cell gene expression, but it is unlikely that these events represent simple, linear pathways. There is growing evidence that actin networks facilitate formation or stabilization of proteinprotein interactions to promote sustained signaling (43, 81). In addition, actin promotes the internalization of TCR signaling complexes and costimulatory molecules, an event that is thought in some cases to downregulate signaling and in others to sustain it (144, 145).
Chemokine-Induced Migration Chemoattractant signaling pathways leading to actomyosin-based motility have been studied in many cell types, but remarkably little is known about how chemokine signaling in T cells reshapes the actin cytoskeleton. Even the role of PI3 kinases, central regulators of migration in other systems, is unclear in lymphocytes (146). In T cells, chemokine receptor engagement induces activation of G protein–coupled receptors. This
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induces activation of Tec kinases (Itk/Rlk), Ilk, Vav, and CrkL (147–150) and downstream activation of small GTPases, especially Rac but also Cdc42 and Rho. The primary function for Cdc42 seems to be in the activation of WASp, which together with WIP promotes T cell migration through tissues (62). In contrast, Rac activation leads to the dephosphorylation of ERM proteins and microvillar collapse that precedes the initiation of polarization and movement. Rac activity also leads to the activation of additional actinregulatory proteins, including PAK, LIMK, and p160ROCK (24, 151, 152). The central role of Rac is highlighted by the migratory defects in cells lacking Rac2, RhoGDI, and the Rac-activating proteins DOCK2 and TIAM1 (25, 126, 153, 154). DOCK2 appears to be a particularly important upstream regulator of Rac in chemokine-activated T cells. T cells from DOCK2−/− mice exhibit profound defects in Rac activation, motility, and microvillar collapse in vitro (155), and diminished migration within lymph nodes, limited egress, and impaired homing in vivo (156, 157). Recently, cofilin has emerged as another central player in signaling pathways leading to T cell migration. Regulation of cofilin activity is maintained by the opposing action of LIMK1 and the slingshot phosphatase SSH1L. Both LIMK1 and SSH1L are required for chemokine-induced T cell migration, but loss of LIMK1 suppresses lamellipodial formation, whereas loss of SSH1L results in the generation of multiple lamellipodia (158). In chemokine-stimulated cells, SSH1L and dephospho-cofilin accumulate in the leading edge, consistent with the idea that SSH1L activates cofilin-dependent actin dynamics locally, establishing actin polarity and directional migration. Other pathways also converge on cofilin activity. For example, actin-interacting protein 1 (Aip1) and caspase-11 function together to promote migration by activating cofilin (159). T cells lacking the β-propeller protein coronin 1 have a distinct phenotype, characterized by excessive F-actin accumulation at the cortex and
drastically impaired cell movement (160). Recent work in nonhematopoietic cells shows that coronin plays a dual role, inhibiting filament nucleation by the Arp2/3 complex and recruiting SSH1L to lamellipodia, where it activates cofilin (161). It remains to be demonstrated whether coronin 1 targets SSH1L in response to chemokine signaling. Nonetheless, because cofilin can promote either actin depolymerization or new growth, depending on whether the Arp2/3 complex is activated in parallel, this axis may prove to be particularly important in controlling lamellipodial dynamics.
DISC: death-inducing signaling complex
Death Receptor Signaling Some T cell signaling pathways leading to apoptosis are highly actin dependent (162). In cells where CD95/FasL signaling induces sufficient active caspase-8 to directly activate downstream caspases (Type I cells), maintenance of an intact actin cytoskeleton is required for assembly of the death-inducing signaling complex (DISC) and CD95 internalization (163). Thus, treatment of these cells with actin depolymerizing agents reduces the generation of activated caspase8 and significantly inhibits apoptosis (164). This mechanism is mediated, in part, by interactions between CD95 and ezrin. Ezrin (but not moesin or radixin) interacts directly with CD95, and antisense suppression of ezrin or mutation of its CD95 binding site inhibits CD95-mediated apoptosis (112, 113). Ezrin is cointernalized with CD95 in Type I cells, and ezrin-suppressed B cells fail to undergo CD95 internalization and DISC formation (165). It remains unclear exactly how ezrin facilitates CD95 uptake or what distinguishes Type I from Type II cells, in which CD95 is not internalized efficiently. No differences in ezrin expression were observed in Type I versus Type II cells, although differences in other actin-regulatory proteins, including HS1, have been described (164). Finally, we note that under some conditions, ERM proteins also function to oppose CD95 www.annualreviews.org • Actin in T Cell Activation
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signaling. Engagement of ICAM-2, an ERM cargo protein within the DPC, leads to tyrosine phosphorylation of ezrin, thereby creating a binding site for PI3K and initiating Akt-dependent survival signaling that protects against apoptosis induced by Fas or TNF-α (111).
PERSPECTIVES
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Actin polymerization at the site of APC binding was recognized as a hallmark of T cell activation over 25 years ago (27), but for many years the cytoskeleton was thought to play a “housekeeping” role in T cell biology. Today, it is well known that regulated actin dynamics are important for T cell development and homeostasis, activation, migration, and effector function. The past few years have seen an explosion in the identifi-
cation of proteins that control actin dynamics in response to environmental cues. Progress has also been made in understanding how signaling from the TCR, in particular, regulates the activity of these molecules. The challenge now is to understand how the function of these proteins is coordinated. It will be interesting to learn how the cytoskeletal response varies with respect to T cell subtype, agonist strength, and costimulatory signaling and how T cells integrate chemokine signals with TCR signals. Finally, it will be important to learn more about how actin dynamics promote T cell activation and effector function. Answers to these basic cell biological questions will provide important insights into how the assembly of signaling modules at the appropriate time and place within the cell works to “fine-tune” the cellular immune response.
SUMMARY POINTS 1. Depending on the physiological context in which they find themselves, T cells exhibit distinct cytoarchitectural features that are required to carry out specialized functions. These features facilitate tethering and rolling in the vasculature, extravasation, and migration through tissues and interactions with APCs. 2. During interaction with APCs, signaling events initiated by ligation of the TCR and costimulatory molecules lead to formation of a dense, branched actin network at the site of APC binding. This network helps to facilitate T cell activation by organizing signaling molecules into microclusters at the IS. The actin network is also important for the movement of signaling molecules to the center of the IS, where the complexes are internalized and signaling is terminated. 3. TCR engagement activates the assembly of a signaling complex containing Vav1, an important GEF for the Rho GTPases Cdc42 and Rac1. These and other events lead to the localized activation of Arp2/3 complex–dependent NPFs, including WASp, WAVE2, and HS1, which work in concert with proteins such as cofilin to generate F-actin filaments at the IS. 4. TCR engagement also leads to the formation of the DPC at the opposite pole of the T cell. Many proteins are brought into the DPC by binding to ezrin and moesin, which link transmembrane and cytoplasmic proteins to actin filaments in a regulated fashion. The function of the DPC is poorly understood. It is proposed to sequester negative regulators of T cell activation and serve to organize overall T cell polarity.
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5. Signaling through chemokine receptors and CD95 also affects actin dynamics. Reorganization of the actin cytoskeleton is important for downstream activation of directed cell migration and cell death, respectively. Some proteins involved in these pathways, e.g., Rac, cofilin, ezrin, are shared with TCR-dependent actin regulatory pathways. Other proteins, e.g., coronin, are so far known to function only in chemokine-mediated signaling.
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FUTURE ISSUES 1. Although the list of proteins known to control actin remodeling in T cells has grown considerably, future research will undoubtedly reveal other key players. Future studies must ask how these proteins work together to generate the appropriate response to specific stimuli. 2. Our understanding of how actin responses affect downstream events such as IL-2 promoter activation is still very rudimentary. Actin responses need to be better defined using video microscopy and electron microscopy, and structure-function analysis of individual actin-regulatory proteins will be needed to separate adaptor functions from events that depend on actin per se. Finally, mathematical modeling and other new tools will be needed to help us envision how cytoarchitectural dynamics can affect signaling cascades. 3. The importance of actin-regulatory proteins for in vivo immune responses is highlighted by the severe immunodeficiency that afflicts patients with mutations in WASp, WIP, or Vav. Recent studies have also linked changes in actin-regulatory proteins to autoimmune disease (166–168). Finally, cytoskeletal proteins play a critical role in infection by HIV and other retroviruses (reviewed in 169). Going forward, it will be important to understand how dysregulation of actin-regulatory proteins contributes to human disease and to develop new therapeutic approaches based on modulating the function of these proteins.
DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS Owing to space limitations, it was impossible to cite every relevant reference. We apologize to those whose work was not included here. We thank Yair Argon, Keri Sanborn, and members of the Burkhardt laboratory for critical reading of the manuscript. This work was supported by NIH grants R01-AI065644 and R01-AI50098 to J.K.B., F31-AI071385 to E.C., and T32HD07516 to M.H.S.
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LITERATURE CITED
Annu. Rev. Immunol. 2008.26:233-259. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
1. Henney CS, Bubbers JE. 1973. Antigen-T lymphocyte interactions: inhibition by cytochalasin B. J. Immunol. 111:85–90 2. Valitutti S, Dessing M, Aktories K, Gallati H, Lanzavecchia A. 1995. Sustained signaling leading to T cell activation results from prolonged T cell receptor occupancy. Role of T cell actin cytoskeleton. J. Exp. Med. 181:577–84 3. Holsinger LJ, Graef IA, Swat W, Chi T, Bautista DM, et al. 1998. Defects in actin-cap formation in Vav-deficient mice implicate an actin requirement for lymphocyte signal transduction. Curr. Biol. 8:563–72 4. Rivas FV, O’Keefe JP, Alegre ML, Gajewski TF. 2004. Actin cytoskeleton regulates calcium dynamics and NFAT nuclear duration. Mol. Cell. Biol. 24:1628–39 5. Majstoravich S, Zhang J, Nicholson-Dykstra S, Linder S, Friedrich W, et al. 2004. Lymphocyte microvilli are dynamic, actin-dependent structures that do not require WiskottAldrich syndrome protein (WASp) for their morphology. Blood 104:1396–403 6. Stein JV, Cheng G, Stockton BM, Fors BP, Butcher EC, von Andrian UH. 1999. lselectin-mediated leukocyte adhesion in vivo: microvillous distribution determines tethering efficiency, but not rolling velocity. J. Exp. Med. 189:37–50 7. Berlin C, Bargatze RF, Campbell JJ, von Andrian UH, Szabo MC, et al. 1995. α 4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell 80:413–22 8. Bruehl RE, Springer TA, Bainton DF. 1996. Quantitation of l-selectin distribution on human leukocyte microvilli by immunogold labeling and electron microscopy. J. Histochem. Cytochem. 44:835–44 9. Brown MJ, Nijhara R, Hallam JA, Gignac M, Yamada KM, et al. 2003. Chemokine stimulation of human peripheral blood T lymphocytes induces rapid dephosphorylation of ERM proteins, which facilitates loss of microvilli and polarization. Blood 102:3890–99 10. Alon R, Feigelson S. 2002. From rolling to arrest on blood vessels: leukocyte tap dancing on endothelial integrin ligands and chemokines at subsecond contacts. Semin. Immunol. 14:93–104 11. Takeuchi K, Sato N, Kasahara H, Funayama N, Nagafuchi A, et al. 1994. Perturbation of cell adhesion and microvilli formation by antisense oligonucleotides to ERM family members. J. Cell Biol. 125:1371–84 12. Kenney D, Cairns L, Remold-O’Donnell E, Peterson J, Rosen F, Parkman R. 1986. Morphological abnormalities in the lymphocytes of patients with the Wiscott-Aldrich Syndrome. Blood 68:1329–32 13. Gallego MD, Santamaria M, Pena J, Molina IJ. 1997. Defective actin reorganization and polymerization of Wiskott-Aldrich T cells in response to CD3-mediated stimulation. Blood 90:3089–97 14. Molina I, Kenney D, Rosen F, Remold-O’Donnell E. 1992. T cell lines characterize events in the pathogenesis of the Wiscott-Aldrich Syndrome. J. Exp. Med. 176:867–74 15. Nieto M, Frade JM, Sancho D, Mellado M, Martinez AC, Sanchez-Madrid F. 1997. Polarization of chemokine receptors to the leading edge during lymphocyte chemotaxis. J. Exp. Med. 186:153–58 16. Wei X, Tromberg BJ, Cahalan MD. 1999. Mapping the sensitivity of T cells with an optical trap: polarity and minimal number of receptors for Ca2+ signaling. Proc. Natl. Acad. Sci. USA 96:8471–76 17. Brown MJ, Hallam JA, Liu Y, Yamada KM, Shaw S. 2001. Cutting edge: integration of human T lymphocyte cytoskeleton by the cytolinker plectin. J. Immunol. 167:641–45 250
Burkhardt
·
Carrizosa
·
Shaffer
Annu. Rev. Immunol. 2008.26:233-259. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-08
ARI
16 February 2008
12:16
18. Friedman RS, Jacobelli J, Krummel MF. 2005. Mechanisms of T cell motility and arrest: deciphering the relationship between intra- and extracellular determinants. Semin. Immunol. 17:387–99 19. Jacobelli J, Chmura SA, Buxton DB, Davis MM, Krummel MF. 2004. A single class II myosin modulates T cell motility and stopping, but not synapse formation. Nat. Immunol. 5:531–38 20. del Pozo MA, Vicente-Manzanares M, Tejedor R, Serrador JM, Sanchez-Madrid F. 1999. Rho GTPases control migration and polarization of adhesion molecules and cytoskeletal ERM components in T lymphocytes. Eur. J. Immunol. 29:3609–20 21. Bustelo XR. 2002. Understanding Rho/Rac biology in T-cells using animal models. BioEssays 24:602–12 22. Bardi G, Niggli V, Loetscher P. 2003. Rho kinase is required for CCR7-mediated polarization and chemotaxis of T lymphocytes. FEBS Lett. 542:79–83 23. Lee JH, Katakai T, Hara T, Gonda H, Sugai M, Shimizu A. 2004. Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation. J. Cell Biol. 167:327–37 24. Volinsky N, Gantman A, Yablonski D. 2006. A Pak- and Pix-dependent branch of the SDF-1α signalling pathway mediates T cell chemotaxis across restrictive barriers. Biochem. J. 397:213–22 25. Ishizaki H, Togawa A, Tanaka-Okamoto M, Hori K, Nishimura M, et al. 2006. Defective chemokine-directed lymphocyte migration and development in the absence of Rho guanosine diphosphate-dissociation inhibitors α and β. J. Immunol. 177:8512–21 26. Ratner S, Piechocki MP, Galy A. 2003. Role of Rho-family GTPase Cdc42 in polarized expression of lymphocyte appendages. J. Leukoc. Biol. 73:830–40 27. Ryser JE, Rungger-Brandle E, Chaponnier C, Gabbiani G, Vassalli P. 1982. The area of attachment of cytotoxic T lymphocytes to their target cells shows high motility and polarization of actin, but not myosin. J. Immunol. 128:1159–62 28. Kupfer A, Dennert G, Singer SJ. 1985. The reorientation of the Golgi apparatus and the microtubule-organizing center in the cytotoxic effector cell is a prerequisite in the lysis of bound target cells. J. Mol. Cell. Immunol. 2:37–49 29. Kupfer H, Monks C, Kupfer A. 1994. Small splenic B cells that bind to antigen-specific T helper (Th) cells and face the site of cytokine production in the Th cells selectively proliferate: immunofluorescence microscopy studies of Th-B antigen-presenting cell interactions. J. Exp. Med. 179:1507–15 30. Delon J, Kaibuchi K, Germain RN. 2001. Exclusion of CD43 from the immunological synapse is mediated by phosphorylation-regulated relocation of the cytoskeletal adaptor moesin. Immunity 15:691–701 31. Cullinan P, Sperling AI, Burkhardt JK. 2002. The distal pole complex: a novel membrane domain distal to the immunological synapse. Immunol. Rev. 189:111–22 32. Faure S, Salazar-Fontana LI, Semichon M, Tybulewicz VL, Bismuth G, et al. 2004. ERM proteins regulate cytoskeleton relaxation promoting T cell-APC conjugation. Nat. Immunol. 5:272–79 33. Selliah N, Brooks WH, Roszman TL. 1996. Proteolytic cleavage of α-actinin by calpain in T cells stimulated with anti-CD3 monoclonal antibody. J. Immunol. 156:3215–21 34. Cairo CW, Mirchev R, Golan DE. 2006. Cytoskeletal regulation couples LFA-1 conformational changes to receptor lateral mobility and clustering. Immunity 25:297–308 35. Morley SC, Sung J, Sun GP, Martelli MP, Bunnell SC, Bierer BE. 2007. Gelsolin overexpression alters actin dynamics and tyrosine phosphorylation of lipid raft-associated proteins in Jurkat T cells. Mol. Immunol. 44:2469–80 www.annualreviews.org • Actin in T Cell Activation
251
ARI
16 February 2008
12:16
36. Luo BH, Carman CV, Springer TA. 2007. Structural basis of integrin regulation and signaling. Annu. Rev. Immunol. 25:619–47 37. Billadeau DD, Nolz JC, Gomez TS. 2007. Regulation of T-cell activation by the cytoskeleton. Nat. Rev. Immunol. 7:131–43 38. Valmu L, Fagerholm S, Suila H, Gahmberg CG. 1999. The cytoskeletal association of CD11/CD18 leukocyte integrins in phorbol ester-activated cells correlates with CD18 phosphorylation. Eur. J. Immunol. 29:2107–18 39. Nurmi SM, Gahmberg CG, Fagerholm SC. 2006. 14-3-3 proteins bind both filamin and αLβ2 integrin in activated T cells. Ann. NY Acad. Sci. 1090:318–25 40. Simonson WT, Franco SJ, Huttenlocher A. 2006. Talin1 regulates TCR-mediated LFA-1 function. J. Immunol. 177:7707–14 41. Kim M, Carman CV, Yang W, Salas A, Springer TA. 2004. The primacy of affinity over clustering in regulation of adhesiveness of the integrin αLβ2. J. Cell Biol. 167:1241–53 42. Tskvitaria-Fuller I, Rozelle AL, Yin HL, Wulfing C. 2003. Regulation of sustained actin dynamics by the TCR and costimulation as a mechanism of receptor localization. J. Immunol. 171:2287–95 43. Campi G, Varma R, Dustin ML. 2005. Actin and agonist MHC-peptide complexdependent T cell receptor microclusters as scaffolds for signaling. J. Exp. Med. 202:1031– 36 44. Sims TN, Soos TJ, Xenias HS, Dubin-Thaler B, Hofman JM, et al. 2007. Opposing effects of PKCθ and WASp on symmetry breaking and relocation of the immunological synapse. Cell 129:773–85 45. Wulfing C, Bauch A, Crabtree GR, Davis MM. 2000. The vav exchange factor is an essential regulator in actin-dependent receptor translocation to the lymphocyte-antigenpresenting cell interface. Proc. Natl. Acad. Sci. USA 97:10150–55 46. Dustin ML, Tseng SY, Varma R, Campi G. 2006. T cell-dendritic cell immunological synapses. Curr. Opin. Immunol. 18:512–16 47. Cemerski S, Shaw A. 2006. Immune synapses in T-cell activation. Curr. Opin. Immunol. 18:298–304 48. Friedl P, den Boer AT, Gunzer M. 2005. Tuning immune responses: diversity and adaptation of the immunological synapse. Nat. Rev. Immunol. 5:532–45 49. Monks CR, Freiberg BA, Kupfer H, Sciaky N, Kupfer A. 1998. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395:82–86 50. Jacobelli J, Andres PG, Boisvert J, Krummel MF. 2004. New views of the immunological synapse: variations in assembly and function. Curr. Opin. Immunol. 16:345–52 51. Mossman KD, Campi G, Groves JT, Dustin ML. 2005. Altered TCR signaling from geometrically repatterned immunological synapses. Science 310:1191–93 52. Cemerski S, Das J, Locasale J, Arnold P, Giurisato E, et al. 2007. The stimulatory potency of T cell antigens is influenced by the formation of the immunological synapse. Immunity 26:345–55 53. Lee KH, Dinner AR, Tu C, Campi G, Raychaudhuri S, et al. 2003. The immunological synapse balances T cell receptor signaling and degradation. Science 302:1218–22 54. Bunnell SC, Hong DI, Kardon JR, Yamazaki T, McGlade CJ, et al. 2002. T cell receptor ligation induces the formation of dynamically regulated signaling assemblies. J. Cell Biol. 158:1263–75 55. Yokosuka T, Sakata-Sogawa K, Kobayashi W, Hiroshima M, Hashimoto-Tane A, et al. 2005. Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP-76. Nat. Immunol. 6:1253–62
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ANRV338-IY26-08
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56. Varma R, Campi G, Yokosuka T, Saito T, Dustin ML. 2006. T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 25:117–27 57. Goley ED, Welch MD. 2006. The ARP2/3 complex: an actin nucleator comes of age. Nat. Rev. Mol. Cell Biol. 7:713–26 58. Gomez TS, Kumar K, Medeiros RB, Shimizu Y, Leibson PJ, Billadeau DD. 2007. Formins regulate the actin-related protein 2/3 complex-independent polarization of the centrosome to the immunological synapse. Immunity 26:177–90 59. Volkman BF, Prehoda KE, Scott JA, Peterson FC, Lim WA. 2002. Structure of the NWASP EVH1 domain-WIP complex: insight into the molecular basis of Wiskott-Aldrich Syndrome. Cell 111:565–76 60. de la Fuente MA, Sasahara Y, Calamito M, Anton IM, Elkhal A, et al. 2007. WIP is a chaperone for Wiskott-Aldrich syndrome protein (WASP). Proc. Natl. Acad. Sci. USA 104:926–31 61. Notarangelo LD, Ochs HD. 2003. Wiskott-Aldrich Syndrome: a model for defective actin reorganization, cell trafficking and synapse formation. Curr. Opin. Immunol. 15:585–91 62. Gallego MD, de la Fuente MA, Anton IM, Snapper S, Fuhlbrigge R, Geha RS. 2006. WIP and WASP play complementary roles in T cell homing and chemotaxis to SDF-1α. Int. Immunol. 18:221–32 63. Zeng R, Cannon JL, Abraham RT, Way M, Billadeau DD, et al. 2003. SLP-76 coordinates Nck-dependent Wiskott-Aldrich syndrome protein recruitment with Vav-1/Cdc42dependent Wiskott-Aldrich syndrome protein activation at the T cell-APC contact site. J. Immunol. 171:1360–68 64. Badour K, Zhang J, Shi F, McGavin MK, Rampersad V, et al. 2003. The Wiskott-Aldrich syndrome protein acts downstream of CD2 and the CD2AP and PSTPIP1 adaptors to promote formation of the immunological synapse. Immunity 18:141–54 65. Kim AS, Kakalis LT, Abdul-Manan N, Liu GA, Rosen MK. 2000. Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein. Nature 404:151–58 66. Torres E, Rosen MK. 2003. Contingent phosphorylation/dephosphorylation provides a mechanism of molecular memory in WASP. Mol. Cell 11:1215–27 67. Badour K, Zhang J, Shi F, Leng Y, Collins M, Siminovitch KA. 2004. Fyn and PTPPEST-mediated regulation of Wiskott-Aldrich syndrome protein (WASp) tyrosine phosphorylation is required for coupling T cell antigen receptor engagement to WASp effector function and T cell activation. J. Exp. Med. 199:99–112 68. Torres E, Rosen MK. 2006. Protein-tyrosine kinase and GTPase signals cooperate to phosphorylate and activate Wiskott-Aldrich syndrome protein (WASP)/neuronal WASP. J. Biol. Chem. 281:3513–20 69. Nolz JC, Gomez TS, Zhu P, Li S, Medeiros RB, et al. 2006. The WAVE2 complex regulates actin cytoskeletal reorganization and CRAC-mediated calcium entry during T cell activation. Curr. Biol. 16:24–34 70. Krawczyk C, Oliveira-dos-Santos A, Sasaki T, Griffiths E, Ohashi PS, et al. 2002. Vav1 controls integrin clustering and MHC/peptide-specific cell adhesion to antigenpresenting cells. Immunity 16:331–43 71. Cannon JL, Burkhardt JK. 2004. Differential roles for Wiskott-Aldrich syndrome protein in immune synapse formation and IL-2 production. J. Immunol. 173:1658–62 72. Zipfel PA, Bunnell SC, Witherow DS, Gu JJ, Chislock EM, et al. 2006. Role for the Abi/wave protein complex in T cell receptor-mediated proliferation and cytoskeletal remodeling. Curr. Biol. 16:35–46 www.annualreviews.org • Actin in T Cell Activation
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73. Miki H, Suetsugu S, Takenawa T. 1998. WAVE, a novel WASP-family protein involved in actin reorganization induced by Rac. EMBO J. 17:6932–41 74. Innocenti M, Zucconi A, Disanza A, Frittoli E, Areces LB, et al. 2004. Abi1 is essential for the formation and activation of a WAVE2 signalling complex. Nat. Cell Biol. 6:319–27 75. Miki H, Yamaguchi H, Suetsugu S, Takenawa T. 2000. IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling. Nature 408:732–35 76. Leng Y, Zhang J, Badour K, Arpaia E, Freeman S, et al. 2005. Abelson-interactor-1 promotes WAVE2 membrane translocation and Abelson-mediated tyrosine phosphorylation required for WAVE2 activation. Proc. Natl. Acad. Sci. USA 102:1098–103 77. Hao JJ, Zhu J, Zhou K, Smith N, Zhan X. 2005. The coiled-coil domain is required for HS1 to bind to F-actin and activate Arp2/3 complex. J. Biol. Chem. 280:37988–94 78. Uruno T, Liu J, Zhang P, Fan Y, Egile C, et al. 2001. Activation of Arp2/3 complexmediated actin polymerization by cortactin. Nat. Cell Biol. 3:259–66 79. Uruno T, Zhang P, Liu J, Hao JJ, Zhan X. 2003. Haematopoietic lineage cell-specific protein 1 (HS1) promotes actin-related protein (Arp) 2/3 complex-mediated actin polymerization. Biochem. J. 371:485–93 80. Weaver AM, Karginov AV, Kinley AW, Weed SA, Li Y, et al. 2001. Cortactin promotes and stabilizes Arp2/3-induced actin filament network formation. Curr. Biol. 11:370–74 81. Gomez TS, McCarney SD, Carrizosa E, Labno CM, Comiskey EO, et al. 2006. HS1 functions as an essential actin-regulatory adaptor protein at the immune synapse. Immunity 24:741–52 82. Eibert SM, Lee KH, Pipkorn R, Sester U, Wabnitz GH, et al. 2004. Cofilin peptide homologs interfere with immunological synapse formation and T cell activation. Proc. Natl. Acad. Sci. USA 101:1957–62 83. DesMarais V, Ghosh M, Eddy R, Condeelis J. 2005. Cofilin takes the lead. J. Cell Sci. 118:19–26 84. Ambach A, Saunus J, Konstandin M, Wesselborg S, Meuer SC, Samstag Y. 2000. The serine phosphatases PP1 and PP2A associate with and activate the actin-binding protein cofilin in human T lymphocytes. Eur. J. Immunol. 30:3422–31 85. Samstag Y, Henning SW, Bader A, Meuer SC. 1992. Dephosphorylation of pp19: a common second signal for human T cell activation mediated through different accessory molecules. Int. Immunol. 4:1255–62 86. Krause M, Sechi AS, Konradt M, Monner D, Gertler FB, Wehland J. 2000. Fyn-binding protein (Fyb)/SLP-76-associated protein (SLAP), Ena/vasodilator-stimulated phosphoprotein (VASP) proteins and the Arp2/3 complex link T cell receptor (TCR) signaling to the actin cytoskeleton. J. Cell Biol. 149:181–94 87. Faix J, Grosse R. 2006. Staying in shape with formins. Dev. Cell 10:693–706 88. Krause M, Dent EW, Bear JE, Loureiro JJ, Gertler FB. 2003. Ena/VASP proteins: regulators of the actin cytoskeleton and cell migration. Annu. Rev. Cell Dev. Biol. 19:541–64 89. Su IH, Dobenecker MW, Dickinson E, Oser M, Basavaraj A, et al. 2005. Polycomb group protein ezh2 controls actin polymerization and cell signaling. Cell 121:425–36 90. Su IH, Tarakhovsky A. 2006. Lysine methylation and ‘signaling memory’. Curr. Opin. Immunol. 18:152–57 91. Gomez TS, Hamann MJ, McCarney S, Savoy DN, Lubking CM, et al. 2005. Dynamin 2 regulates T cell activation by controlling actin polymerization at the immunological synapse. Nat. Immunol. 6:261–70 92. Kruchten AE, McNiven MA. 2006. Dynamin as a mover and pincher during cell migration and invasion. J. Cell Sci. 119:1683–90
Annu. Rev. Immunol. 2008.26:233-259. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-08
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Burkhardt
·
Carrizosa
·
Shaffer
Annu. Rev. Immunol. 2008.26:233-259. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-08
ARI
16 February 2008
12:16
93. Cullinan P, Sperling AI, Burkhardt JK. 2002. The distal pole complex: a novel membrane domain distal to the immunological synapse. Immunol. Rev. 189:111–22 94. Allenspach EJ, Cullinan P, Tong J, Tang Q, Tesciuba AG, et al. 2001. ERM-dependent movement of CD43 defines a novel protein complex distal to the immunological synapse. Immunity 15:739–50 95. Savage ND, Kimzey SL, Bromley SK, Johnson KG, Dustin ML, Green JM. 2002. Polar redistribution of the sialoglycoprotein CD43: implications for T cell function. J. Immunol. 168:3740–46 96. Ludford-Menting MJ, Oliaro J, Sacirbegovic F, Cheah ET, Pedersen N, et al. 2005. A network of PDZ-containing proteins regulates T cell polarity and morphology during migration and immunological synapse formation. Immunity 22:737–48 97. Roumier A, Olivo-Marin JC, Arpin M, Michel F, Martin M, et al. 2001. The membranemicrofilament linker ezrin is involved in the formation of the immunological synapse and in T cell activation. Immunity 15:715–28 98. Round JL, Humphries LA, Tomassian T, Mittelstadt P, Zhang M, Miceli MC. 2007. Scaffold protein Dlgh1 coordinates alternative p38 kinase activation, directing T cell receptor signals toward NFAT but not NF-κB transcription factors. Nat. Immunol. 8:154– 61 99. Round JL, Tomassian T, Zhang M, Patel V, Schoenberger SP, Miceli MC. 2005. Dlgh1 coordinates actin polymerization, synaptic T cell receptor and lipid raft aggregation, and effector function in T cells. J. Exp. Med. 201:419–30 100. Lin J, Weiss A. 2003. The tyrosine phosphatase CD148 is excluded from the immunologic synapse and down-regulates prolonged T cell signaling. J. Cell Biol. 162:673–82 101. Arp J, Kirchhof MG, Baroja ML, Nazarian SH, Chau TA, et al. 2003. Regulation of T-cell activation by phosphodiesterase 4B2 requires its dynamic redistribution during immunological synapse formation. Mol. Cell. Biol. 23:8042–57 102. Moscat J, Rennert P, Diaz-Meco MT. 2006. PKCζ at the crossroad of NF-κB and Jak1/Stat6 signaling pathways. Cell Death Differ. 13:702–11 103. Costello PS, Gallagher M, Cantrell DA. 2002. Sustained and dynamic inositol lipid metabolism inside and outside the immunological synapse. Nat. Immunol. 3:1082–89 104. Stefanova I, Hemmer B, Vergelli M, Martin R, Biddison WE, Germain RN. 2003. TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat. Immunol. 4:248–54 105. Itoh K, Sakakibara M, Yamasaki S, Takeuchi A, Arase H, et al. 2002. Cutting edge: negative regulation of immune synapse formation by anchoring lipid raft to cytoskeleton through Cbp-EBP50-ERM assembly. J. Immunol. 168:541–44 106. Nakahira M, Tanaka T, Robson BE, Mizgerd JP, Grusby MJ. 2007. Regulation of signal transducer and activator of transcription signaling by the tyrosine phosphatase PTP-BL. Immunity 26:163–76 107. del Rio R, Rincon M, Layseca-Espinosa E, Fierro NA, Rosenstein Y, Pedraza-Alva G. 2004. PKCθ is required for the activation of human T lymphocytes induced by CD43 engagement. Biochem. Biophys. Res. Commun. 325:133–43 108. Sperling AI, Green JM, Mosley RL, Smith PL, DiPaolo RJ, et al. 1995. CD43 is a murine T cell costimulatory receptor that functions independently of CD28. J. Exp. Med. 182:139–46 109. Oliaro J, Pasam A, Waterhouse NJ, Browne KA, Ludford-Menting MJ, et al. 2006. Ligation of the cell surface receptor, CD46, alters T cell polarity and response to antigen presentation. Proc. Natl. Acad. Sci. USA 103:18685–90 www.annualreviews.org • Actin in T Cell Activation
255
ARI
16 February 2008
12:16
110. Kemper C, Verbsky JW, Price JD, Atkinson JP. 2005. T-cell stimulation and regulation: with complements from CD46. Immunol. Res. 32:31–43 111. Perez OD, Kinoshita S, Hitoshi Y, Payan DG, Kitamura T, et al. 2002. Activation of the PKB/AKT pathway by ICAM-2. Immunity 16:51–65 112. Parlato S, Giammarioli AM, Logozzi M, Lozupone F, Matarrese P, et al. 2000. CD95 (APO-1/Fas) linkage to the actin cytoskeleton through ezrin in human T lymphocytes: a novel regulatory mechanism of the CD95 apoptotic pathway. EMBO J. 19:5123–34 113. Lozupone F, Lugini L, Matarrese P, Luciani F, Federici C, et al. 2004. Identification and relevance of the CD95-binding domain in the N-terminal region of ezrin. J. Biol. Chem. 279:9199–207 114. Li Q, Nance MR, Kulikauskas R, Nyberg K, Fehon R, et al. 2007. Self-masking in an intact ERM-merlin protein: an active role for the central α-helical domain. J. Mol. Biol. 365:1446–59 115. Bretscher A, Edwards K, Fehon RG. 2002. ERM proteins and merlin: integrators at the cell cortex. Nat. Rev. Mol. Cell Biol. 3:586–99 116. Nijhara R, van Hennik PB, Gignac ML, Kruhlak MJ, Hordijk PL, et al. 2004. Rac1 mediates collapse of microvilli on chemokine-activated T lymphocytes. J. Immunol. 173:4985– 93 117. Muller N, Avota E, Schneider-Schaulies J, Harms H, Krohne G, Schneider-Schaulies S. 2006. Measles virus contact with T cells impedes cytoskeletal remodeling associated with spreading, polarization, and CD3 clustering. Traffic 7:849–58 118. Thuillier L, Hivroz C, Fagard R, Andreoli C, Mangeat P. 1994. Ligation of CD4 surface antigen induces rapid tyrosine phosphorylation of the cytoskeletal protein ezrin. Cell. Immunol. 156:322–31 119. Egerton M, Burgess WH, Chen D, Druker BJ, Bretscher A, Samelson LE. 1992. Identification of ezrin as an 81-kDa tyrosine-phosphorylated protein in T cells. J. Immunol. 149:1847–52 120. Autero M, Heiska L, Ronnstrand L, Vaheri A, Gahmberg CG, Carpen O. 2003. Ezrin is a substrate for Lck in T cells. FEBS Lett. 535:82–86 121. Gautreau A, Poullet P, Louvard D, Arpin M. 1999. Ezrin, a plasma membranemicrofilament linker, signals cell survival through the phosphatidylinositol 3-kinase/Akt pathway. Proc. Natl. Acad. Sci. USA 96:7300–5 122. Ivetic A, Deka J, Ridley A, Ager A. 2002. The cytoplasmic tail of l-selectin interacts with members of the Ezrin-Radixin-Moesin (ERM) family of proteins: cell activationdependent binding of Moesin but not Ezrin. J. Biol. Chem. 277:2321–29 123. Suzuki A, Ohno S. 2006. The PAR-aPKC system: lessons in polarity. J. Cell Sci. 119:979– 87 124. Xavier R, Seed B. 2005. PDZ domains and the politics of polarity in lymphocytes. Immunity 22:655–56 125. Xavier R, Rabizadeh S, Ishiguro K, Andre N, Ortiz JB, et al. 2004. Discs large (Dlg1) complexes in lymphocyte activation. J. Cell Biol. 166:173–78 126. Gerard A, Mertens AE, Van Der Kammen RA, Collard JG. 2007. The Par polarity complex regulates Rap1- and chemokine-induced T cell polarization. J. Cell Biol. 176:863– 75 127. Chang JT, Palanivel VR, Kinjyo I, Schambach F, Intlekofer AM, et al. 2007. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315:1687– 91 128. Fuller CL, Braciale VL, Samelson LE. 2003. All roads lead to actin: the intimate relationship between TCR signaling and the cytoskeleton. Immunol. Rev. 191:220–36
Annu. Rev. Immunol. 2008.26:233-259. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-08
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·
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·
Shaffer
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ANRV338-IY26-08
ARI
16 February 2008
12:16
129. Bustelo XR. 2002. Regulation of Vav proteins by intramolecular events. Front. Biosci. 7:d24–30 130. Dombroski D, Houghtling RA, Labno CM, Precht P, Takesono A, et al. 2005. Kinaseindependent functions for Itk in TCR-induced regulation of Vav and the actin cytoskeleton. J. Immunol. 174:1385–92 131. Labno CM, Lewis CM, You D, Leung DW, Takesono A, et al. 2003. Itk functions to control actin polymerization at the immune synapse through localized activation of Cdc42 and WASP. Curr. Biol. 13:1619–24 132. Fischer KD, Kong YY, Nishina H, Tedford K, Marengere LE, et al. 1998. Vav is a regulator of cytoskeletal reorganization mediated by the T-cell receptor. Curr. Biol. 8:554– 62 133. Michel F, Mangino G, Attal-Bonnefoy G, Tuosto L, Alcover A, et al. 2000. CD28 utilizes Vav-1 to enhance TCR-proximal signaling and NF-AT activation. J. Immunol. 165:3820– 29 134. Han J, Luby-Phelps K, Das B, Shu X, Xia Y, et al. 1998. Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav. Science 279:558–60 135. Finkelstein LD, Schwartzberg PL. 2004. Tec kinases: shaping T-cell activation through actin. Trends Cell Biol. 14:443–51 136. Wabnitz GH, Nebl G, Klemke M, Schroder AJ, Samstag Y. 2006. Phosphatidylinositol 3kinase functions as a Ras effector in the signaling cascade that regulates dephosphorylation of the actin-remodeling protein cofilin after costimulation of untransformed human T lymphocytes. J. Immunol. 176:1668–74 137. Wabnitz GH, Kocher T, Lohneis P, Stober C, Konstandin MH, et al. 2007. Costimulation induced phosphorylation of l-plastin facilitates surface transport of the T cell activation molecules CD69 and CD25. Eur. J. Immunol. 37:649–62 138. Delaguillaumie A, Lagaudriere-Gesbert C, Popoff MR, Conjeaud H. 2002. Rho GTPases link cytoskeletal rearrangements and activation processes induced via the tetraspanin CD82 in T lymphocytes. J. Cell Sci. 115:433–43 139. Zaffran Y, Destaing O, Roux A, Ory S, Nheu T, et al. 2001. CD46/CD3 costimulation induces morphological changes of human T cells and activation of Vav, Rac, and extracellular signal-regulated kinase mitogen-activated protein kinase. J. Immunol. 167:6780–85 140. Nukada Y, Okamoto N, Konakahara S, Tezuka K, Ohashi K, et al. 2006. AILIM/ICOSmediated elongation of activated T cells is regulated by both the PI3-kinase/Akt and Rho family cascade. Int. Immunol. 18:1815–24 141. Zhang J, Shehabeldin A, da Cruz LA, Butler J, Somani AK, et al. 1999. Antigen receptorinduced activation and cytoskeletal rearrangement are impaired in Wiskott-Aldrich syndrome protein-deficient lymphocytes. J. Exp. Med. 190:1329–42 142. Cianferoni A, Massaad M, Feske S, de la Fuente MA, Gallego L, et al. 2005. Defective nuclear translocation of nuclear factor of activated T cells and extracellular signal-regulated kinase underlies deficient IL-2 gene expression in Wiskott-Aldrich syndrome. J. Allergy Clin. Immunol. 116:1364–71 143. Costello PS, Walters AE, Mee PJ, Turner M, Reynolds LF, et al. 1999. The Rho-family GTP exchange factor Vav is a critical transducer of T cell receptor signals to the calcium, ERK, and NF-κB pathways. Proc. Natl. Acad. Sci. USA 96:3035–40 144. Badour K, McGavin MK, Zhang J, Freeman S, Vieira C, et al. 2007. Interaction of the Wiskott-Aldrich syndrome protein with sorting nexin 9 is required for CD28 endocytosis and cosignaling in T cells. Proc. Natl. Acad. Sci. USA 104:1593–98 www.annualreviews.org • Actin in T Cell Activation
257
ARI
16 February 2008
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145. McGavin MK, Badour K, Hardy LA, Kubiseski TJ, Zhang J, Siminovitch KA. 2001. The intersectin 2 adaptor links Wiskott Aldrich Syndrome protein (WASp)-mediated actin polymerization to T cell antigen receptor endocytosis. J. Exp. Med. 194:1777–87 146. Ward SG. 2004. Do phosphoinositide 3-kinases direct lymphocyte navigation? Trends Immunol. 25:67–74 147. Takesono A, Horai R, Mandai M, Dombroski D, Schwartzberg PL. 2004. Requirement for Tec kinases in chemokine-induced migration and activation of Cdc42 and Rac. Curr. Biol. 14:917–22 148. Liu E, Sinha S, Williams C, Cyrille M, Heller E, et al. 2005. Targeted deletion of integrinlinked kinase reveals a role in T-cell chemotaxis and survival. Mol. Cell. Biol. 25:11145–55 149. Vicente-Manzanares M, Cruz-Adalia A, Martin-Cofreces NB, Cabrero JR, Dosil M, et al. 2005. Control of lymphocyte shape and the chemotactic response by the GTP exchange factor Vav. Blood 105:3026–34 150. Arai A, Aoki M, Weihua Y, Jin A, Miura O. 2006. CrkL plays a role in SDF-1-induced activation of the Raf-1/MEK/Erk pathway through Ras and Rac to mediate chemotactic signaling in hematopoietic cells. Cell. Signal. 18:2162–71 151. Nishita M, Aizawa H, Mizuno K. 2002. Stromal cell-derived factor 1α activates LIM kinase 1 and induces cofilin phosphorylation for T-cell chemotaxis. Mol. Cell. Biol. 22:774– 83 152. Vicente-Manzanares M, Cabrero JR, Rey M, Perez-Martinez M, Ursa A, et al. 2002. A role for the Rho-p160 Rho coiled-coil kinase axis in the chemokine stromal cell-derived factor1α-induced lymphocyte actomyosin and microtubular organization and chemotaxis. J. Immunol. 168:400–10 153. Croker BA, Handman E, Hayball JD, Baldwin TM, Voigt V, et al. 2002. Rac2-deficient mice display perturbed T-cell distribution and chemotaxis, but only minor abnormalities in TH1 responses. Immunol. Cell Biol. 80:231–40 154. Fukui Y, Hashimoto O, Sanui T, Oono T, Koga H, et al. 2001. Haematopoietic cellspecific CDM family protein DOCK2 is essential for lymphocyte migration. Nature 412:826–31 155. Shulman Z, Pasvolsky R, Woolf E, Grabovsky V, Feigelson SW, et al. 2006. DOCK2 regulates chemokine-triggered lateral lymphocyte motility but not transendothelial migration. Blood 108:2150–58 156. Nombela-Arrieta C, Mempel TR, Soriano SF, Mazo I, Wymann MP, et al. 2007. A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphatemediated egress. J. Exp. Med. 204:497–510 157. Nombela-Arrieta C, Lacalle RA, Montoya MC, Kunisaki Y, Megias D, et al. 2004. Differential requirements for DOCK2 and phosphoinositide-3-kinase γ during T and B lymphocyte homing. Immunity 21:429–41 158. Nishita M, Tomizawa C, Yamamoto M, Horita Y, Ohashi K, Mizuno K. 2005. Spatial and temporal regulation of cofilin activity by LIM kinase and Slingshot is critical for directional cell migration. J. Cell Biol. 171:349–59 159. Li J, Brieher WM, Scimone ML, Kang SJ, Zhu H, et al. 2007. Caspase-11 regulates cell migration by promoting Aip1-Cofilin-mediated actin depolymerization. Nat. Cell Biol. 9:276–86 160. Foger N, Rangell L, Danilenko DM, Chan AC. 2006. Requirement for coronin 1 in T lymphocyte trafficking and cellular homeostasis. Science 313:839–42 161. Cai L, Marshall TW, Uetrecht AC, Schafer DA, Bear JE. 2007. Coronin 1B coordinates Arp2/3 complex and cofilin activities at the leading edge. Cell 128:915–29
Annu. Rev. Immunol. 2008.26:233-259. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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·
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Shaffer
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ANRV338-IY26-08
ARI
16 February 2008
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162. Celeste Morley S, Sun GP, Bierer BE. 2003. Inhibition of actin polymerization enhances commitment to and execution of apoptosis induced by withdrawal of trophic support. J. Cell. Biochem. 88:1066–76 163. Algeciras-Schimnich A, Shen L, Barnhart BC, Murmann AE, Burkhardt JK, Peter ME. 2002. Molecular ordering of the initial signaling events of CD95. Mol. Cell. Biol. 22:207– 20 164. Algeciras-Schimnich A, Peter ME. 2003. Actin dependent CD95 internalization is specific for Type I cells. FEBS Lett. 546:185–88 165. Chakrabandhu K, Herincs Z, Huault S, Dost B, Peng L, et al. 2007. Palmitoylation is required for efficient Fas cell death signaling. EMBO J. 26:209–20 166. Otsuka J, Horiuchi T, Yoshizawa S, Tsukamoto H, Sawabe T, et al. 2004. Association of a four-amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: molecular and functional analysis. Arthritis Rheum. 50:871–81 167. Sawabe T, Horiuchi T, Koga R, Tsukamoto H, Kojima T, et al. 2003. Aberrant HS1 molecule in a patient with systemic lupus erythematosus. Genes Immun. 4:122–31 168. Li Y, Harada T, Juang YT, Kyttaris VC, Wang Y, et al. 2007. Phosphorylated ERM is responsible for increased T cell polarization, adhesion, and migration in patients with systemic lupus erythematosus. J. Immunol. 178:1938–47 169. Fackler OT, Krausslich HG. 2006. Interactions of human retroviruses with the host cell cytoskeleton. Curr. Opin. Microbiol. 9:409–15
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Annual Review of Immunology
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:233-259. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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Contents
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Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader Department of Molecular Genetics and Microbiology, Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts 01655-012; email:
[email protected],
[email protected],
[email protected] Annu. Rev. Immunol. 2008. 26:261–92
Key Words
The Annual Review of Immunology is online at immunol.annualreviews.org
AID, UNG, AP endonuclease, DNA Pol β, DNA-PK, XRCC4-DNA ligase IV, ATM, Mre11-Nbs1-Rad50, 53BP1, γH2AX, germline transcripts, R-loops, end joining
This article’s doi: 10.1146/annurev.immunol.26.021607.090248 c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0261$20.00
Abstract Antibody class switching occurs in mature B cells in response to antigen stimulation and costimulatory signals. It occurs by a unique type of intrachromosomal deletional recombination within special G-rich tandem repeated DNA sequences [called switch, or S, regions located upstream of each of the heavy chain constant (CH ) region genes, except Cδ]. The recombination is initiated by the B cell– specific activation-induced cytidine deaminase (AID), which deaminates cytosines in both the donor and acceptor S regions. AID activity converts several dC bases to dU bases in each S region, and the dU bases are then excised by the uracil DNA glycosylase UNG; the resulting abasic sites are nicked by apurinic/apyrimidinic endonuclease (APE). AID attacks both strands of transcriptionally active S regions, but how transcription promotes AID targeting is not entirely clear. Mismatch repair proteins are then involved in converting the resulting single-strand DNA breaks to double-strand breaks with DNA ends appropriate for end-joining recombination. Proteins required for the subsequent S-S recombination include DNA-PK, ATM, Mre11-Rad50-Nbs1, γH2AX, 53BP1, Mdc1, and XRCC4ligase IV. These proteins are important for faithful joining of S regions, and in their absence aberrant recombination and chromosomal translocations involving S regions occur.
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INTRODUCTION AND OVERVIEW
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CSR: class switch recombination SHM (somatic hypermutation): the process that introduces mostly single-nucleotide mutations into the variable regions of antibodies after antigen activation during infection or after immunization AID: activation-induced cytidine deaminase GC (germinal centers): highly dividing B cells undergoing SHM that form in B cell follicles in spleen and lymph nodes during a T cell–dependent immune response
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Antibody class, or isotype, is determined by the heavy chain constant (CH ) region, which is important for determining the antibody’s effector function. The CH region is bound by cell-surface receptors, e.g., Fc receptors on many cell types and poly immunoglobulin (Ig) receptors on mucosal epithelial cells, and also by complement. Different CH regions have different affinities for these proteins, thus greatly influencing antibody function and determining whether antibody-antigen complexes will activate cells that help to eliminate pathogens, e.g., macrophages, NK cells, or mast cells. Also, the CH region determines whether an antibody can be transcytosed through epithelial membranes at mucosal surfaces, can diffuse into tissues, and will polymerize and thereby have a greater avidity. The CH region also influences the stability of the antibody (reviewed in 1). The membrane-bound forms of the various isotypes differ in their intracytoplasmic carboxy termini; the different termini result in varying abilities to associate at cell membranes with intracellular signaling proteins, although the biological roles of these differences are not yet understood (2–4). Ig isotype switching occurs by an intrachromosomal deletional recombination event, diagrammed in Figure 1 for the mouse H chain locus. The human H chain locus is similarly organized but not identical. Class switch recombination (CSR) occurs between switch (S) regions located upstream of each of the CH regions except Cδ and results in a change from IgM and IgD expression by naive B cells to expression of one of the downstream isotypes. IgD expression occurs by alternative transcription termination/splicing of the CμCδ genes. S regions consist of tandem repeats of short G-rich sequences (20–80 bp), which differ for each isotype, with an overall length varying from ∼1 kb to 12 kb, and CSR can occur anywhere within or near the S regions (5, 6). CSR occurs by an end-joining type of
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recombination, rather than by homologous recombination (7, 8). CSR and somatic hypermutation (SHM) are initiated by activation-induced cytidine deaminase (AID), which converts cytosines in S regions and Ig variable regions to uracils by deamination (9–14). Subsequent repair of the dU residues leads to single-strand DNA breaks (SSBs) that must be converted to double-strand breaks (DSBs) within the donor Sμ region and within an acceptor Sx region, to initiate the process of intrachromosomal DNA recombination. This review focuses mainly on the overall mechanism of CSR, which is discussed in the next section. Although there are interesting similarities and differences between CSR and SHM, we do not discuss them owing to space constraints. SHM is reviewed in another article in this volume by M.D. Scharff (15). Also, we do not extensively review all the information available about AID, as this protein is extensively discussed in the Scharff article (15) and in several other reviews (16–19). B cells undergo antibody, or Ig, class switching in vivo after immunization or infection or upon appropriate activation in culture. Engagement of the CD40 receptor on B cells by CD154 (CD40L) or, specifically for mouse B cells, the Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS), provides crucial signaling for CSR. AID expression is induced in mouse splenic B cells activated to switch in culture, and also in vivo, with especially high levels detected in germinal center (GC) B cells, which are undergoing SHM and probably CSR (9, 20, 21). Most investigations into the roles of various genes in CSR examine their effects in mouse splenic B cells induced to switch in culture. This model allows one to use the numerous mouse gene knockout models and also ensures that the effects of the genes are B cell intrinsic and not due to effects on other cell types. CSR requires cell proliferation, appearing to require a minimum of two complete rounds of cell division for IgG and IgA CSR and perhaps additional rounds for IgE CSR
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Heavy chain genes in IgM-expressing cells VDJ
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Figure 1 Diagram of Ig class switch recombination (CSR) to IgA. (a) The mouse IgH locus in B cells expressing IgM and IgD (by alternative RNA transcription/processing). During CSR, activation-induced cytidine deaminase (AID) deaminates dC residues in the top and bottom strands of transcriptionally active S regions (Sμ and Sα in the diagram shown), initiating a process (described in the text) that results in double-strand DNA breaks (DSBs) in both S regions and CSR by intrachromosomal deletion (b). (c) The IgH locus after CSR to IgA. Splicing diagrams of the μ, δ mRNAs and the germline α transcript are indicated below the diagram of the locus. Similar germline transcripts are induced from unrearranged Cγ, Cε, and Cα genes, depending on the cytokine stimulation received by the B cell.
(22–25). This requirement appears to be at least partly due to the requirements for induction of AID expression (25). Transcription of AID mRNA is induced synergistically by IL4 and CD40 signaling via induction of Stat6 and NF-κB transcription factors (26). However, these signals are very rapid. Pax5 is also essential for AID mRNA transcription, and Pax5 binds to the AID promoter in LPS+IL4-treated splenic B cells (27). Most interestingly, binding of Pax5 to the AID promoter is not detected until two days after addition of the activators, suggesting that the kinetics
of Pax5 binding might be important for explaining the requirement for cell division for AID induction. Furthermore, AID function is regulated by active export from the nucleus (28–30), which might also contribute to the delay in CSR. Naive B cells have the potential to switch to any isotype, and cytokines secreted by T cells and other cells direct the isotype switch (reviewed in 7, 31, 32). Although there is more to be discovered, the predominant mechanism for regulating isotype specificity is by regulation of transcription through S regions, www.annualreviews.org • Class Switch Recombination
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BER (base excision repair): a ubiquitous repair pathway that repairs damaged DNA bases
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and only transcriptionally active S regions undergo CSR. The regulation of isotype specificity is further discussed in the section on “Regulation of Switching.”
MECHANISM OF CSR
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Recently, the greatest progress in the field of CSR has occurred in identifying and understanding the roles of the enzymes and proteins involved in both creating DNA breaks and recombining the S regions. This, then, is the focus of our review. In this section, we start with the enzymes that create the DSBs required for CSR and then discuss the joining mechanism and its regulation. We restrict our discussion to proteins known to contribute to CSR and do not mention proteins shown not to be involved or for which the contribution is only suggestive or might have only minor effects. Pan-Hammarstrom et al. (33) comprehensively reviewed which DNA repair proteins are involved in V(D)J, CSR, and/or SHM. Other recent reviews discuss the mechanism and regulation of CSR (18, 34–37).
Creation of DSBs for CSR A reasonably convincing model for how single-strand breaks (SSBs) are introduced into S regions and how they are converted to the DSBs required for CSR has been developed in recent years. After initiation of the process by AID, the base excision repair (BER) pathway creates the SSBs, and if the SSBs on opposite strands are sufficiently near, this results in a DSB. However, conversion of more distal SSBs to DSBs appears to require another DNA repair pathway, mismatch repair (MMR). The proteins and their function at each step in this process are discussed in this section. Activation-induced cytidine deaminase (AID). The finding that AID is essential for both CSR and SHM was a major breakthrough for these fields (9, 10). Although originally investigators postulated that AID is an 264
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RNA-editing enzyme, owing to its homology with the RNA-editing cytidine deaminase APOBEC-1 (9), a second major breakthrough came with the discovery that the role of AID is to initiate these processes by deamination of dC nucleotides within S regions and antibody variable regions (11–14, 38, 39). In 2000, a model was proposed by Poltoratsky et al. (40) for how deamination of dC in DNA could lead to the SSBs required for CSR, and shortly thereafter Petersen-Mahrt et al. (11) provided evidence for this model. This model is now supported by numerous studies. Using the technique of linker-ligation-mediated PCR (LM-PCR), researchers demonstrated that AID is required for generation of S region DSBs in both mouse and human B cells (21, 41, 42). Also, localization of γH2AX foci at the Ig locus during CSR is AID-dependent (43). Figure 2a presents the portion of this model that is relevant for CSR. Purified recombinant AID converts dC to dU nucleotides in single-stranded (ss) DNA and in supercoiled transcribed plasmids (12– 16, 18, 44–46). It is clear that ssDNA but not dsDNA is the AID substrate. When transcribed duplex DNA substrates are used in vitro or in Escherichia coli, the nontranscribed strand (top strand if the DNA sequence is oriented with the 5 side to the left) is preferentially targeted. This may be because the nontranscribed strand in these substrates is single-stranded at the small bubble formed by RNA polymerase, whereas the transcribed strand is transiently hydrogen bonded to RNA (12, 14, 44, 47). However, both strands can be targeted by AID in vitro in transcribed supercoiled plasmid DNA, presumably because single-strand extrusions can occur in supercoiled plasmids (45, 46). It is clear that in B cells, dC on both transcribed and nontranscribed strands is equally mutated in proportion to its distribution in V genes and S regions, indicating that AID attacks both strands (48–50). AID preferentially, but not exclusively, deaminates the underlined dC in WRC (W = A or T, R = purine, Y = pyrimidine), the
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Figure 2 Diagrams of (a) model for generation of DNA breaks, mutations, and translocations in IgS regions by AID-UNG-APE and (b) model for conversion of SSBs to DSBs by mismatch repair. (a) AID deaminates dC, resulting in dU bases, which are excised by one of the uracil DNA glycosylases, UNG. Abasic sites are cut by AP-endonuclease (APE1 and APE2) (74), creating SSBs that can spontaneously form DSBs if they are near each other on opposite DNA strands, or, if not, mismatch repair activity converts them to DSBs (see b). Alternatively, DNA Pol β can correctly repair the nick, preventing CSR, or error-prone translesion polymerases can repair the nick but introduce mutations. Finally, the DNA breaks can lead to aberrant recombinations/translocations. (b) AID is hypothesized to introduce several dU residues in S regions during one cell cycle. Some of the dU residues are excised by UNG, and some of the abasic sites are nicked by APE. The U:G mismatches that remain would be substrates for Msh2-Msh6 (100). Msh2-Msh6, along with Mlh1-Pms2, recruit Exo1 (and accessory proteins) to a nearby 5 nick, from where Exo1 begins to excise toward the mismatch (90, 91), creating a DSB with a 5 single-strand overhang, which can be filled in by DNA polymerase. Fill-in synthesis is probably performed by translesion polymerases owing to the presence of abasic sites. Alternatively, the overhang is removed by a 5 flap endonuclease (Fen1) or by Exo1.
AID hotspot target (51–53), in transcribed targets in vitro (54), in oligonucleotide substrates (55), and in vivo (50). S regions contain numerous AID hotspot targets. However, experiments using purified recombinant AID and plasmid DNA substrates suggest that AID is highly processive (14, 45, 54), and in this process AID deaminates many dC nucleotides
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APE (APE1 and APE2): apurinic/ apyrimidinic endonuclease, incises DNA at abasic sites
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by protein kinase A at S38 and T27, and alanine mutations at either of these sites nearly eliminate the ability of AID to initiate CSR when retrovirally transduced into aid−/− splenic B cells (56, 57, 58). Phosphorylation by protein kinase A is required for binding of AID by replication protein A, which enables AID to deaminate transcribed duplex DNA. Replication protein A appears to increase the interaction of AID with DNA. Another very interesting but not understood discovery about AID is that the C-terminal 10 amino acids of AID are required for CSR but not for SHM (59, 60). The C terminus may be required for interaction with a protein essential for CSR but not for SHM.
UNG. Removal of the dU residues by enzymes within the BER pathway is required to introduce the DNA breaks necessary for CSR (11, 21, 38). BER consists of highly active ubiquitous DNA repair pathways for repairing oxidized and deaminated bases, which are generated more than 104 times per cell per day by oxidation, especially during inflammation, and by spontaneous hydrolysis (61). There are four mammalian uracil DNA glycosylases in the BER pathway (i.e., enzymes that excise dU bases), UNG, SMUG1, MBD4, and TDG. CSR is reduced by 95% in B cells from UNGdeficient mice and in patients that have deleterious mutations in UNG (21, 38, 62). Furthermore, S region DSBs are also greatly reduced in ung−/− mouse splenic B cells induced to undergo CSR (21). Thus, it is reasonable to conclude that UNG is the uracil DNA glycosylase that excises the dU residue created by AID activity. Two other uracil glycosylases (MBD4 and SMUG1) appear to have no role in CSR (38, 63). However, when SMUG1 is greatly overexpressed by retroviral transduction, it can support a limited amount of CSR in ung−/− cells, although in the presence of UNG, SMUG1 actually inhibits CSR (64). These data suggest that UNG may be specifically recruited to sites of AID activity and perhaps has a unique property that makes it the 266
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preferred uracil DNA glycosylase for generation of the DNA breaks required for CSR. Apurinic/apyrimidinic endonuclease (AP endonuclease/APE). The BER enzyme that repairs the abasic sites left by UNG activity is APE, which incises the phosphate backbone of DNA at abasic sites, producing SSBs (61). In mammals, there are three enzymes with AP endonuclease activity, APE1 and APE2, which share homology (65), and a very different, recently discovered enzyme, PALF/APLF/XIP1 (66–68). The main AP endonuclease known to be involved in BER is APE1. APE1 endonuclease activity is essential for early embryonic development and for viability of human cell lines (69, 70). Much less is known about APE2, which is encoded on the X chromosome. APE2-deficient mice show a slight growth defect and have a twofold reduction of white blood cells in the periphery, mainly affecting T and B cells (71). Enzyme assays using abasic site-containing oligonucleotide substrates showed that purified recombinant human APE2 has weaker AP endonuclease activity than APE1 (65, 72, 73). Examination of APE1- and/or APE2deficient mouse splenic B cells activated to switch in culture demonstrated that both of these enzymes contribute to CSR (74). Because APE1 is an essential gene, the investigators used ape1+/− mice, which have DNA repair defects (75, 76), although the phenotype was probably less severe than if ape1−/− mice could have been studied. Splenic B cells from mice deficient for APE2 and heterozygous for APE1 switch 60%–80% as well as wild-type B cells, depending on the isotype, and have very few S region DSBs, almost as few as in aid−/− cells, which have approximately 10% of wildtype (77). These cells divide in culture as well as wild-type cells, so the reduced CSR is not due to poor proliferation (74). Although CSR is modestly reduced, the much greater reduction in Sμ DSBs suggests that Sμ DSBs are not limiting for CSR. In wild-type cells, AID-dependent blunt and staggered DSBs in the Sμ region occur
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preferentially at G:C bp and at AID hotspot targets, with p values for blunt DSBs ≤ 0.002 relative to random (21, 74). This indicates that SSBs and DSBs occur at the dC nucleotides that are targeted by AID, as predicted by the DNA-deamination model (Figure 2a). In aid−/− or ung−/− or APE-deficient cells, DSBs do not specifically occur at AID hotspot targets, although B cells deficient in only one of the APEs maintain some specificity for AID targets (21, 74). These data suggest that APE1 and APE2 both serve as endonucleases to incise abasic sites introduced by AID and UNG. However, whether the third AP endonuclease PALF/APLF/XIP-1 also has a role is unknown. DNA polymerase β (Pol β). In the canonical BER pathway, the single-nucleotide gap generated by the action of UNG and APE is filled in by DNA polymerase β (Pol β) (78, 79). A multiprotein complex that can perform BER and that contains UNG2 (nuclear form of UNG), APE1, Pol β, replicative DNA polymerases δ and ε, XRCC1, and DNA ligase I has been isolated from both proliferating and growth-arrested HeLa cells and also from human peripheral blood lymphocytes (80, 81). Furthermore, physical interactions among BER enzymes increase repair efficiency (82–84). These findings suggest that BER will proceed to completion once it is initiated by UNG. Therefore, Pol β activity could reduce SSBs and therefore reduce CSR. Hence, an intriguing question arises as to how S region breaks are spared from faithful repair. One appealing hypothesis is that BER components downstream of UNG and APE might be downregulated in cells undergoing CSR or specifically prevented from accessing S region lesions. As Pol β is recruited by APE1 (78), the levels of Pol β or its activity may be inhibited during CSR, or APE2 may not recruit Pol β, which could explain why APE2 is used for CSR. Alternatively, the introduction of numerous S region lesions may overwhelm the BER machinery, although BER activity is not inhibited during CSR. A recent
report supports the second alternative (85). Pol β levels were increased in nuclear extracts from mouse splenic B cells induced to undergo CSR, and chromatin immunoprecipitation showed that Pol β associates specifically with the Sμ region, but not with Cμ or Cα genes, in switching B cells. Although Pol β–deficient mice die in utero, one can obtain polβ −/− splenic B cells by transfer of polβ −/− fetal liver cells into irradiated wild-type mice. Using polβ −/− and polβ +/+ splenic B cells obtained by fetal liver transfer, investigators found that polβ −/− cells actually show modestly increased CSR (1.5to 1.7-fold) to a subset of isotypes (IgG2a, IgG2b, and IgG3) relative to polβ +/+ controls. Furthermore, LM-PCR experiments showed that polβ −/− cells have a two- to threefold increase in Sμ and Sγ3 DSBs and a twofold increase in mutations in the germline (GL) Sμ and recombined Sμ segments. These data indicate that Pol β indeed functions to accurately repair AID-instigated SSBs but cannot repair them all, and the authors hypothesize that Pol β only inhibits switching when SSBs are limiting (85). If B cells were to downregulate BER during CSR, this could be dangerous, given the great amount of reactive oxygen species produced during B cell activation and proliferation (86). Therefore, it is plausible that instead a mechanism is adopted that endows S regions with such numerous AID targets that the ability of BER to repair them is overwhelmed, rather than abrogating overall BER ability and thus jeopardizing the integrity of the B cell genome. Consistent with this hypothesis is the finding that, in ung−/− msh2−/− B cells, AID introduces many more lesions into the Sμ region than result in mutations in wild-type cells, most likely because they are correctly repaired in wildtype cells (50). Furthermore, recent experiments show that artificially introduced I-SceI sites in Sμ and Sγ1 regions mediate CSR to IgG1. These experiments suggest that only a single DSB in the donor and acceptor S region is sufficient for CSR (87). Introduction of www.annualreviews.org • Class Switch Recombination
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numerous dU residues increases the likelihood of DSBs occurring in the donor and acceptor S regions simultaneously. In conclusion, Pol β may function normally during CSR to repair AID-initiated DNA lesions, but the numerous AID lesions overwhelm it, and thus some breaks remain unrepaired. Role of mismatch repair in CSR: to convert SSBs to DSBs. A second repair pathway, mismatch repair (MMR), contributes to CSR but is not essential. The major role of MMR in all cells is to correct misincorporated nucleotides during DNA synthesis (88). This process involves recognition of the mismatch by a heterodimer of Msh2-Msh6 (for nucleotide substitutions and small loops) or Msh2-Msh3 (for larger loops), followed by recruitment of the Mlh1-Pms2 heterodimer (88). The combined heterotetramer recruits replication factor C, the processivity factor proliferating cell nuclear antigen (PCNA), and Exonuclease1 (Exo1) to a nearby nick, and together they excise the single-strand segment containing the mutated nucleotide (89, 90). The excised single-strand patch can be hundreds of nucleotides long in vitro, but the length in vivo is unknown. MMR specifically repairs the newly synthesized DNA strand, probably because of its predilection to excise and resynthesize the nicked DNA strand (91). In mice that lack one of the MMR genes (Msh2, Msh6, Mlh1, Pms2, or Exo1), CSR is reduced by two- to sevenfold, depending on the gene and the Ig isotype (92–98). The most attractive model for the role of MMR during CSR is to convert SSBs that are not near each other on the opposite DNA strands to DSBs (77, 99). If the SSBs that are introduced by AID-UNG-APE are near each other on opposite DNA strands, they can spontaneously form a DSB, but if not, the SSBs do not destabilize the duplex and are simply repaired. As S regions are large and the breaks appear to occur anywhere within S regions (5, 6, 21), it seems unlikely that the SSBs would be sufficiently proximal to form a DSB most of the time. MMR could conStavnezer
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vert these distal SSBs to the DSBs that are required for CSR. Figure 2b presents a model for how MMR could do this (99). Msh2-Msh6 can recognize and bind U:G mismatches created by AID activity (100). Mlh1-Pms2 would be recruited and Exo1 would excise from the nearest 5 SSB created by AID-UNG-APE activity toward the mismatched dU:dG. Exo1 is hypothesized to continue past the mismatch until it reaches a SSB on the other strand, thus creating a DSB. Several additional experimental results support this model. First, B cells in which the tandem repeats of Sμ have been deleted (SμTR−/− ), which thus have very few AID hotspot targets, only show a ∼twofold reduction in CSR (101). However, in these B cells, CSR is nearly ablated in the absence of Msh2 or Mlh1 (77, 102; J. Eccleston, C.E. Schrader, J. Stavnezer & E. Selsing, manuscript in preparation). Second, IgG2a, the isotype with the fewest AID hotspot targets in its S region, is the isotype most dependent upon MMR (93). Third, the great majority of S-S junctions in msh2−/− B cells occurs within the Sμ tandem repeat region, whereas in wild-type cells they can also occur upstream of Sμ, where the AID hotspot targets are infrequent (92). Fourth, the S-S junctions differ between wild-type and MMR-deficient B cells as to the lengths of microhomology between the donor (Sμ) and acceptor (downstream) S regions. This suggests that MMR is involved in end processing from the sites of the SSBs, resulting in different lengths of single-stranded tails that can participate in homology search during S-S recombination (94, 95, 98, 103). Fifth and most importantly, LMPCR experiments show that MMR-deficient B cells have fewer S region DSBs than do wildtype B cells (77). End processing and mutations. After DSB formation, 5 or 3 single-strand overhangs remain. These tails must be either excised or filled in to create blunt, or nearly blunt, DSBs appropriate for an end-joining recombination with the other S region. The
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structure-specific endonuclease ERCC1XPF excises 3 single-strand tails at the junction with dsDNA and has a minor role in CSR (104). MMR normally recruits PCNA and replicative DNA polymerase for fill-in synthesis of 5 overhangs (88). However, replicative Pol cannot replicate past an abasic site, resulting in the recruitment of error-prone translesion Pols. Msh2-Msh6 recruit the translesion Pol η (100), which is the most important translesion Pol for introducing mutations at A:T bps into V region genes and into both unrecombined (GL) Sμ and recombined S-S junction regions during CSR (105, 106). There are numerous mutations at both A:T and G:C bp in the regions surrounding S-S junctions (107, 108, 145). The mutations at G:C bp could be due to fill-in DNA synthesis across dU nucleotides by replicative Pols or across abasic sites, probably by the translesion DNA Pol θ (109–111). Additionally, not all mutations in S regions are likely to be due to fill-in DNA synthesis after creation of DSBs. It is likely that sometimes the excision by Exo1 does not lead to DSBs, but instead the single-strand patch is simply repaired by translesion Pols. Also, sometimes DSBs will form that do not successfully synapse with acceptor downstream S regions and that result in internal Sμ deletions rather than S-S recombination (112, 113).
Joining of Donor and Acceptor S Regions After formation of the DSBs in the donor and acceptor S regions, the S regions are recombined using ubiquitous proteins that perform nonhomologous end-joining (NHEJ) in all cell types. These proteins are observed within a complex visible by in situ immunofluorescence in cells that have been treated with gamma radiation to induce DSBs, which is consistent with the fact that these proteins are involved in repair of DSBs after gamma radiation as well as repair of DSBs generated during CSR. Many of these proteins are also
involved in V(D)J recombination during lymphocyte development. S-S recombination occurs by an endjoining type of recombination. DNA DSBs can be induced by ionizing radiation or during repair of oxidative damage or replication. Numerous ubiquitous repair proteins exist that rapidly repair DSBs in all cells, many of which are also involved in CSR. DSBs produced during DNA replication or during G2 phase of the cell cycle are generally repaired by homologous recombination, as there is a chromosomal homolog that can be copied. However, S region DSBs in B cells induced during CSR are generated and resolved during G1 phase (77), and S regions lack sufficient homology to undergo homologous recombination. Four proteins known to be essential for NHEJ, Ku70, Ku80, and the two-protein ligase complex XRCC4-ligase IV, are very important for CSR (113–120). Ku70-Ku80 binds to the DNA ends and serves as a tool belt for the end-joining reaction by recruiting enzymes that effect the recombination. Ku70Ku80 improves the binding of XRCC4-ligase IV to DNA ends (121–123). Although Kudeficient cells apoptose upon induction of CSR, Reina-San-Martin et al. (113) showed by CFSE staining that, at each cell division, CSR in the few viable ku80−/− cells is nearly ablated. These investigators also increased cell viability by expressing Bcl2 from a transgene in ku80−/− cells and again showed that CSR is nearly ablated. XRCC4 or ligase IV deficiency is incompatible with life owing to problems during brain development, although human patients with hypomorphic mutations have been described, and mice with deficiencies have been created (120, 124, 125). Mice entirely lacking XRCC4 were produced by mating xrcc4+/− mice with p53-deficient mice, allowing survival of xrcc4−/− mice, which have ∼25% of normal levels of CSR, indicating that XRCC4 is important but not essential for CSR (125). Also, humans with mutations in ligase IV have fewer peripheral blood cells that have www.annualreviews.org • Class Switch Recombination
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ATM (ataxia telangiectasia mutated): a phosphoinositol 3-kinase-like kinase, which is mutated in the human syndrome Ataxia telangiectasia
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undergone CSR than normal controls (119). Examination of the S-S junctions in the xrcc4−/− mouse B cells and in the human patients demonstrated that the S-S junctions are aberrant, as they have greatly increased lengths of junctional microhomology (119, 125). Numerous studies have shown that SS junctions in wild-type mice or normal individuals show very little microhomology, or identity, between the donor Sμ and acceptor S regions at the junction, usually 0 or 1 bp of identity (5), consistent with recombination by NHEJ. In contrast, in the xrcc4−/− mice and human ligase IV hypomorphs, many junctions have up to 10 bp or more of identity. Taken together, the data indicate that CSR occurs by NHEJ but can also occur by an alternative type of end-joining reaction that favors the use of microhomologies. XRCC4-ligase IV in the presence of Ku70-Ku80 ligates incompatible ends, consistent with the lack of microhomology at S-S junctions in wild-type cells (126). It is unknown, however, whether in wild-type cells the alternative pathway is actually used. A fundamental unanswered question regarding the joining process is whether the donor and acceptor S regions are in close proximity before AID attacks the donor (Sμ) or acceptor (downstream) S region. It is attractive to expect that they are preassociated in order to increase the likelihood of correct S-S recombination. This association could be directed to the correct S region by GL transcription. Another reasonable possibility is that the association occurs immediately after AID attacks Sμ. In situ studies suggest that the Ig loci form loops, apparently bringing the V and J genes in proximity prior to V(D)J recombination (127, 128). Mre11-Rad50-Nbs1. Accumulating evidence indicates that this complex of three proteins (MRN complex) travels along the DNA duplex scanning for DNA breaks and that MRN binds DSBs within seconds of their formation (129, 130). However, owing to its great abundance, Ku is likely to bind
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DSBs even faster during CSR (see the section below, Ku70-Ku80-DNA-PKcs). When a DSB is encountered, the conformation of Mre11 and Rad50 changes, resulting in unwinding the DNA ends at the break. Mre11 is a globular protein associated with the DNA, whereas Rad50 forms a long coiled-coil that at its middle abruptly reverses direction, forming a loop with a zinc hook at its apex. The hooks from two Rad50 molecules associate homotypically, and this is thought to be important for holding two DNA duplexes together at the DSB (131, 132). Once bound to a DSB, the kinase ataxia telangiectasia mutated (ATM) binds the complex via Nbs1, becomes activated, and phosphorylates several substrates, among which are Nbs1, 53BP1, p53, Chk2, and H2AX, causing a further accumulation of MRN and several other repair proteins and also activating cell-cycle checkpoints (133– 135) (Figure 3). Thus, MRN is upstream of a cascade of events that function to sense the DSB, resulting in repair by end joining or by homologous recombination. Null mutations in any component of MRN are lethal, and hypomorphic mutations result in aberrant chromosomes and translocations (136) and the disease syndromes Nijmegen breakage syndrome (Nbs-1 mutations) and ataxia-telangiectasia-like disorder (Mre11 mutations), characterized by increased sensitivity to ionizing radiation and other DSB-inducing agents (137, 138). Two groups have shown that CSR is reduced two- to threefold in cultured splenic B cells from mice in which the Nbs1 gene is inactivated by a conditional mutation (136, 139). The reduced CSR was analyzed in cells stained with CFSE, measuring switched cells at each cell division, as cell viability and proliferation are reduced in the mutant cells. Because some Nbs1 remains in the cells, these are most likely underestimates of the importance of Nbs1 for CSR. When wildtype mouse splenic B cells are treated with switch inducers in culture, the Sμ region undergoes rare translocations with the c-myc
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DNA-PKcs H4-K20me2 H2AX
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CH3 CH3
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P ATM
Cell-cycle regulation, apoptosis Figure 3 Proteins that bind to DSBs that are involved in CSR. The evidence supporting this diagram is discussed in the text. DNA-PK, which consists of Ku70-Ku80 and DNA-PKcs, most likely binds DSB ends first. Mre11-Rad50-Nbs1 (MRN) probably binds next, perhaps helping to hold the DNA ends together, and MRN recruits and activates ATM (ataxia telangiectasia mutated), which phosphorylates H2AX, 53BP1, and Mdc1, resulting in accumulation of large amounts of these proteins and MRN around the DSB sites. After the DNA ends are brought sufficiently near by activities of these other proteins, DNA-PK can hold the DNA ends in the correct position for recombination. These proteins are all important for correct S-S recombination, and they inhibit aberrant recombinations and translocations. ATM also phosphorylates proteins that regulate the cell cycle and induce apoptosis, but nothing is known about how important this is during CSR.
gene, which is located on a different chromosome (140–142). This translocation is AIDdependent and, most interestingly, occurs six times more frequently in Nbs1-hypomorph B cells than in wild-type B cells (140, 143). Patients with hypomorphic mutations in Nbs1 or Mre11 also have a lower percentage of peripheral blood lymphocytes that have undergone CSR, as assayed by detection of Sμ-Sα junctions in these cells (33, 144, 145). Further evidence for the participation of Nbs1 in CSR is the demonstration by immunocytochemistry-fluorescence in situ hybridization (immuno-FISH) that Nbs1 foci colocalize with the IgH loci, but not with Igκ loci, in wild-type, but not aid−/− , splenic B cells induced to undergo CSR (43). The finding of increased translocations with c-myc in MRN-deficient B cells suggests that the MRN
complex is involved in organizing efficient and accurate S-S recombination.
Ataxia telangiectasia mutated (ATM). ATM is a ser/thr protein kinase, a member of the phosphoinositol 3-kinase-like kinase (PIKK) family, which includes DNA-PKcs and ATR and which is involved in cell-cycle control and DNA damage responses. Upon activation by MRN, ATM accumulates at repair foci, orchestrates repair of the DSB, and initiates a cell-cycle checkpoint until repair is complete (146, 147). Recently, investigators demonstrated that V(D)J recombination is abnormal and that DSBs resulting from incomplete V(D)J recombination during lymphocyte development are maintained over several cell generations in atm−/− mice (148–150). www.annualreviews.org • Class Switch Recombination
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RAGs (recombinationactivating genes): initiate and are required for V(D)J recombination
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Thus, both repair and the cell-cycle checkpoints are compromised, as atm−/− lymphocytes continue to replicate despite chromosomal breaks (142, 143). CSR is reduced about threefold at each cell division cycle in cultured atm−/− splenic B cells relative to wild-type B cells (151, 152). Also, lower titers of switched antibodies are detected in sera after immunization. However, GL transcripts are expressed at normal levels. In B cells induced to switch in culture, the Sμ region undergoes translocations with the c-myc gene eight times more frequently in atm−/− cells than in wild-type cells (143). Thus, it seems likely that when atm−/− B cells are activated to switch, DSBs are generated as usual, are maintained longer than usual, and do not undergo normal Sμ-Sx recombination; this can result in aberrant recombinations with other chromosomes. Ataxia telangiectasia patients often have IgA and IgG deficiencies and have peripheral blood lymphocytes with fewer Sμ-Sα junctions than normal individuals, similar to patients with mutated Nbs1 or Mre11 and consistent with reduced CSR (33, 144). Thus, during CSR, ATM likely organizes the repair complex and perhaps halts the cell cycle, and it contributes to the correct positioning of DSBs together during the long-range interaction required for accurate S-S recombination. In the absence of ATM, prolonged duration of unrepaired DSBs and aberrant recombination events result in translocations. 53BP1. 53BP1 was first discovered in a yeast two-hybrid screen as a protein that binds p53 (153). 53BP1 is a transcriptional coactivator for p53, binding through its tandem Tudor domains to p53 dimethylated at lysine 370 (154). However, this is not its only function. 53BP1 accumulates at DSBs within 2 min after ionizing radiation treatment (155). Its initial recruitment to DSBs does not depend on any other known protein, including Nbs1, ATM, or DNA-PK (156), although its subsequent accumulation in foci does depend on γH2AX and Mdc1 (157–159). 53BP1 func-
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tions to induce phosphorylation of ATM and ATR (160), and thus it might also increase MRN activity and MRN’s accumulation at DSBs. Strikingly, CSR is reduced about 90% in cultured 53bp1−/− splenic B cells relative to wild-type B cells, which is not due to decreased cell proliferation nor to reduced GL transcripts. Serum IgG, IgE, and IgA isotypes are reduced even more, although IgM levels are normal (161, 162). The S-S junctions are normal. 53BP1-deficient cells do not have a dramatic increase in general chromosome instability, unlike atm−/− and h2ax−/− cells, but a much higher proportion of the chromosomal aberrancies in 53bp1−/− cells involve the IgH locus, suggesting that 53BP1 has a special role at this locus (142, 159). Another hint about the role of 53BP1 in CSR comes from the finding that there is a threefold increase in internal deletions within S regions in IgM hybridomas produced from 53bp1−/− B cells induced to undergo CSR in culture in comparison to IgM hybridomas from wildtype mice (163). Interestingly, these deletions are not increased in atm−/− or h2ax−/− B cells, despite the general increase in unrepaired DSBs in the genome. These results suggest that 53BP1 might also be important for bringing together, or synapsing, the donor Sμ and downstream S regions (159, 161). How 53BP1 performs this role, however, is completely unknown. This role would be consistent with the lack of a role for 53BP1 during V(D)J joining because the RAG complex itself possesses synaptic activity (161, 162). Mammalian 53BP1 binds dimethyl-lysine 20 of histone H4 (H4-K20-me2), but not mono- or trimethyl K20, via its Tudor domains (164). Most interestingly, 53BP1 with single amino acid mutations within the Tudor domains that prevent H4-K20me2-binding and RNAi-mediated knockdown of PrSet7/Set8, the histone methyltransferase that monomethylates K20 (a prerequisite for the dimethylation), decrease 53BP1 foci (164). Association of 53BP1 with
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irradiation-induced foci is disrupted by RNase A treatment, suggesting that there may be an RNA component involved in its binding (155). Taken together, H4-K20-me2 may be important for recruiting 53BP1 to chromatin, perhaps to the IgH locus, although this modification would probably need to be present before induction of DSBs during CSR because 53BP1 binding to DSBs is so rapid. The GL RNA transcribed from S regions may help 53BP1 recruitment. This hypothesis requires that the H4-K20-me2 mark is associated with actively transcribed regions on the IgH locus during G1 phase, which would differ from its distribution on bulk chromatin. γH2AX (phosphorylated form of H2AX). H2AX is a variant of histone H2A, representing about 15% of the cellular pool of H2A. It is randomly incorporated into nucleosomes (165). Within seconds after formation of a DSB induced by ionizing radiation or by a restriction enzyme, the extended C-terminal tail of H2AX is phosphorylated by a PIKK kinase, most frequently ATM (166, 167), and this phosphorylation spreads over a region estimated to span up to a megabase surrounding the break (147, 168). In fact, the peak accumulation of γH2AX (phosphorylated H2AX) is not directly at the DSB but instead located at 8–10 kb on either side in mammals (168). ATM also phosphorylates 53BP1, Nbs1, and Mdc1, which then all bind the phosphorylated tail of γH2AX, which serves as a docking site for these proteins. This phosphorylation results in a rapid assembly of these factors, plus Mre11, Rad50, and Brca1, into a large multiprotein complex. γH2AX is required for the accumulation of these proteins into foci near DSBs (169, 170). However, mice lacking H2AX can still repair DSBs, although with lower efficiency, and they can still induce cellcycle checkpoints (169), probably because the initial assembly of repair proteins, including MRN, ATM, and 53BP1, does not depend on γH2AX (157). CSR is markedly reduced in H2AXdeficient mice. In vitro CSR to IgG3 and IgG1
is reduced to ∼25%–30% of wild-type, and this is not due to defective cell proliferation. The antigen-specific IgG1 response to immunization is reduced to about 30% of wild-type mice, and nonimmune serum levels of IgG1, IgG3, and IgA are all reduced to 15%–50% of wild-type (43, 113, 142, 169). Similar to cells deficient in either ATM, 53BP1, or Mdc1 or cells having Mre11 or Nbs1 hypomorphic mutations, h2ax−/− B cells show numerous chromosome breaks and aberrant recombination events (142, 143, 169, 171). In h2ax−/− B cells induced to switch in culture, there is a greater than tenfold increase in AID-dependent chromosome breaks within the IgH locus relative to wild-type cells, resulting in separation of the V genes and 3 end of the CH genes and translocations in metaphase chromosome spreads (142). The breaks occur on both chromatids, indicating that they occur prior to S phase, consistent with evidence that S region DSBs are observed in G1 phase (77). Also, foci containing γH2AX (and Nbs1) colocalize with the IgH locus in mouse splenic B cells induced to switch, in wild-type cells in the G1/early S phase of the cell cycle, but not in aid−/− cells, as detected by immuno-FISH (43). Taken together, these data suggest that γH2AX, like MRN, Mdc1, ATM, and 53BP1, is involved in holding AID-initiated DSBs in a structure that promotes accurate synapsis between Sμ and the downstream acceptor S region and also prevents recombinations with DSBs on other chromosomes.
Mdc1 (mediator of DNA damage checkpoint protein 1). Mdc1 is a mediator protein that is recruited to DSBs by binding to Nbs1 and is phosphorylated by ATM (172, 173). Mdc1 subsequently recruits ATM to γH2AX and is required for accumulation of γH2AX at DSBs (167, 173). Without Mdc1, the initial recruitment by MRN of ATM and γH2AX occurs, but the complexes are unstable and do not form the large repair foci observed in wildtype cells. CSR in cultured mdc1−/− B cells is www.annualreviews.org • Class Switch Recombination
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only mildly reduced, to about 50%–70% of wild-type B cells (167).
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Ku70-Ku80, DNA-PKcs. The proteins discussed above are all involved in repairing DSBs both by end joining and by homologous recombination. However, Ku70 and Ku80 are only involved in end joining and appear to prevent the use of homologies during recombination. Ku70-Ku80 binds DNA ends at DSBs and telomeres and mediates synapsis of the two DNA ends, positioning the ends to allow end processing and direct end-to-end joining (174, 175). Ku70-Ku80 forms a ring with a broad base that encircles DNA and can only dissociate at an end (176). After binding, Ku slides away from the ends, allowing the catalytic subunit, the kinase DNA-PKcs, to bind to each end (177). Ku binds the nuclear matrix, and this binding might localize the DSBs and telomeres to the matrix (178). DNA-PKcs is transphosphorylated by the other DNA-PKcs bound at the other end of the DSB and also phosphorylates Ku70, Ku80, and XRCC4 (175, 179). Thus, DNA-PK appears to be acting both as an activator and scaffold during the actual ligation event. DNA-PKcs has several transautophosphorylation sites, and mutation studies demonstrate that their phosphorylation regulates the accessibility of the DNA ends to end-processing activities required for recombination (179). All three components of the DNA-PK holocomplex are involved in CSR, as they are essential for NHEJ, although Ku70 and Ku80 are much more important than DNA-PKcs. All three proteins are essential for V(D)J recombination, which occurs by NHEJ, so mice lacking any of these proteins do not develop B cells, unless they are supplied with transgenic (Tg) recombined heavy (H) and light (L) chain genes. Ku70- and Ku80-deficient B cells reconstituted with a Tg L chain gene and a H chain gene knocked into the endogenous locus do not have switched isotypes in their serum nor do they undergo CSR when induced to switch in culture, although they 274
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have normal levels of GL transcripts (113, 117, 118). Unlike wild-type cells, internal Sμ deletions do not occur in ku80−/− cells (113). These data suggest that Ku80-deficient B cells that sustain DNA breaks owing to AID activity cannot recombine these DSBs, even by internal Sμ deletions, and therefore die. This would also explain why cells with mutations in the unrecombined Sμ segment are not observed in ku80−/− cells (113). Although the investigators did not demonstrate that ku80−/− cells express AID, this is highly likely. It is puzzling, however, that transition mutations that result from dU bases being replicated prior to UNG and APE activity, which would not lead to DNA breaks, were not observed in the GL Sμ. Perhaps Sμ regions with dU bases also have UNG-APE induced DNA breaks, resulting in death of these Ku-deficient cells. It is surprising that Ku is essential for CSR, although XRCC4 is not, given the evidence that CSR can occur by an alternative endjoining pathway. This suggests that Ku might have another function and perhaps even function in the alternative pathway. Also, Ku appears to be more important than MRN for CSR. Ku is one of the most abundant nuclear proteins (∼4 × 105 molecules per cell) and has a very high affinity for DNA ends (5 × 10−10 ) (174). Thus, it might bind prior to MRN. Perhaps MRN is more important for recruiting additional proteins involved in chromatin accessibility and perhaps for cellcycle regulation, whereas Ku is bound at the ends, positioning them precisely for recombination and for end processing by nucleases and polymerases and for recruiting XRCC4DNA ligase-IV (121, 122). It is interesting that Ku is required for V(D)J recombination, but MRN is not, suggesting that the synaptic activity of RAG cannot replace the role of Ku but can replace MRN. By contrast, DNA-PKcs is not essential for CSR, and its importance is controversial, with different results obtained by three different groups. DNA-PKcs deletion was reported to eliminate CSR in cultured B cells to every isotype except IgG1 (180, 181). Two
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groups (182, 183) studied B cells from scid mice, which have a deletion in the DNAPKcs gene resulting in loss of the C-terminal 83 amino acids, in barely detectable protein levels, and in no detectable kinase activity. These two groups found a smaller reduction in CSR. It was reduced to 25%–50% of wildtype for all isotypes in the study by Cook et al. (183), but CSR occurred at 50%–100% of wild-type, depending on the isotype, in the Bosma et al. (182) study. There was no difference in proliferation between the wild-type and DNA-PKcs-deficient B cells induced to switch, but there was more cell death in the mutant cell cultures (183). It is difficult to reconcile the different results among the three groups, except that Manis et al. (180, 181) studied mice with no DNA-PKcs, whereas the Bosma (182) and Cook (183) groups studied scid mice, suggesting that the tiny amount of protein present that lacks kinase activity has some function, perhaps as a scaffolding protein. The differences in CSR between the scid mice studied by the two groups might be due to different amounts of back-crossing, as B cells from different mouse strains have different abilities to switch (184). The role of DNA-PKcs in V(D)J recombination appears to be to stimulate the hairpin cutting activity of Artemis (185), which is consistent with its importance for joining the coding ends but not the signal ends. As CSR does not involve hairpin ends, and Artemis appears to have no role in CSR (181), DNAPKcs must have another role in CSR. This may involve its ability to regulate end processing, which may help recombination at some S-S junctions and possibly involves its ability to phosphorylate other proteins (174).
REGULATION OF SWITCHING Germline (GL) Transcripts As described above, CD40 and/or TLR stimulation provides essential activation for B cells to undergo CSR. Additionally, cytokines produced by T helper cells and dendritic cells de-
termine the isotype to which B cells will switch by inducing transcription from GL promoters located upstream, i.e., 5 , to each acceptor S region. The resulting GL transcripts do not encode proteins and are therefore also referred to as sterile RNAs. Figure 1 shows the transcription unit and splicing diagram for an example, GL α RNA. The exon located 5 to the S region is called the I exon. Each GL transcript has a similar transcription and splicing pattern (31). There is also a similar GL Sμ RNA, initiating near the μ intron enhancer. Gene-targeting experiments in which a single I exon and/or promoter for a specific GL transcript is deleted showed that GL transcription of the acceptor S region is required for CSR to that isotype and that the GL transcription only functions in cis, i.e., not on the other chromosome (186, 187). Surprisingly, deletion of the GL γ1 exon splice donor also prevents IgG1 CSR, although there is no known role for the spliced transcript (31, 188, 189). The role of splicing is an intriguing unanswered question. GL promoters have cytokine-responsive elements within them. GL γ1 and promoters, which are induced by IL-4, have binding sites for the IL-4-induced transcriptional activator Stat6. Several promoters have binding sites for NF-κB, which is induced in response to both CD40 and TLR signaling. GL γ2b and α promoters have binding sites for Smad and Runx, two factors induced by TGF-β, which induces CSR to IgG2b and IgA. A thorough review of GL transcriptional regulation was recently published (32). The function of GL transcription appears to be to direct AID to a specific S region and to make the S region a suitable substrate for AID. There are at least three possible roles for GL transcription, which are not mutually exclusive. First, the substrate for AID is ssDNA, and the act of transcription creates short regions of ssDNA at the transcription bubble. In addition, RNA transcribed from S regions is G-rich and therefore can form an RNA-DNA hybrid (R-loop) with the bottom C-rich DNA strand. This hybrid formation leaves the top www.annualreviews.org • Class Switch Recombination
R-loops: RNA-DNA hybrids that form cotranscriptionally if the DNA is highly G-rich, which results in extensive single-strand regions on the G-rich DNA strand
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G-rich DNA strand single-stranded over long stretches (190, 191), thereby making the top strand a target for AID. However, as AID appears to target both top and bottom strands equally in vivo (50), this makes the importance of R-loops unclear. Furthermore, when the Xenopus Sμ region, which is A:T rich and cannot form R-loops, is substituted into the Sγ1 locus by gene targeting, CSR is reduced only about twofold relative to a Sγ1 segment of the same length (192, 193). However, as R-loops form at both the Sμ and acceptor S regions normally, the effect of both R-loops might be to increase CSR by fourfold, which should be physiologically significant. Evidence suggests that R-loops at the Sμ region begin upstream of the tandem repeats, at a particular sequence GGGGCTGGG, which is within a zone that has a high content of G (50%) (190), and, interestingly, S-S junctions often involve sequences 5 to Sμ, although many also occur 5 to this sequence (5, 102). Mice with a targeted deletion of the Sμ tandem repeats retain this sequence and have R-loops and extensive single-strand regions on the nontranscribed strand, consistent with their modest reduction in CSR efficiency (101, 190). A likely explanation for why both the top and bottom strands are equally targeted during SHM of Ig V regions comes from the recent demonstration by Ronai et al. (194) that in human B cell lines undergoing SHM both the top and bottom VH region strands have single-strand patches averaging ∼11 nucleotides in length. These single-strand patches were detected by treating fixed, permeabilized nuclei with sodium bisulfite, which deaminates dC bases within ssDNA. This group also showed that in these cell lines V regions are transcribed in both directions, and the length of the patches are consistent with being caused by the bubble that forms at the site of transcription. However, no one has shown that S regions are transcribed in both directions, and thus it is not known if this explains why the top and bottom S region strands are equally targeted by AID. Ronai et al. (194) found that if they first depro-
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teinized the V region DNA they could not detect the single-strand patches, and thus far experiments to detect single-strand patches in S regions have always used deproteinized DNA. Thus, undetected single-strand patches may exist on both strands at S regions. However, the putative antisense transcripts would not be G-rich and therefore should not form R-loops. The second likely role for GL transcription is to recruit AID. AID coimmunoprecipitates with RNA polymerase II in splenic B cells undergoing CSR (195). This hypothesis is also supported by the finding that AID-induced dU lesions are found in a region beginning ∼150 bp 3 to the GL RNA initiation site and extending over several kb downstream, with more mutations near the 5 end of the S regions and fewer at the 3 ends (50). Thus, investigators have proposed that AID is recruited to RNA Pol II either at the initiation phase of transcription or when it switches to the elongation phase at ∼150 bp 3 to the initiation site (18, 19, 49). AID may leave the transcription complex stochastically as it progresses through the S region. A third possible role is that transcription can alter histone modification of the transcribed region, which might make the DNA more accessible to AID (196–198). Transcription clearly does alter chromatin accessibility, but whether the histone modifications affect AID binding has not yet been shown.
Roles of IgH Intron Enhancer and 3 Enhancers There are two enhancer regions in the IgH locus. The μ intron enhancer is located 3 to JH 4 and just 5 to the Sμ region and is essential during B cell development for normal V(D)J recombination. Consistent with the fact that the Iμ promoter lies within the enhancer core, deletion of the enhancer core reduces CSR on that allele by about twofold (199). As neither GL Sμ transcription nor DJ transcription is eliminated, this might explain why CSR, albeit at a reduced frequency, still occurs. There
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are matrix attachment regions located 5 and 3 to the core enhancer, but this same study found no role for the matrix attachment regions in CSR. A second set of enhancers is located 3 to the Cα gene in mouse and 3 to each of the two Cα genes in human. The mouse 3 IgH enhancers are spread over 30 kb and contain four DNase hypersensitive regions, termed (from 5 to 3 ) hs3A, hs1,2, hs3B, and hs4. Although the entire 30-kb enhancer region has not been successfully deleted, various segments have been deleted by gene targeting using Cre-mediated deletion after insertion of loxP sites. Deletion of hs3A or hs1,2 has no effect on CSR (200); however, combined deletion of hs3B and hs4 greatly reduces CSR to all isotypes except IgG1 (201). Neither hs3B nor hs4 has been individually deleted. The hs3Bhs4 deletion eliminates GL transcripts (except for GLγ1 RNA). Thus far, the only known role for hs3B-hs4 during CSR is to enhance GL transcription. The levels of Ig μ mRNA are also reduced in these mice. Further evidence that the role of the 3 IgH enhancer is to stimulate GL transcription was provided by transient transfection experiments in which a DNA segment containing all four human 3 DNase-hypersensitive sites was found to stimulate human GL γ3 RNA promoter activity (202). There is some evidence from transgene experiments that the region just 5 to Sγ1 has enhancer activity for GL γ1 RNA, perhaps explaining the independence of IgG1 and GLγ1 transcripts from hs3B-hs4 (203, 204). As the hs3B-hs4 enhancers are located far downstream from the GL promoters, their ability to stimulate GL transcription likely involves formation of a loop between the 3 IgH enhancers and GL promoters (32). This might involve complex formation between transcription-activating factors bound to the enhancers and promoters, as has been demonstrated between the T cell receptor Dβ promoter and the 3 T cell receptor β enhancer (205). This complex would most likely recruit histone acetylases and other chromatin modifiers to increase accessibility of the promot-
ers to RNA polymerase and also position the donor and acceptor S regions near each other. Direct evidence for the existence of loops between the 3 IgH enhancers and the DNA segments containing the promoters for specific GL transcripts in splenic B cells under conditions that induce CSR to that specific isotype has recently been obtained using the chromosome conformation capture technique (206). Most interestingly, the loops depend on the hs3B-hs4 enhancer segment and are reduced in aid−/− cells. It will be very interesting and important to determine which sequences and proteins are involved.
Regulation of Isotype Specificity by S Regions Although GL transcription is clearly essential for CSR, a few reports suggest that isotype specificity is also regulated by the S region sequence. The evidence for this was obtained by using transiently transfected plasmid switch substrates (207). The acceptor S region isotype determines whether the plasmid will switch in particular B cell lines or in splenic B cells activated under conditions that induce CSR on the chromosome to specific isotypes. For example, plasmids containing an acceptor Sγ1 or Sγ3 sequence will not switch in two different B cell lines that switch on their endogenous chromosome to IgA, but not to IgG1 or IgG3. However, plasmids with acceptor Sα sequences will undergo Sμ-Sα recombination in these cell lines. Likewise, a plasmid with the Sγ1 acceptor S region will undergo Sμ-Sγ1 recombination in splenic B cells treated with LPS+IL-4, which induces IgG1 CSR on the chromosome, but not if the B cells are treated with LPS alone, which induces IgG3 but not IgG1 CSR. Likewise, the plasmid with an Sγ3 acceptor S region will undergo CSR in B cells induced with LPS, but not if the cells are treated with LPS+IL4. Kenter et al. (208) also showed that mutations of 3 bp within a repeat unit of the Sγ1 sequence to the sequence found in Sγ3 allowed the plasmid to switch in the absence www.annualreviews.org • Class Switch Recombination
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of IL-4, further supporting the hypothesis that isotype specificity is also controlled by switch sequences. The element that was mutated is part of a NF-κB binding motif, which therefore might be involved in determining the isotype specificity. It was not determined whether the mutations affected transcription across the plasmid S regions, although there are no Ig isotype–specific promoters in these plasmids, so this is an unlikely explanation. Another example of isotype specific regulation by a S region comes from the finding that plasmid Sμ-Sα recombination in cell lines and splenic B cells can be stimulated threefold and tenfold, respectively, by the histone methyltransferase Suv39h1, which trimethylates histone H3 on lysine 9. Suv39h1 does not stimulate switch recombination in plasmids with any other acceptor S region (209). Mice deficient in Suv39h1 show a 50% reduction in chromosomal CSR to IgA, but to no other isotype. This reduction is not accompanied by a reduction in GL α transcripts, suggesting that the Sα sequence itself is responding to Suv39h1. The Suv39h1 target in these switching cells is unknown. Furthermore, the K9-trimethyl mark is repressive and is usually found on heterochromatin associated with centromeres, making the stimulatory role of Suv39h1 on IgA switching even more puzzling. Taken together, these two sets of results suggest that isotype specificity is not regulated solely by GL transcription but is also regulated by S region sequences by an unknown mechanism.
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ISOTYPE SWITCHING OCCURS PRIOR TO GERMINAL CENTER (GC) FORMATION, AND PERHAPS ALSO IN GCs The GC provides a unique environment that allows rapid proliferation of cells despite sustaining DNA damage initiated by AID activity. Bcl-6 is upregulated in GC cells and is required for GC formation (210, 211). Ranuncolo et al. (212) suggest that GC centroblasts are uniquely able to withstand the DNA 278
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damage caused by AID because of the repression of the ATR damage-sensing pathway by Bcl-6. Protection from cell death in GC cells had previously been thought to be due to the downregulation of p53 by Bcl-6, as demonstrated in Ramos cells (213), but Ranuncolo et al. (212) found that primary human centroblasts express p53 and that its expression is not affected by downregulation or inhibition of Bcl-6. Although both isotype-switched cells and high levels of AID are found in GCs, class switching clearly can occur very early after antigen exposure, prior to GC formation. By adoptive transfer of B cell receptor Tg B cells and carrier-specific Tg CD4 T cells into normal recipients, Pape et al. (214) were able to visualize very early stages in the antibody response, tracking the B cells with anti-idiotype antibody. Tg+ isotype-switched B cells (IgG2a+ ) appeared in splenic B cell follicles as early as two days after immunization with cognate antigen and peaked on days 3 and 4, prior to formation of GCs. The B cells had divided at least three times and appeared to have migrated away from the Tg T cells. Their appearance was antigenand T cell–dependent. By day 4, progeny of the Tg+ IgG2a+ follicular B cells could be found in the outer edges of the periarteriolar lymphoid sheath near the red pulp, in the marginal zone, and in pre-GCs. By day 10, GCs contained PNA+ IgG2a+ Tg B cells that showed evidence of many cell divisions. IgM+ Tg B cells were abundant in follicles and the marginal zone at this time but were not in GCs. As only IgG2a+ Tg B cells were found in GCs, this suggests that CSR does not occur in GCs in this model, but instead occurs prior to GC formation. In another model, normal mice infected with attenuated Salmonella typhimurium also showed very rapid (day 4) Tdependent IgG2a isotype switching, occurring much before GC formation (215). Also, AID is expressed in large proliferating B cells in the extrafollicular areas of human tonsil and lymph node (216). However, Kolar et al. (217) have recently suggested that a population that
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expresses IgD+ CD38− CD23− FSChi CD71+ in human tonsil may be the initial GC cell to express AID. V region mutation frequency places these cells between naive and GC cells. This finding is consistent with previous assumptions that CSR also occurs in GCs. CSR can also occur independently of T cell help. B cell activating factor (BAFF) can synergize with IL-4 to induce AID expression in CD40−/− B cells in culture (218). Near normal levels of gut IgA were detected in CD40−/− mice despite a lack of GCs (219). The site where this T-independent IgA switching occurred was not identified in this study, although the authors excluded the gutassociated lymphoid tissue (GALT), the lamina propria, and the peritoneal cavity. Mucosal epithelial cells lining the crypts of human tonsils can support class switching through the production of BAFF and IL-10 upon TLR stimulation. These epithelial cells also secrete thymic stromal lymphopoietin (TSLP), which stimulates production of BAFF by dendritic cells (220, 221). Furthermore, CSR is detectable in pre-B and immature B cells isolated from bone marrow, as assayed by AID expression, detection of transcripts from excised DNA circles owing to S-S recombination, and detection of postswitch (Iμ-Cx) transcripts (222, 223). AID expression, circle transcripts, and postswitch transcripts were also observed in developing B cells from nude mice, further indicating T cell independence. The expression of AID in both wild-type and nude mice depends on B cell receptor signaling
through Bruton’s agammaglobulinemia tyrosine kinase (BTK) in immature B cells and on TLR signaling in both pre-B and immature B cells (222).
REMAINING QUESTIONS Numerous interesting questions remain in the field of CSR. For example, how does AID target the V and S regions specifically? CSR and SHM do not appear to occur simultaneously in a cell. Why not? What determines whether a cell will undergo CSR or instead undergo SHM? What proteins does AID interact with? Most interestingly, what is the role of the C terminus of AID? Why is UNG required for CSR, i.e., why do other uracil DNA glycosylases not substitute? Why is APE2 used to create SSBs in S regions, in addition to APE1? Is another AP endonuclease also involved? How is synapsis of two distal S regions achieved? What is the contribution of S region sequence to isotype specificity? What is the role of 53BP1? Does 53BP1 bind specifically to the IgH locus? If so, does it require a specific histone modification, and is this modification specific to the IgH locus? How is this regulated? Does the binding require GL transcripts? Why is Ku70-Ku80 essential for CSR but XRCC4-ligase IV is not? Is the ability of Ku to bind nuclear matrix important for CSR? Many very interesting questions are approachable with current techniques and will be addressed in the near future, thus promising much excitement for this field in the coming years.
DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS We thank Drs. Katheryn Meek for helpful information on DNA-PK and Amy Kenter for her manuscript in press. We acknowledge support by NIH to J.S. (RO1AI23283, RO1 AI63026, R21AI62738) and to C.E.S. (RO1 AI65639) and a postdoctoral fellowship from the Cancer Research Institute to J.E.J.G. www.annualreviews.org • Class Switch Recombination
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LITERATURE CITED
Annu. Rev. Immunol. 2008.26:261-292. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
1. Snapper CM, Finkelman FD. 1998. Immunoglobulin class switching. In Fundamental Immunology, ed. WE Paul, pp. 831–61, Philadelphia: Lippincott-Raven. 4th ed. 2. Martin SW, Goodnow CC. 2002. Burst-enhancing role of the IgG membrane tail as a molecular determinant of memory. Nat. Immunol. 3:182–88 3. Waisman A, Kraus M, Seagal J, Ghosh S, Melamed D, et al. 2007. IgG1 B cell receptor signaling is inhibited by CD22 and promotes the development of B cells whose survival is less dependent on Ig α/β. J. Exp. Med. 204:747–58 4. Horikawa K, Martin SW, Pogue SL, Silver K, Peng K, et al. 2007. Enhancement and suppression of signaling by the conserved tail of IgG memory-type B cell antigen receptors. J. Exp. Med. 204:759–69 5. Dunnick W, Hertz GZ, Scappino L, Gritzmacher C. 1993. DNA sequences at immunoglobulin switch region recombination sites. Nucleic Acids Res. 21:365–72 6. Min I, Rothlein L, Schrader C, Stavnezer J, Selsing E. 2005. Shifts in targeting of class switch recombination sites in mice that lack μ switch region tandem repeats or Msh2. J. Exp. Med. 201:1885–90 7. Stavnezer J. 1996. Antibody class switching. Adv. Immunol. 61:79–146 8. Manis JP, Tian M, Alt FW. 2002. Mechanism and control of class-switch recombination. Trends Immunol. 23:31–39 9. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T. 2000. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102:553–63 10. Revy P, Muto T, Levy Y, Geissmann F, Plebani A, et al. 2000. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 102:565–75 11. Petersen-Mahrt SK, Harris RS, Neuberger MS. 2002. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418:99–104 12. Chaudhuri J, Tian M, Khuong C, Chua K, Pinaud E, Alt FW. 2003. Transcriptiontargeted DNA deamination by the AID antibody diversification enzyme. Nature 422:726– 30 13. Dickerson SK, Market E, Besmer E, Papavasiliou FN. 2003. AID mediates hypermutation by deaminating single stranded DNA. J. Exp. Med. 197:1291–96 14. Pham P, Bransteitter R, Petruska J, Goodman MF. 2003. Processive AID-catalysed cytosine deamination on single-stranded DNA simulates somatic hypermutation. Nature 424:103–7 15. Peled JU, Kuang FL, Iglesias-Ussel MD, Roa S, Kalis SL, et al. 2008. The biochemistry of somatic hypermutation. Annu. Rev. Immunol. 26:481–511 16. Barreto VM, Ramiro AR, Nussenzweig MC. 2005. Activation-induced deaminase: controversies and open questions. Trends Immunol. 26:90–96 17. Ramiro A, San-Martin BR, McBride K, Jankovic M, Barreto V, et al. 2007. The role of activation-induced deaminase in antibody diversification and chromosome translocations. Adv. Immunol. 94:75–107 18. Longerich S, Basu U, Alt F, Storb U. 2006. AID in somatic hypermutation and class switch recombination. Curr. Opin. Immunol. 18:164–74 19. Bransteitter R, Sneeden JL, Allen S, Pham P, Goodman MF. 2006. First AID (activationinduced cytidine deaminase) is needed to produce high affinity isotype-switched antibodies. J. Biol. Chem. 281:16833–36 280
Stavnezer
·
Guikema
·
Schrader
Annu. Rev. Immunol. 2008.26:261-292. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-09
ARI
16 February 2008
12:18
20. Muramatsu M, Sankaranand VS, Anant S, Sugai M, Kinoshita K, et al. 1999. Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNAediting deaminase family in germinal center B cells. J. Biol. Chem. 274:18470–76 21. Schrader CE, Linehan EK, Mochegova SN, Woodland RT, Stavnezer J. 2005. Inducible DNA breaks in Ig S regions are dependent upon AID and UNG. J. Exp. Med. 202:561–68 22. Hodgkin PD, Lee J-H, Lyons AB. 1996. B cell differentiation and isotype switching is related to division cycle number. J. Exp. Med. 184:277–81 23. Hasbold J, Lyons AB, Kehry MR, Hodgkin PD. 1998. Cell division number regulates IgG1 and IgE switching of B cells following stimulation by CD40 ligand and IL-4. Eur. J. Immunol. 28:1040–51 24. Deenick EK, Hasbold J, Hodgkin PD. 1999. Switching to IgG3, IgG2b, and IgA is division linked and independent, revealing a stochastic framework for describing differentiation. J. Immunol. 163:4707–14 25. Rush JS, Liu M, Odegard VH, Unniraman S, Schatz DG. 2005. Expression of activationinduced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination. Proc. Natl. Acad. Sci. USA 102:13242–47 26. Dedeoglu F, Horwitz B, Chaudhuri J, Alt FW, Geha RS. 2004. Induction of activationinduced cytidine deaminase gene expression by IL-4 and CD40 ligation is dependent on STAT6 and NFκB. Int. Immunol. 16:395–404 27. Gonda H, Sugai M, Nambu Y, Katakai T, Agata Y, et al. 2003. The balance between Pax5 and Id2 activities is the key to AID gene expression. J. Exp. Med. 198:1427–37 28. Ito S, Nagaoka H, Shinkura R, Begum N, Muramatsu M, et al. 2004. Activation-induced cytidine deaminase shuttles between nucleus and cytoplasm like apolipoprotein B mRNA editing catalytic polypeptide 1. Proc. Natl. Acad. Sci. USA 101:1975–80 29. McBride KM, Barreto V, Ramiro AR, Stavropoulos P, Nussenzweig MC. 2004. Somatic hypermutation is limited by CRM1-dependent nuclear export of activation-induced deaminase. J. Exp. Med. 199:1235–44 30. Brar SS, Watson M, Diaz M. 2004. Activation-induced cytosine deaminase (AID) is actively exported out of the nucleus but retained by the induction of DNA breaks. J. Biol. Chem. 279:26395–401 31. Stavnezer J. 1996. Immunoglobulin class switching. Curr. Opin. Immunol. 8:199–205 32. Cogne M, Birshtein BK. 2004. Regulation of class switch recombination. In Molecular Biology of B Cells, ed. T Honjo, FW Alt, MS Neuberger, pp. 289–305. London: Elsevier 33. Pan-Hammarstrom Q, Zhao Y, Hammarstrom L. 2007. Class switch recombination: a comparison between mouse and human. Adv. Immunol. 93:1–61 34. Chaudhuri J, Alt FW. 2004. Class-switch recombination: interplay of transcription, DNA deamination and DNA repair. Nat. Rev. Immunol. 4:541–52 35. Li Z, Woo CJ, Iglesias-Ussel MD, Ronai D, Scharff MD. 2004. The generation of antibody diversity through somatic hypermutation and class switch recombination. Genes Dev. 18:1–11 36. Kenter AL. 2005. Class switch recombination: an emerging mechanism. Curr. Top. Microbiol. Immunol. 290:171–99 37. Stavnezer J, Kinoshita K, Muramatsu M, Honjo T. 2004. Molecular mechanisms of class switch recombination. In Molecular Biology of B Cells, ed. T Honjo, MS Neuberger, FW Alt, pp. 307–26. London: Elsevier 38. Rada C, Williams GT, Nilsen H, Barnes DE, Lindahl T, Neuberger MS. 2002. Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Curr. Biol. 12:1748–55 www.annualreviews.org • Class Switch Recombination
281
ARI
16 February 2008
12:18
39. Di Noia J, Neuberger MS. 2002. Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature 419:43–48 40. Poltoratsky V, Goodman MF, Scharff MD. 2000. Error-prone candidates vie for somatic mutation. J. Exp. Med. 192:F27–30 41. Catalan N, Selz F, Imai K, Revy P, Fischer A, Durandy A. 2003. The block in immunoglobulin class switch recombination caused by activation-induced cytidine deaminase deficiency occurs prior to the generation of DNA double strand breaks in switch μ region. J. Immunol. 171:2504–9 42. Rush JS, Fugmann SD, Schatz DG. 2004. Staggered AID-dependent DNA double strand breaks are the predominant DNA lesions targeted to Sμ in Ig class switch recombination. Int. Immunol. 16:549–57 43. Petersen S, Casellas R, Reina-San-Martin B, Chen HT, Difilippantonio MJ, et al. 2001. AID is required to initiate Nbs1/γ-H2AX focus formation and mutations at sites of class switching. Nature 414:660–65 44. Ramiro AR, Stavropoulos P, Jankovic M, Nussenzweig MC. 2003. Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand. Nat. Immunol. 4:452–56 45. Shen HM, Storb U. 2004. Activation-induced cytidine deaminase (AID) can target both DNA strands when the DNA is supercoiled. Proc. Natl. Acad. Sci. USA 101:12997–3002 46. Shen HM, Ratnam S, Storb U. 2005. Targeting of the activation-induced cytosine deaminase is strongly influenced by the sequence and structure of the targeted DNA. Mol. Cell. Biol. 25:10815–21 47. Martomo SA, Fu D, Yang WW, Joshi NS, Gearhart PJ. 2005. Deoxyuridine is generated preferentially in the nontranscribed strand of DNA from cells expressing activationinduced cytidine deaminase. J. Immunol. 174:7787–91 48. Milstein C, Neuberger MS, Staden R. 1998. Both DNA strands of antibody genes are hypermutation targets. Proc. Natl. Acad. Sci. USA 95:8791–94 49. Longerich S, Tanaka A, Bozek G, Nicolae D, Storb U. 2005. The very 5 end and the constant region of Ig genes are spared from somatic mutation because AID does not access these regions. J. Exp. Med. 202:1443–54 50. Xue K, Rada C, Neuberger MS. 2006. The in vivo pattern of AID targeting to immunoglobulin switch regions deduced from mutation spectra in msh2−/− ung−/− mice. J. Exp. Med. 203:2085–94 51. Betz AG, Milstein C, Gonzalez-Fernandez A, Pannell R, Larson T, Neuberger MS. 1994. Elements regulating somatic hypermutation of an immunoglobulin κ gene: critical role for the intron enhancer/matrix attachment region. Cell 77:239–48 52. Rogozin IB, Kolchanov NA. 1992. Somatic hypermutagenesis in immunoglobulin genes. II. Influence of neighbouring base sequences on mutagenesis. Biochim. Biophys. Acta 1171:11–18 53. Shapiro GS, Aviszus K, Ikle D, Wysocki LJ. 1999. Predicting regional mutability in antibody V genes based solely on di- and trinucleotide sequence composition. J. Immunol. 163:259–68 54. Bransteitter R, Pham P, Calabrese P, Goodman MF. 2004. Biochemical analysis of hypermutational targeting by wild type and mutant activation-induced cytidine deaminase. J. Biol. Chem. 279:51612–21 55. Yu K, Huang FT, Lieber MR. 2004. DNA substrate length and surrounding sequence affect the activation-induced deaminase activity at cytidine. J. Biol. Chem. 279:6496–500 56. Chaudhuri J, Khuong C, Alt FW. 2004. Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature 430:992–98
Annu. Rev. Immunol. 2008.26:261-292. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-09
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Stavnezer
·
Guikema
·
Schrader
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ANRV338-IY26-09
ARI
16 February 2008
12:18
57. Basu U, Chaudhuri J, Alpert C, Dutt S, Ranganath S, et al. 2005. The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation. Nature 438:508– 11 58. McBride KM, Gazumyan A, Woo EM, Barreto VM, Robbiani DV, et al. 2006. Regulation of hypermutation by activation-induced cytidine deaminase phosphorylation. Proc. Natl. Acad. Sci. USA 103:8798–803 59. Ta VT, Nagaoka H, Catalan N, Durandy A, Fischer A, et al. 2003. AID mutant analyses indicate requirement for class-switch-specific cofactors. Nat. Immunol. 4:843–48 60. Barreto V, Reina-San-Martin B, Ramiro AR, McBride KM, Nussenzweig MC. 2003. C-terminal deletion of AID uncouples class switch recombination from somatic hypermutation and gene conversion. Mol. Cell 12:501–8 61. Christmann M, Tomicic MT, Roos WP, Kaina B. 2003. Mechanisms of human DNA repair: an update. Toxicology 193:3–34 62. Imai K, Slupphaug G, Lee WI, Revy P, Nonoyama S, et al. 2003. Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat. Immunol. 4:1023–28 63. Bardwell PD, Martin A, Wong E, Li Z, Edelmann W, Scharff MD. 2003. Cutting edge: the G-U mismatch glycosylase methyl-CpG binding domain 4 is dispensable for somatic hypermutation and class switch recombination. J. Immunol. 170:1620–24 64. Di Noia JM, Rada C, Neuberger MS. 2006. SMUG1 is able to excise uracil from immunoglobulin genes: insight into mutation vs repair. EMBO J. 25:585–95 65. Hadi MZ, Ginalski K, Nguyen LH, Wilson DM 3rd. 2002. Determinants in nuclease specificity of Ape1 and Ape2, human homologues of Escherichia coli exonuclease III. J. Mol. Biol. 316:853–66 66. Kanno S, Kuzuoka H, Sasao S, Hong Z, Lan L, et al. 2007. A novel human AP endonuclease with conserved zinc-finger-like motifs involved in DNA strand break responses. EMBO J. 26:2094–103 67. Iles N, Rulten S, El-Khamisy SF, Caldecott KW. 2007. APLF (C2orf13) is a novel human protein involved in the cellular response to chromosomal DNA strand breaks. Mol. Cell. Biol. 27:3793–803 68. Bekker-Jensen S, Fugger K, Danielsen JR, Gromova I, Sehested M, et al. 2007. Human xip1 (c2orf13) is a novel regulator of cellular responses to DNA strand breaks. J. Biol. Chem. 282:19638–43 69. Xanthoudakis S, Smeyne RJ, Wallace JD, Curran T. 1996. The redox/DNA repair protein, Ref-1, is essential for early embryonic development in mice. Proc. Natl. Acad. Sci. USA 93:8919–23 70. Fung H, Demple B. 2005. A vital role for Ape1/Ref1 protein in repairing spontaneous DNA damage in human cells. Mol. Cell 17:463–70 71. Ide Y, Tsuchimoto D, Tominaga Y, Nakashima M, Watanabe T, et al. 2004. Growth retardation and dyslymphopoiesis accompanied by G2/M arrest in APEX2-null mice. Blood 104:4097–103 72. Ide Y, Tsuchimoto D, Tominaga Y, Iwamoto Y, Nakabeppu Y. 2003. Characterization of the genomic structure and expression of the mouse Apex2 gene. Genomics 81:47–57 73. Burkovics P, Szukacsov V, Unk I, Haracska L. 2006. Human Ape2 protein has a 3 -5 exonuclease activity that acts preferentially on mismatched base pairs. Nucleic Acids Res. 34:2508–15 74. Guikema JEJ, Linehan EK, Tsuchimoto D, Nakabeppu Y, Strauss PR, et al. 2007. APE1 and APE2 dependent DNA breaks in immunoglobulin class switch recombination. J. Exp. Med. 204:3017–26 www.annualreviews.org • Class Switch Recombination
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16 February 2008
12:18
75. Meira LB, Devaraj S, Kisby GE, Burns DK, Daniel RL, et al. 2001. Heterozygosity for the mouse Apex gene results in phenotypes associated with oxidative stress. Cancer Res. 61:5552–57 76. Raffoul JJ, Cabelof DC, Nakamura J, Meira LB, Friedberg EC, Heydari AR. 2004. Apurinic/apyrimidinic endonuclease (APE/REF-1) haploinsufficient mice display tissuespecific differences in DNA polymerase β-dependent base excision repair. J. Biol. Chem. 279:18425–33 77. Schrader CE, Guikema JEJ, Linehan EK, Selsing E, Stavnezer J. 2007. AID-dependent DNA breaks in class switch recombination occur during G1 phase and are mismatch repair-dependent. J. Immunol. 179:6064–71 78. Barnes DE, Lindahl T. 2004. Repair and genetic consequences of endogenous DNA base damage in mammalian cells. Annu. Rev. Genet. 38:445–76 79. Beard WA, Wilson SH. 2006. Structure and mechanism of DNA polymerase β. Chem. Rev. 106:361–82 80. Akbari M, Otterlei M, Pena-Diaz J, Aas PA, Kavli B, et al. 2004. Repair of U/G and U/A in DNA by UNG2-associated repair complexes takes place predominantly by shortpatch repair both in proliferating and growth-arrested cells. Nucleic Acids Res. 32:5486– 98 81. Parlanti E, Locatelli G, Maga G, Dogliotti E. 2007. Human base excision repair complex is physically associated to DNA replication and cell cycle regulatory proteins. Nucleic Acids Res. 35:1569–77 82. Wong D, Demple B. 2004. Modulation of the 5 -deoxyribose-5-phosphate lyase and DNA synthesis activities of mammalian DNA polymerase β by apurinic/apyrimidinic endonuclease 1. J. Biol. Chem. 279:25268–75 83. Parsons JL, Dianova II, Allinson SL, Dianov GL. 2005. DNA polymerase β promotes recruitment of DNA ligase IIIα-XRCC1 to sites of base excision repair. Biochemistry 44:10613–19 84. Liu Y, Prasad R, Beard WA, Kedar PS, Hou EW, et al. 2007. Coordination of steps in single-nucleotide base excision repair mediated by apurinic/apyrimidinic endonuclease 1 and DNA polymerase β. J. Biol. Chem. 282:13532–41 85. Wu X, Stavnezer J. 2007. DNA polymerase β is able to repair breaks in switch regions and plays an inhibitory role during immunoglobulin class switch recombination. J. Exp. Med. 204:1677–89 86. Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, et al. 2004. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431:997– 1002 87. Zarrin AA, Del Vecchio C, Tseng E, Gleason M, Zarin P, et al. 2007. Antibody class switching mediated by yeast endonuclease-generated DNA breaks. Science 315:377–81 88. Kunkel T, Erie D. 2005. DNA mismatch repair. Annu. Rev. Biochem. 74:681–710 89. Genschel J, Bazemore LR, Modrich P. 2002. Human exonuclease I is required for 5 and 3 mismatch repair. J. Biol. Chem. 277:13302–11 90. Genschel J, Modrich P. 2003. Mechanism of 5 -directed excision in human mismatch repair. Mol. Cell 12:1077–86 91. Kadyrov FA, Dzantiev L, Constantin N, Modrich P. 2006. Endonucleolytic function of MutLα in human mismatch repair. Cell 126:297–308 92. Ehrenstein MR, Neuberger MS. 1999. Deficiency in Msh2 affects the efficiency and local sequence specificity of immunoglobulin class-switch recombination: parallels with somatic hypermutation. EMBO J. 18:3484–90
Annu. Rev. Immunol. 2008.26:261-292. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-09
284
Stavnezer
·
Guikema
·
Schrader
Annu. Rev. Immunol. 2008.26:261-292. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-09
ARI
16 February 2008
12:18
93. Schrader CE, Edelmann W, Kucherlapati R, Stavnezer J. 1999. Reduced isotype switching in splenic B cells from mice deficient in mismatch repair enzymes. J. Exp. Med. 190:323–30 94. Ehrenstein MR, Rada C, Jones AM, Milstein C, Neuberger MS. 2001. Switch junction sequences in PMS2-deficient mice reveal a microhomology-mediated mechanism of Ig class switch recombination. Proc. Natl. Acad. Sci. USA 98:14553–58 95. Li Z, Scherer SJ, Ronai D, Iglesias-Ussel MD, Peled JU, et al. 2004. Examination of Msh6- and Msh3-deficient mice in class switching reveals overlapping and distinct roles of MutS homologues in antibody diversification. J. Exp. Med. 200:47–59 96. Martin A, Li Z, Lin DP, Bardwell PD, Iglesias-Ussel MD, et al. 2003. Msh2 ATPase activity is essential for somatic hypermutation at A-T basepairs and for efficient class switch recombination. J. Exp. Med. 198:1171–78 97. Martomo SA, Yang WW, Gearhart PJ. 2004. A role for Msh6 but not Msh3 in somatic hypermutation and class switch recombination. J. Exp. Med. 200:61–68 98. Bardwell PD, Woo CJ, Wei K, Li Z, Martin A, et al. 2004. Altered somatic hypermutation and reduced class-switch recombination in exonuclease 1-mutant mice. Nat. Immunol. 5:224–29 99. Stavnezer J, Schrader CE. 2006. Mismatch repair converts AID-instigated nicks to double-strand breaks for antibody class-switch recombination. Trends Genet. 22:23–28 100. Wilson TM, Vaisman A, Martomo SA, Sullivan P, Lan L, et al. 2005. MSH2-MSH6 stimulates DNA polymerase η, suggesting a role for A:T mutations in antibody genes. J. Exp. Med. 201:637–45 101. Luby TM, Schrader CE, Stavnezer J, Selsing E. 2001. The μ switch region tandem repeats are important, but not required, for antibody class switch recombination. J. Exp. Med. 193:159–68 102. Min I, Schrader C, Vardo J, D’Avirro N, Luby T, et al. 2003. The Sμ tandem repeat region is critical for isotype switching in the absence of Msh2. Immunity 19:515–24 103. Schrader CE, Vardo J, Stavnezer J. 2002. Role for mismatch repair proteins Msh2, Mlh1, and Pms2 in immunoglobulin class switching shown by sequence analysis of recombination junctions. J. Exp. Med. 195:367–73 104. Schrader CE, Vardo J, Linehan E, Twarog MZ, Niedernhofer LJ, et al. 2004. Deletion of the nucleotide excision repair gene Ercc1 reduces Ig class switching and alters mutations near switch recombination junctions. J. Exp. Med. 200:321–30 105. Faili A, Aoufouchi S, Weller S, Vuillier F, Stary A, et al. 2004. DNA polymerase η is involved in hypermutation occurring during immunoglobulin class switch recombination. J. Exp. Med. 199:265–70 106. Delbos F, Aoufouchi S, Faili A, Weill JC, Reynaud CA. 2007. DNA polymerase η is the sole contributor of A/T modifications during immunoglobulin gene hypermutation in the mouse. J. Exp. Med. 204:17–23 107. Dunnick W, Wilson M, Stavnezer J. 1989. Mutations, duplications, and deletion of recombined switch regions suggest a role for DNA replication in the immunoglobulin heavy chain switch. Mol. Cell. Biol. 9:1850–56 108. Schrader CE, Bradley SP, Vardo J, Mochegova SN, Flanagan E, Stavnezer J. 2003. Mutations occur in the Ig Sμ region but rarely in Sγ regions prior to class switch recombination. EMBO J. 22:5893–903 109. Masuda K, Ouchida R, Takeuchi A, Saito T, Koseki H, et al. 2005. DNA polymerase θ contributes to the generation of C/G mutations during somatic hypermutation of Ig genes. Proc. Natl. Acad. Sci. USA 102:13986–91 www.annualreviews.org • Class Switch Recombination
285
ARI
16 February 2008
12:18
110. Zan H, Shima N, Xu Z, Al-Qahtani A, Evinger AJ Iii, et al. 2005. The translesion DNA polymerase θ plays a dominant role in immunoglobulin gene somatic hypermutation. EMBO J. 24:3757–69 111. Masuda K, Ouchida R, Hikida M, Nakayama M, Ohara O, et al. 2006. Absence of DNA polymerase θ results in decreased somatic hypermutation frequency and altered mutation patterns in Ig genes. DNA Repair 5:1384–91 112. Dudley DD, Manis JP, Zarrin AA, Kaylor L, Tian M, Alt FW. 2002. Internal IgH class switch region deletions are position-independent and enhanced by AID expression. Proc. Natl. Acad. Sci. USA 99:9984–89 113. Reina-San-Martin B, Difilippantonio S, Hanitsch L, Masilamani RF, Nussenzweig A, Nussenzweig MC. 2003. H2AX is required for recombination between immunoglobulin switch regions but not for intraswitch region recombination or somatic hypermutation. J. Exp. Med. 197:1767–78 114. Rooney S, Chaudhuri J, Alt FW. 2004. The role of the nonhomologous end-joining pathway in lymphocyte development. Immunol. Rev. 200:115–31 115. Ma Y, Lu H, Schwarz K, Lieber MR. 2005. Repair of double-strand DNA breaks by the human nonhomologous DNA end joining pathway: the iterative processing model. Cell Cycle 4:1193–200 116. Sonoda E, Hochegger H, Saberi A, Taniguchi Y, Takeda S. 2006. Differential usage of nonhomologous end-joining and homologous recombination in double strand break repair. DNA Repair 5:1021–29 117. Manis JP, Gu Y, Lansford R, Sonoda E, Ferrini R, et al. 1998. Ku70 is required for late B cell development and immunoglobulin heavy chain switching. J. Exp. Med. 187:2081– 89 118. Casellas R, Nussenzweig A, Wuerffel R, Pelanda R, Reichlin A, et al. 1998. Ku80 is required for immunoglobulin isotype switching. EMBO J. 17:2404–11 119. Pan-Hammarstrom Q, Jones AM, Lahdesmaki A, Zhou W, Gatti RA, et al. 2005. Impact of DNA ligase IV on nonhomologous end joining pathways during class switch recombination in human cells. J. Exp. Med. 201:189–94 120. Soulas-Sprauel P, Guyader GL, Rivera-Munoz P, Abramowski V, Olivier-Martin C, et al. 2007. Role for DNA repair factor XRCC4 in immunoglobulin class switch recombination. J. Exp. Med. 204:1717–27 121. Chen L, Trujillo K, Sung P, Tomkinson AE. 2000. Interactions of the DNA ligase IVXRCC4 complex with DNA ends and the DNA-dependent protein kinase. J. Biol. Chem. 275:26196–205 122. Nick McElhinny SA, Snowden CM, McCarville J, Ramsden DA. 2000. Ku recruits the XRCC4-ligase IV complex to DNA ends. Mol. Cell. Biol. 20:2996–3003 123. Costantini S, Woodbine L, Andreoli L, Jeggo PA, Vindigni A. 2007. Interaction of the Ku heterodimer with the DNA ligase IV/Xrcc4 complex and its regulation by DNA-PK. DNA Repair 6:712–22 124. Frank KM, Sekiguchi JM, Seidl KJ, Swat W, Rathbun GA, et al. 1998. Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature 396:173–77 125. Yan CT, Boboila C, Souza EK, Franco S, Hickernell TR, et al. 2007. IgH class switching and translocations use a robust nonclassical end-joining pathway. Nature. 449:478–82 126. Gu J, Lu H, Tippin B, Shimazaki N, Goodman MF, Lieber MR. 2007. XRCC4:DNA ligase IV can ligate incompatible DNA ends and can ligate across gaps. EMBO J. 26:1010– 23
Annu. Rev. Immunol. 2008.26:261-292. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-09
286
Stavnezer
·
Guikema
·
Schrader
Annu. Rev. Immunol. 2008.26:261-292. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-09
ARI
16 February 2008
12:18
127. Sayegh C, Jhunjhunwala S, Riblet R, Murre C. 2005. Visualization of looping involving the immunoglobulin heavy-chain locus in developing B cells. Genes. Dev. 19:322–27 128. Roldan E, Fuxa M, Chong W, Martinez D, Novatchkova M, et al. 2005. Locus ‘decontraction’ and centromeric recruitment contribute to allelic exclusion of the immunoglobulin heavy-chain gene. Nat. Immunol. 6:31–41 129. Moreno-Herrero F, de Jager M, Dekker NH, Kanaar R, Wyman C, Dekker C. 2005. Mesoscale conformational changes in the DNA-repair complex Rad50/Mre11/Nbs1 upon binding DNA. Nature 437:440–43 130. Lee JH, Paull TT. 2005. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 308:551–54 131. Hopfner KP, Karcher A, Shin DS, Craig L, Arthur LM, et al. 2000. Structural biology of Rad50 ATPase: ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily. Cell 101:789–800 132. de Jager M, Dronkert ML, Modesti M, Beerens CE, Kanaar R, van Gent DC. 2001. DNA-binding and strand-annealing activities of human Mre11: implications for its roles in DNA double-strand break repair pathways. Nucleic Acids Res. 29:1317–25 133. Difilippantonio S, Celeste A, Fernandez-Capetillo O, Chen HT, Reina San Martin B, et al. 2005. Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models. Nat. Cell Biol. 7:675–85 134. Falck J, Coates J, Jackson SP. 2005. Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434:605–11 135. Cerosaletti K, Wright J, Concannon P. 2006. Active role for nibrin in the kinetics of atm activation. Mol. Cell. Biol. 26:1691–99 136. Reina-San-Martin B, Nussenzweig MC, Nussenzweig A, Difilippantonio S. 2005. Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1. Proc. Natl. Acad. Sci. USA 102:1590–95 137. Carney JP, Maser RS, Olivares H, Davis EM, LeBeau M, et al. 1998. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair (DBSR) to the cellular DNA damage response. Cell 93:477–86 138. Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, et al. 1998. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93:467–76 139. Kracker S, Bergmann Y, Demuth I, Frappart PO, Hildebrand G, et al. 2005. Nibrin functions in Ig class-switch recombination. Proc. Natl. Acad. Sci. USA 102:1584– 89 140. Ramiro AR, Jankovic M, Eisenreich T, Difilippantonio S, Chen-Kiang S, et al. 2004. AID is required for c-myc/IgH chromosome translocations in vivo. Cell 118:431–38 141. Unniraman S, Zhou S, Schatz DG. 2004. Identification of an AID-independent pathway for chromosomal translocations between the Igh switch region and Myc. Nat. Immunol. 5:1117–23 142. Franco S, Gostissa M, Zha S, Lombard DB, Murphy MM, et al. 2006. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol. Cell 21:201–14 143. Ramiro AR, Jankovic M, Callen E, Difilippantonio S, Chen HT, et al. 2006. Role of genomic instability and p53 in AID-induced c-myc-Igh translocations. Nature 440:105–9 144. Pan Q, Petit-Frere C, Lahdesmaki A, Gregorek H, Chrzanowska KH, Hammarstrom L. 2002. Alternative end joining during switch recombination in patients with ataxiatelangiectasia. Eur. J. Immunol. 32:1300–8 www.annualreviews.org • Class Switch Recombination
287
ARI
16 February 2008
12:18
145. Lahdesmaki A, Taylor AM, Chrzanowska KH, Pan-Hammarstrom Q. 2004. Delineation of the role of the Mre11 complex in class switch recombination. J. Biol. Chem. 279:16479– 87 146. Bakkenist CJ, Kastan MB. 2003. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506 147. Downs JA, Nussenzweig MC, Nussenzweig A. 2007. Chromatin dynamics and the preservation of genetic information. Nature 447:951–58 148. Bredemeyer AL, Sharma GG, Huang CY, Helmink BA, Walker LM, et al. 2006. ATM stabilizes DNA double-strand-break complexes during V(D)J recombination. Nature 442:466–70 149. Callen E, Jankovic M, Difilippantonio S, Daniel JA, Chen HT, et al. 2007. ATM prevents the persistence and propagation of chromosome breaks in lymphocytes. Cell. 130:63–75 150. Vacchio MS, Olaru A, Livak F, Hodes RJ. 2007. ATM deficiency impairs thymocyte maturation because of defective resolution of T cell receptor a locus coding end breaks. Proc. Natl. Acad. Sci. USA 104:6323–28 151. Lumsden JM, McCarty T, Petiniot LK, Shen R, Barlow C, et al. 2004. Immunoglobulin class switch recombination is impaired in Atm-deficient mice. J. Exp. Med. 200:1111–21 152. Reina-San-Martin B, Chen HT, Nussenzweig A, Nussenzweig MC. 2004. ATM is required for efficient recombination between immunoglobulin switch regions. J. Exp. Med. 200:1103–10 153. Iwabuchi K, Bartel PL, Li B, Marraccino R, Fields S. 1994. Two cellular proteins that bind to wild-type but not mutant p53. Proc. Natl. Acad. Sci. USA 91:6098–102 154. Huang J, Sengupta R, Espejo B, Lee MG, Dorsey JA, et al. 2007. p53 is regulated by the lysine demethylase LSD1. Nature 449:105–8 155. Pryde F, Khalili S, Robertson K, Selfridge J, Ritchie AM, et al. 2005. 53BP1 exchanges slowly at the sites of DNA damage and appears to require RNA for its association with chromatin. J. Cell Sci. 118:2043–55 156. Schultz LB, Chehab NH, Malikzay A, Halazonetis TD. 2000. p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks. J. Cell Biol. 151:1381–90 157. Celeste A, Fernandez-Capetillo O, Kruhlak MJ, Pilch DR, Staudt DW, et al. 2003. Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat. Cell Biol. 5:675–79 158. Ward IM, Minn K, Jorda KG, Chen J. 2003. Accumulation of checkpoint protein 53BP1 at DNA breaks involves its binding to phosphorylated histone H2AX. J. Biol. Chem. 278:19579–82 159. Adams MM, Carpenter PB. 2006. Tying the loose ends together in DNA double strand break repair with 53BP1. Cell Div. 1:19 160. Mochan TA, Venere M, DiTullio RA Jr, Halazonetis TD. 2004. 53BP1, an activator of ATM in response to DNA damage. DNA Repair 3:945–52 161. Manis JP, Morales JC, Xia Z, Kutok JL, Alt FW, Carpenter PB. 2004. 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nat. Immunol. 5:481–87 162. Ward IM, Reina-San-Martin B, Olaru A, Minn K, Tamada K, et al. 2004. 53BP1 is required for class switch recombination. J. Cell Biol. 165:459–64 163. Reina-San-Martin B, Chen J, Nussenzweig A, Nussenzweig MC. 2007. Enhanced intraswitch region recombination during immunoglobulin class switch recombination in 53BP1−/− B cells. Eur. J. Immunol. 37:235–39
Annu. Rev. Immunol. 2008.26:261-292. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-09
288
Stavnezer
·
Guikema
·
Schrader
Annu. Rev. Immunol. 2008.26:261-292. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-09
ARI
16 February 2008
12:18
164. Botuyan MV, Lee J, Ward IM, Kim JE, Thompson JR, et al. 2006. Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell 127:1361–73 165. Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. 1998. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273:5858–68 166. Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ. 2001. ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J. Biol. Chem. 276:42462–67 167. Lou Z, Minter-Dykhouse K, Franco S, Gostissa M, Rivera MA, et al. 2006. MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Mol. Cell 21:187–200 168. Berkovich E, Monnat RJ Jr, Kastan MB. 2007. Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair. Nat. Cell Biol. 9:683–90 169. Celeste A, Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT, et al. 2002. Genomic instability in mice lacking histone H2AX. Science 296:922–27 170. Fernandez-Capetillo O, Celeste A, Nussenzweig A. 2003. Focusing on foci: H2AX and the recruitment of DNA-damage response factors. Cell Cycle 2:426–27 171. Bassing CH, Suh H, Ferguson DO, Chua KF, Manis J, et al. 2003. Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114:359–70 172. Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ. 2003. MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature 421:961–66 173. Stucki M, Clapperton JA, Mohammad D, Yaffe MB, Smerdon SJ, Jackson SP. 2005. MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 123:1213–26 174. Lieber MR, Ma Y, Pannicke U, Schwarz K. 2003. Mechanism and regulation of human nonhomologous DNA end-joining. Nat. Rev. Mol. Cell Biol. 4:712–20 175. Meek K, Gupta S, Ramsden DA, Lees-Miller SP. 2004. The DNA-dependent protein kinase: the director at the end. Immunol. Rev. 200:132–41 176. Walker JR, Corpina RA, Goldberg J. 2001. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 412:607–14 177. Spagnolo L, Rivera-Calzada A, Pearl LH, Llorca O. 2006. Three-dimensional structure of the human DNA-PKcs/Ku70/Ku80 complex assembled on DNA and its implications for DNA DSB repair. Mol. Cell 22:511–19 178. Soutoglou E, Dorn JF, Sengupta K, Jasin M, Nussenzweig A, et al. 2007. Positional stability of single double-strand breaks in mammalian cells. Nat. Cell Biol. 9:675–82 179. Meek K, Douglas P, Cui X, Ding Q, Lees-Miller SP. 2007. Trans autophosphorylation at DNA-dependent protein kinase’s two major autophosphorylation site clusters facilitates end processing but not end joining. Mol. Cell. Biol. 27:3881–90 180. Manis JP, Dudley D, Kaylor L, Alt FW. 2002. IgH class switch recombination to IgG1 in DNA-PKcs-deficient B cells. Immunity 16:607–17 181. Rooney S, Alt FW, Sekiguchi J, Manis JP. 2005. Artemis-independent functions of DNAdependent protein kinase in Ig heavy chain class switch recombination and development. Proc. Natl. Acad. Sci. USA 102:2471–75 182. Bosma GC, Kim J, Urich T, Fath DM, Cotticelli MG, et al. 2002. DNA-dependent protein kinase activity is not required for immunoglobulin class switching. J. Exp. Med. 196:1483–95 183. Cook AJ, Oganesian L, Harumal P, Basten A, Brink R, Jolly CJ. 2003. Reduced switching in SCID B cells is associated with altered somatic mutation of recombined S regions. J. Immunol. 171:6556–64 www.annualreviews.org • Class Switch Recombination
289
ARI
16 February 2008
12:18
184. Kaminski DA, Stavnezer J. 2007. Antibody class switching differs among SJL, C57BL/6 and 129 mice. Int. Immunol. 19:545–56 185. Ma Y, Pannicke U, Schwarz K, Lieber MR. 2002. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell 108:781–94 186. Jung S, Rajewsky K, Radbruch A. 1993. Shutdown of class switch recombination by deletion of a switch region control element. Science 259:984–87 187. Bottaro A, Lansford R, Xu L, Zhang J, Rothman P, Alt F. 1994. I region transcription (per se) promotes basal IgE class switch recombination but additional factors regulate the efficiency of the process. EMBO J. 13:665–74 188. Lorenz M, Jung S, Radbruch A. 1995. Switch transcripts in immunoglobulin class switching. Science 267:1825–28 189. Hein K, Lorenz MG, Siebenkotten G, Petry K, Christine R, Radbruch A. 1998. Processing of switch transcripts is required for targeting of antibody class switch recombination. J. Exp. Med. 188:2369–74 190. Huang FT, Yu K, Balter BB, Selsing E, Oruc Z, et al. 2007. Sequence-dependence of chromosomal R-loops at the immunoglobulin heavy chain Sμ class switch region. Mol. Cell. Biol. 27:5921–32 191. Yu K, Chedin F, Hsieh CL, Wilson TE, Lieber MR. 2003. R-loops at immunoglobulin class switch regions in the chromosomes of stimulated B cells. Nat. Immunol. 4:442–51 192. Zarrin AA, Alt FW, Chaudhuri J, Stokes N, Kaushal D, et al. 2004. An evolutionarily conserved target motif for immunoglobulin class-switch recombination. Nat. Immunol. 5:1275–81 193. Zarrin AA, Tian M, Wang J, Borjeson T, Alt FW. 2005. Influence of switch region length on immunoglobulin class switch recombination. Proc. Natl. Acad. Sci. USA 102:2466–70 194. Ronai D, Iglesias-Ussel MD, Fan M, Li Z, Martin A, Scharff MD. 2007. Detection of chromatin-associated single-stranded DNA in regions targeted for somatic hypermutation. J. Exp. Med. 204:181–90 195. Nambu Y, Sugai M, Gonda H, Lee CG, Katakai T, et al. 2003. Transcription-coupled events associating with immunoglobulin switch region chromatin. Science 302:2137– 40 196. Workman JL. 2006. Nucleosome displacement in transcription. Genes Dev. 20:2009–17 197. Woo CJ, Martin A, Scharff MD. 2003. Induction of somatic hypermutation is associated with modifications in immunoglobulin variable region chromatin. Immunity 19:479–89 198. Wang L, Whang N, Wuerffel R, Kenter AL. 2006. AID-dependent histone acetylation is detected in immunoglobulin S regions. J. Exp. Med. 203:215–26 199. Sakai E, Bottaro A, Alt FW. 1999. The Ig heavy chain intronic enhancer core region is necessary and sufficient to promote efficient class switch recombination. Int. Immunol. 11:1709–13 200. Manis JP, van der Stoep N, Tian M, Ferrini R, Davidson L, et al. 1998. Class switching in B cells lacking 3 immunoglobulin heavy chain enhancers. J. Exp. Med. 188:1421– 31 201. Pinaud E, Khamlichi AA, Le Morvan C, Drouet M, Nalesso V, et al. 2001. Localization of the 3 IgH locus elements that effect long-distance regulation of class switch recombination. Immunity 15:187–99 202. Pan Q, Petit-Frere C, Stavnezer J, Hammarstrom L. 2000. Regulation of the promoter for human immunoglobulin γ3 germ-line transcription and its interaction with the 3 α enhancer. Eur. J. Immunol. 30:1019–29
Annu. Rev. Immunol. 2008.26:261-292. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-09
290
Stavnezer
·
Guikema
·
Schrader
Annu. Rev. Immunol. 2008.26:261-292. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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203. Cunningham K, Ackerly H, Alt F, Dunnick W. 1998. Potential regulatory elements for germline transcription in or near murine Sγ1. Int. Immunol. 10:527–36 204. Adams K, Ackerly H, Cunningham K, Dunnick W. 2000. A DNase I hypersensitive site near the murine γ1 switch region contributes to insertion site independence of transgenes and modulates the amount of transcripts induced by CD40 ligation. Int. Immunol. 12:1705–13 205. Oestreich KJ, Cobb RM, Pierce S, Chen J, Ferrier P, Oltz EM. 2006. Regulation of TCRβ gene assembly by a promoter/enhancer holocomplex. Immunity 24:381–91 206. Wuerffel R, Wang L, Grigera F, Manis J, Selsing E, et al. 2007. S/S synapsis during class switch recombination is promoted by distantly located transcriptional elements and activation-induced deaminase. Immunity. 27:711–22 207. Shanmugam A, Shi M-J, Yauch L, Stavnezer J, Kenter AL. 2000. Evidence for class specific factors in immunoglobulin isotype switching. J. Exp. Med. 191:1365–80 208. Kenter AL, Wuerffel R, Dominguez C, Shanmugam A, Zhang H. 2004. Mapping of a functional recombination motif that defines isotype specificity for μ->γ3 switch recombination implicates NF-κB p50 as the isotype-specific switching factor. J. Exp. Med. 199:617–27 209. Bradley SP, Kaminski DA, Peters AH, Jenuwein T, Stavnezer J. 2006. The histone methyltransferase Suv39h1 increases class switch recombination specifically to IgA. J. Immunol. 177:1179–88 210. Dent AL, Shaffer AL, Yu X, Allman D, Staudt LM. 1997. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 276:589–92 211. Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, et al. 1997. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat. Genet. 16:161–70 212. Ranuncolo SM, Polo JM, Dierov J, Singer M, Kuo T, et al. 2007. Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR. Nat. Immunol. 8:705–14 213. Phan RT, Dalla-Favera R. 2004. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 432:635–39 214. Pape KA, Kouskoff V, Nemazee D, Tang HL, Cyster JG, et al. 2003. Visualization of the genesis and fate of isotype-switched B cells during a primary immune response. J. Exp. Med. 197:1677–87 215. Cunningham AF, Gaspal F, Serre K, Mohr E, Henderson IR, et al. 2007. Salmonella induces a switched antibody response without germinal centers that impedes the extracellular spread of infection. J. Immunol. 178:6200–7 216. Cattoretti G, Buttner M, Shaknovich R, Kremmer E, Alobeid B, Niedobitek G. 2006. Nuclear and cytoplasmic AID in extrafollicular and germinal center B cells. Blood 107:3967– 75 217. Kolar GR, Mehta D, Pelayo R, Capra JD. 2007. A novel human B cell subpopulation representing the initial germinal center population to express AID. Blood 109:2545–52 218. Castigli E, Wilson SA, Scott S, Dedeoglu F, Xu S, et al. 2005. TACI and BAFF-R mediate isotype switching in B cells. J. Exp. Med. 201:35–39 219. Bergqvist P, Gardby E, Stensson A, Bemark M, Lycke NY. 2006. Gut IgA class switch recombination in the absence of CD40 does not occur in the lamina propria and is independent of germinal centers. J. Immunol. 177:7772–83 220. Xu W, He B, Chiu A, Chadburn A, Shan M, et al. 2007. Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI. Nat. Immunol. 8:294–303 www.annualreviews.org • Class Switch Recombination
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221. He B, Xu W, Santini PA, Polydorides AD, Chiu A, et al. 2007. Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 26:812–26 222. Han JH, Akira S, Calame K, Beutler B, Selsing E, Imanishi-Kari T. 2007. Class switch recombination and somatic hypermutation in early mouse B cells are mediated by B cell and Toll-like receptors. Immunity 27:64–75 223. Ueda Y, Liao D, Yang K, Patel A, Kelsoe G. 2007. T-independent activation-induced cytidine deaminase expression, class-switch recombination, and antibody production by immature/transitional 1 B cells. J. Immunol. 178:3593–601
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:261-292. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph,1 Jordi Ochando,2 and Santiago Partida-S´anchez3 1
Department of Gene and Cell Medicine, Immunology Institute, Mount Sinai School of Medicine, New York, New York 10029; email:
[email protected] 2
Unidad de Immunolog´ıa de Trasplantes, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, 28220 Madrid, Spain
3
Department of Pediatrics, The Research Institute at Nationwide Children’s Hospital and Ohio State University College of Medicine, Columbus, Ohio 43205
Annu. Rev. Immunol. 2008. 26:293–316
Key Words
First published online as a Review in Advance on November 28, 2007
chemotaxis, lymphatic vessel, postcapillary venule, lymph node
The Annual Review of Immunology is online at immunol.annualreviews.org This article’s doi: 10.1146/annurev.immunol.26.021607.090254 c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0293$20.00
Abstract The ability of dendritic cells (DCs) to initiate and orchestrate immune responses is a consequence of their localization within tissues and their specialized capacity for mobilization. The migration of a given DC subset is typified by a restricted capacity for recirculation, contrasting markedly with T cells. Routes of DC migration into lymph nodes differ notably for distinct DC subsets. Here, we compare the distinct migratory patterns of plasmacytoid DCs (pDCs), CD8α+ DCs, Langerhans cells, and conventional myeloid DCs and discuss how the highly regulated patterns of DC migration in vivo may affect their roles in immunity. Finally, to gain a more molecular appreciation of the specialized migratory properties of DCs, we review the signaling cascades that govern the process of DC migration.
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INTRODUCTION
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Dendritic cells (DCs) are highly efficient antigen-presenting cells that are central to the induction and regulation of most adaptive immune responses. Their specialized capacities for acquiring, processing, retaining, and finally presenting peptides on major histocompatibility complex (MHC) molecules are critical properties that account in part for their superior role in antigen presentation (1). Unlike other antigen-presenting cells, DCs are specialized for homing efficiently to the T cell zones of lymphoid organs for optimal interactions with T lymphocytes. Their migratory capacity distinguishes them from macrophages. For example, alveolar macrophages outnumber DCs by 100-fold in the airways, yet DCs that migrate from the airways to lung-draining lymph nodes vastly outnumber macrophages that migrate through lymph (2). The distinct migratory properties that lead to DCs being present where macrophages clearly are not found underlie a critical difference in the distinct immune-priming capacity of these two cell types. For example, even in instances when macrophages and DCs bear viral antigens for presentation, productive presentation to CD8+ T cells is limited to DCs, seemingly in part because macrophages are not appropriately localized (3). Many DCs in lymph nodes mobilize, with antigen in tow, from peripheral tissues that drain to downstream lymph nodes via a network of lymphatic vessels (4), though some antigens may travel to the lymph node freely through lymph and then gain access to DCs therein. Molecules smaller than ≈70 kDa that travel within lymph are filtered from the subcapsular sinus into conduits that limit, but do not prevent, access of lymph node DCs to these antigens (5–7). Thus, some DCs may pick up antigens directly in lymph nodes. Regardless of whether DCs pick up antigen before or after entering lymphoid organs, the pathways and mechanisms that govern how DCs migrate to lymphoid and nonlym-
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phoid tissues figure importantly in immune responses. Thus, we discuss herein how different subpopulations of DCs get to where they are going and how the migratory routes that they take affect their role in immune responses. In many instances, molecular details behind the routes of trafficking we discuss are unknown. After discussing DC migratory behavior in the context of DC subtypes and the anatomy of trafficking at the level of the whole organism, we take a step back and view the DC more generically, but with more molecular detail: We consider the signaling cascades that occur during DC mobilization, as these signals unite many DC subtypes around the potent capacity for migration in general.
DENDRITIC CELL MIGRATION AND LYMPHOID ORGANS: TRAFFICKING FROM SKIN TO LYMPH NODES AS A PARADIGM Given that the genesis of immune responses occurs largely in secondary lymphoid organs, the spleen and lymph nodes, the first consideration with regard to DC trafficking is to ask how DCs seed these organs. The spleen is one of the most widely studied sources of DCs in mice, but the mechanisms by which DC precursors access the spleen have not been explored in detail. The anatomic properties of the spleen preclude a role for lymphatics as a means of DC delivery (8). Instead, DC precursors, continuously replenished from blood precursors (9), necessarily arrive to the spleen by a hematogenous route and likely initially gain access to the marginal zone as they develop into “conventional” populations of immature DCs: CD8α− and CD8α+ DC subpopulations (10). DCs do not arise from monocytes in resting spleen, but instead derive from other blood precursors that are difficult to detect in the circulation owing to low frequency. Consequently, entry of DC precursors into spleen has not been characterized in detail, but there is evidence that they largely reside as immature DCs in the marginal zone.
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During maturation/terminal activation, DCs mobilize from the marginal zone to the T cell zone of the splenic white pulp, as they upregulate CCR7 and become responsive to CCR7 ligands CCL19 and CCL21 therein (11–13). In the absence of these signals, DCs are found scattered in the spleen in regions outside of the white pulp or in the marginal zone (12, 13).
Dendritic Cells in Lymph Nodes: Arrival by Afferent Lymphatics As in the spleen, the subsets of DCs in lymph nodes also include CD8α− and CD8α+ DCs. CD8α− DCs in lymph nodes are not absolute counterparts to splenic CD8α− DCs, in part because lymph node CD8α− DCs include DCs that travel through afferent lymph from upstream peripheral organs. CD8α− DCs in spleen and lymph nodes have different rates of turnover (14). At least some CD8α− DCs within peripheral organs can arise from monocytes (15), whereas splenic DCs cannot (15, 16); thus, some DCs in lymph nodes, but not spleen, are expected to be monocyte derived. The classical view regarding how lymph nodes are populated with DCs suggests that they emigrate there from tissues through afferent lymph constitutively (4). Lymph output of DCs in the steady state is substantial and is further augmented during inflammatory conditions (17, 18). The potent effects of inflammation in inducing DC migration are related to the fact that inflammatory cues will trigger maturation of DCs and concomitant upregulation of CCR7, the chemokine receptor centrally required for DC trafficking to lymph nodes (19, 20). The functional advantage of trafficking through afferent lymph is that it permits DCs to acquire and process antigen within peripheral organs; some antigen may be cell associated and unable to travel freely through lymph to reach the T cell zone of lymph nodes for optimal interactions with T cells.
Lymph Node–Homing Langerhans Cells: Seemingly Slower and Fewer than Expected Langerhans cells, the DCs present within epidermis, have for many years served as a paradigm for the general study of DC biology (21). Yet, as we have learned over the past few years, many aspects of their life cycle do not comply with the paradigmatic view previously developed. First, they are not continuously replenished by migratory blood precursors as anticipated, but rather renew through local proliferation under homeostatic conditions (22). Furthermore, older, seemingly established models regarding the mobilization of DCs from the epidermis to lymph nodes in response to activating stimuli are not entirely accurate, as described below. A popular assay to study DC migration involves the epicutaneous application of fluorescent contact sensitizers (23) that were once widely thought primarily to label Langerhans cells within the epidermis. However, two recent developments allowed the contribution of Langerhans cells to contact sensitization and the overall migratory DC population after epicutaneous fluorochrome application to be directly and definitively assessed: (a) the identification of the Langerhans cell–restricted (but not entirely specific) marker Langerin (24) and (b) the generation of transgenic mice in which the Langerin promoter drives GFP expression (25), such that Langerhans cells are largely distinguished from other sources of DCs. The astounding surprise resulting from the application of these new tools was that peak arrival of Langerhans cells in the lymph node is slow (Figure 1), reaching a maximum three to four days after application of sensitizer (14, 25) when immune responses are already well under way. The vast majority of contact antigen–bearing DCs are Langerin− , and they arrive within the lymph node abundantly during the first two days after sensitization. The late entry of Langerhans cells to the lymph node, along with additional recent evidence that Langerhans cells may not
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“dDC” Day 1 LC Day 3 pDC
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Afferent lymphatic
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Venule (HEV)
Rare return to blood Venule in nonlymphoid organ
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Figure 1 Anatomical routes of dendritic cell (DC) trafficking. Many DCs that seed peripheral organs enter lymph nodes through afferent lymph. In skin, apparent dermal DCs migrate to lymph nodes much faster than epidermal Langerhans cells after contact sensitization. These different types of DCs emigrate to distinct areas of the lymph node. Only a few DCs enter the blood either through reentry into venules found within peripheral tissues or through escape into efferent lymph. CD8α+ DCs are often referred to as lymph node–resident DCs, and they are believed to enter the lymph node through high endothelial venules (HEVs), rather than afferent lymphatics. However, their true trafficking patterns remain to be determined. By contrast, plasmacytoid DCs (pDCs) are known to enter inflamed lymph nodes through HEVs; unlike other DCs, they appear incapable of mobilizing from peripheral organs into afferent lymph. 296
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be essential for immune priming to at least some antigens that enter skin (25–27), raises the possibility that Langerhans cells in particular fulfill an immunoregulatory role upon their tardy arrival to the lymph node. This revised concept raises many new questions in the field. From the perspective of migration, it will be important to determine whether Langerhans cells are sometimes more rapidly and robustly mobilized to lymph nodes than observed thus far in response to contact sensitizers. Studies using TNF-α, rather than contact sensitizers, should be useful to address this question. Within 1 h, local, exogenous TNF-α dramatically reduces the density of Langerhans cells from the epidermis, presumably as a result of robust migration to lymph nodes (28, 29), whereas a far more modest reduction in Langerhans cell density within epidermis is seen one day after contact sensitization (30). The rapid and robust mobilization of Langerhans cells induced by exogenous TNF-α might lead to a correspondingly rapid and robust accumulation of Langerhans cells in the T cell zone of lymph nodes. If so, then it would be important to determine if Langerhans cells participate more centrally in immune priming under conditions where they are more efficiently mobilized, as compared with their apparently dispensable role in contact sensitivity.
Dermal Dendritic Cells Take Center Stage The failure of Langerhans cells to account for the migratory skin DCs after contact sensitization has turned renewed attention to dermal DCs (25), because the ready explanation for the origin of the Langerin− migratory DC population was that these were dermal DCs. However, it remains to be determined how many of the DCs mobilized by application of contact sensitizer are dermalresident DCs. Hypothetically, the migratory DC population could also include blood DC precursors like monocytes that enter the skin, acquire labeled antigen/sensitizer as they ma-
ture, and then rapidly mobilize to the lymph node.
Distinct Localization of Dendritic Cell Subtypes Within Lymph Nodes Upon arrival of so-called dermal DCs and Langerhans cells to the lymph node through lymphatics, the two populations assume distinctive positions within the lymph node. At all times examined, Langerin+ DCs mobilized to the deep paracortex of the T cell zone, but dermal DCs remained nearer B cell follicles (25). This distinct localization likely permits these different DC populations to carry out nonoverlapping roles in immune responses. The molecular events that account for the differing distribution of DC subtypes within the lymph nodes are unknown. One regulatory event affecting DC localization may relate to how strongly particular DCs bind to conduits in the lymph node. Compared with more mature DCs, immature DCs are anticipated to have a stronger capacity to bind to conduits (6). Thus, the phenotype and relative maturation status of a given DC type upon entry into the lymph node may dictate its positioning therein.
HEMATOGENOUS ENTRY INTO LYMPH NODES Although accumulation of DCs in lymph nodes by way of afferent lymphatics is the most well-established route of entry, the presence of DCs in lymph nodes does not depend entirely on input of DCs from afferent lymph. Some DCs or their DC precursors can enter lymph nodes through the same hematogenous route that naive lymphocytes use to access lymph nodes: passage across the specialized high endothelial venules (HEVs) within lymph nodes. DCs thought to use this route into the lymph node include CD8α+ DCs or their precursors (14), plasmacytoid DCs (pDCs) (31, 32), and CCR2hi monocytes (33) (Figure 1). For example, some monocytes that enter through the HEV during the www.annualreviews.org • Migration of Dendritic Cell Subsets
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course of Leishmania infection may develop into DCs within the lymph node, although routes of trafficking for these monocytes that later became DCs were not directly explored (34).
CD8α+ DCs: From Blood to Lymph Node
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The idea that CD8α+ DCs enter lymph nodes through the blood, by crossing HEVs, rather than through afferent lymph is widely circulated. The concept bears substantial consequences on the events that initiate immune responses. CD8α+ DCs possess superior capacity for cross-presentation of antigen to CD8+ T cells, but if these DCs do not pick up antigens in peripheral organs to transport them through lymph, then their access to antigen for cross-priming may depend on antigen transfer from other DCs that do traffic through lymph (35, 36). Consequently, some DCs, such as monocyte-derived DCs that mediate cross-presentation (37), may mainly function to deliver, but not present, antigen to lymph node T cells, at least in the context of certain infections or conditions. We now review the evidence that CD8α+ DCs enter lymph nodes only through a blood route, requiring passage across HEVs. Organs that feed lymph nodes through lymphatic drainage do not contain DCs with a CD8α+ phenotype. When CD8α+ DCs are adoptively transferred into skin, they do not migrate to downstream LNs via afferent lymphatics (38), in contrast to their CD8α− counterparts. Moreover, the rate of labeling with bromo-deoxyuridine is observed to be more rapid in CD8α+ DCs from skin-draining lymph nodes than the rate in dermal and epidermal DCs that accumulate in the same lymph nodes, suggesting that CD8α+ DCs probably did not arise from these skin-derived populations (14). In addition, CD8α+ DCs in lymph nodes never seem to acquire tracers like epicutaneously applied FITC that mark other DCs that originated within peripheral organs (35, 36), but there is precedence for 298
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the possibility that the tracers tested may not be accessible to all DCs within a given peripheral organ (39). Finally, researchers have argued that the population of CD8α+ DCs in the spleen must by nature of the organ come from a blood route, so this is likely true of the lymph node CD8α+ DCs as well (21). However, entry of DCs into the spleen from the blood is not regulated by passage across an HEV (8), so there is little basis for suggesting that the pathways of entry into the two lymphoid organs would be similar. Attempts to demonstrate directly that CD8α+ DCs traverse HEV to enter lymph nodes have so far failed. Specifically, Reinhardt and colleagues created knockin mice that expressed eYFP from the p40 IL-12/23 subunit locus. CD8α+ DCs robustly produce IL-12 upon activation, so eYFP+ CD8α+ DCs were readily detected in this model (40). Following lipopolysaccharide injection or Leishmania monocytogenes infection, the number of eYFP+ CD8α+ DCs in lymph nodes was greatly elevated. Migration seemed required to elevate the number of CD8α+ DCs in lymph nodes because their increase was blocked with pertussis toxin. However, the increased number of CD8α+ DCs was surprisingly unaffected by neutralizing mAb to CD62L (40), a selectin typically required for leukocyte passage across HEV. Thus, these data failed to support a model in which CD8α+ DCs enter the lymph node via the bloodstream/HEV route, at least during inflammation. Therefore, at present, the concept that CD8α+ DCs enter lymph nodes only through a blood route, rather than through lymph, is supported only by indirect evidence, as attempts to provide direct evidence have not succeeded. Without this pattern of trafficking established, some of the strength behind the idea that CD8α+ DCs must acquire antigen through transfer from DCs that migrated through lymph dissipates because the CD8α+ DCs may be among the lymph-migrating DC population. Of course, antigen transfer can also take place between two DCs that emigrate into the lymph node
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from lymphatics. Identification of the elusive circulating precursor for CD8α+ lymph node DCs would permit a direct analysis of the migratory routes and mechanisms by which this population of DCs seeds lymph nodes.
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Plasmacytoid Dendritic Cells: Definitive Use of a Hematogenous Route to the Lymph Node In contrast to CD8α+ DCs, pDCs have been experimentally established to have the capacity to enter lymph nodes through HEV (Figure 1). In humans, markers for pDCs include BDCA-2, BDCA-4, and IL-3 receptor (41, 42). pDCs, in contrast to myeloid DCs and monocytes in humans, lack expression of CD11c. In mice, pDCs are identified as CD11clo cells that coexpress B220, Gr-1, and 120G8 (42, 43) and selectively express siglec-H (44, 45). Functionally, in both species, they are well known as principal producers of type I interferon and hence are often alternatively called interferon-producing cells (IPCs). Soon after the discovery of this cell type, Cella and colleagues reported that IPCs accumulated in human inflamed lymph nodes just beneath HEVs, suggesting that they may enter lymph nodes through this route (31). Formal demonstration of this trafficking pattern was carried out in mouse models by intravital microscopy (32). Noninflamed lymph nodes support adhesion but not transmigration of pDCs, whereas inflamed lymph nodes permit robust emigration of pDCs across the HEV in a manner that utilizes L-selectin (CD62L) and E-selectin (CD62E) during attachment and rolling, and involves β1 and β2 integrins for firm attachment to the endothelium (32). Accordingly, pDCs are reduced in lymph nodes of CD62L-deficient mice (46). Contrary to expectations that CXCR3 would be a requisite chemokine receptor for pDC migration across HEVs (31), CCR5 but not CXCR3 was found to have a critical role (32).
In humans, chemokine-like receptor 1 (CMKLR1), also called ChemR23, is expressed by pDCs and appears to mediate their recruitment across HEVs (47, 48), which facilitate recruitment by displaying chemerin, the ligand for this receptor. In mice, CMKLR1 is not expressed by pDCs and may instead participate in macrophage recruitment (48).
MYELOID AND PLASMACYTOID DENDRITIC CELL RECRUITMENT AND INTERPLAY IN PERIPHERAL ORGANS Myeloid Blood Dendritic Cells and Monocytes As with lymphoid organs, the seeding of peripheral organs with DCs is a topic of immunological relevance because DCs in peripheral organs are the first to interact with most pathogens. However, it is not possible to discuss some DC precursors or subsets in depth with regard to trafficking or function because so little is known about them. In particular, CD14− BDCA-1+ /CD1c+ and CD14− BDCA-3+ DCs (41), which may be very relevant human DC precursors in the blood, have no established destinations in vivo. Some studies have operated under the assumption that BDCA-1+ DCs within human tissues arise from BDCA-1+ DCs in blood, but this point has not been firmly established and seems unlikely given that BDCA1+ myeloid DCs in blood are CD14− , whereas some BDCA-1+ cells in lung are CD14+ (49). Moreover, the murine counterparts to these cells are also unknown. Indeed, among potential DC precursors, only pDCs and monocytes have been studied in sufficient detail for researchers to begin to develop a picture of their full life cycle. Monocytes can serve as precursors for DCs in the periphery during various conditions of inflammation (10) or in the absence of inflammation (15). Monocytes may thus serve as www.annualreviews.org • Migration of Dendritic Cell Subsets
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precursors for many of the myeloid peripheral tissue DCs that ultimately emigrate through afferent lymph, although they play a small role in becoming splenic DCs (15). The signals and molecular events involved in recruitment of monocytes into tissues have been recently reviewed in detail (50).
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Compared with the difficulty of discerning whether myeloid DCs in peripheral organs are derived from monocytes or myeloid blood DCs or are otherwise macrophages, pDCs are easy to trace by staining for their particular signature markers within tissues. pDCs can apparently enter normal organs at very low levels in humans (49, 51, 52) and mice (53, 54). However, they are far more numerous in diseased or inflamed tissues. For example, in humans and mice, they have been described in skin inflammatory diseases (47, 55), in allergic diseases of the airway (52), and in mouse allografts (56). pDCs also home to the small intestine of mice in the steady state, with increased recruitment during inflammation, by a mechanism that relies on CCR9 (54). By contrast, CCR9 is not required for pDC entry into lymph nodes or other organs. Thus, there may be specific requirements for pDC migration into peripheral organs that are distinct from mechanisms used by pDCs to enter lymphoid organs. However, some receptors may be used by pDCs to traffic to multiple tissues. For example, CKLR1/ChemR23 appears to mediate human pDC migration into lymph nodes and inflamed skin (47).
Exit of Plasmacytoid Dendritic Cells from Peripheral Organs The classical paradigm that activated DCs become induced to enter lymphatic vessels from tissues (Figure 1) prompts the possibility that pDCs within tissues will enter lymph nodes through not only HEVs (as discussed 300
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above), but also afferent lymphatics. Surprisingly, this predicted pattern of trafficking has not been upheld experimentally. On the contrary, afferent lymph is devoid of pDCs under homeostatic and inflammatory conditions (57). Researchers drew this conclusion in a rat model (57) using a well-established technique to sample pseudoafferent lymph directly (17). The possibility that pDCs do not enter afferent lymph vessels has pivotal implications for the role of tissue pDCs in presenting antigen that they may acquire within tissues. Without the capacity to home to a T cell–rich environment, pDCs that localize to peripheral tissues may not be there primarily to acquire antigen for the purposes of antigen presentation. They may instead mainly support the antigen-presentation function of myeloid DCs. For instance, the activation of pDCs within the intestine in turn enhances mobilization of myeloid DCs during intestinal inflammation (47). On the other hand, limited lymphatic access may not affect the capacity of pDCs to bring tissue-derived antigens to lymph nodes. Following allograft transplantation, pDCs acquire MHC II antigen-containing peptide derived from the allograft, and these pDCs are found in the blood and accumulate in lymph nodes by a CD62L-dependent mechanism (56). Putting these data together with the observations described above generates an unexpected picture in which pDCs have access to lymph nodes through only a hematogenous route, in striking contrast to the trafficking patterns of conventional DCs.
CAN MATURE DENDRITIC CELLS RETURN TO THE BLOOD AND ENTER OTHER ORGANS? The possibility that pDCs carry antigen from an allograft or spleen to lymph nodes via a hematogenous route raises the broader issue of whether DCs derived from a peripheral organ or lymph node can generally mobilize back into blood and ultimately home
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to another organ. Mechanisms to reenter the bloodstream would include either (a) direct migration across vascular endothelium in the ablumenal-to-lumenal direction, or (b) failure of DCs to be trapped in lymph nodes such that they emerge into efferent lymph that accesses the bloodstream through the thoracic duct. Either route of entry into the bloodstream could have a major impact on immunity and inflammation. For example, such trafficking might facilitate the spread of infectious microbes from tissue to tissue, carried by DCs serving as Trojan horses. Indirect evidence for this possibility exists (58, 59). In addition, presentation of antigen at distal sites may become possible. A fraction of DCs is known to enter efferent lymph at a low frequency (4, 60, 61). Until recently, researchers had only indirect evidence for the possibility that immune responses are mediated by DCs that pass through the lymph node into efferent lymph or return to blood directly (4). In addition to gaining access to the bloodstream, DCs would need to express the right subset of molecules to home into other organs, but mature DCs have downregulated many chemokine receptors and adhesion molecules that are generally used for leukocyte homing into other organs. In mice whose lymphotoxin β receptor pathway has been manipulated so that the mice lack skin-draining lymph nodes, but possess mesenteric lymph nodes (62), endogenous skin DCs are not filtered by skindraining lymph nodes and therefore enter the efferent lymph and blood unimpeded. After accessing blood, these DCs fail to accumulate in the spleen but instead enter in mesenteric lymph nodes (62), implying that, against expectations, homing mechanisms are in place for matured skin DCs to enter mesenteric lymph nodes. The molecular nature of this homing pathway is unknown. Other recent publications, discussed below, have elaborated on whether and with what consequences DCs leave one tissue, traverse blood, and enter another tissue to modulate immunity. Bone marrow–derived
DCs injected into the rear footpad of mice migrate exclusively to popliteal lymph nodes as expected. However, coinjecting these mice with vitamin D3 (63) appears to cause the transferred DCs to home to mesenteric lymph node and Peyer’s patches (63), allowing induction of mucosal immunity. Homing of adoptively transferred splenic DCs from the footpad to the bone marrow, where central memory T cells expand, has also been described (60). This migration occurred at a very low frequency. Nonetheless, on the basis of the frequency of labeled DCs found in the bone marrow, researchers developed the argument that the migration most likely involved direct reentry into the bloodstream by the transferred DCs rather than passage through efferent lymph (60). Both of these studies used adoptive transfer models and did not probe endogenous DCs. When large numbers of endogenous skin DCs were labeled by epicutaneous administration of a fluorescent sensitizer, labeled endogenous DCs were not recovered in the bone marrow (61), suggesting that the bone marrow is an extremely minor destination for endogenous DCs, at least those from skin.
Dendritic Cell Migration to the Thymus If antigen-bearing DCs that return to blood subsequently emigrate into the thymus, they may be a source of self-antigen for the induction of central tolerance (64). This issue assumes that regulation by autoimmune regulator (AIRE) of the expression of tissuerestricted antigens by thymic epithelium (65) leaves gaps in the repertoire of self-antigens that are presented to thymocytes during thymic selection and that antigen-bearing DCs that enter from the periphery might be able to present antigen to fill in those gaps (64). When millions of labeled crude splenic cells, mainly CD11c+ cells, were injected directly into the bloodstream as a model designed to mimic DC reentry into blood, bypassing the tremendous hurdle of www.annualreviews.org • Migration of Dendritic Cell Subsets
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leaving a peripheral organ, a few labeled DCs entered the thymus by a mechanism that required P-selectin and α4β1 integrin (66). Studies in parabiotic mice confirmed that blood DCs or their precursors can enter the thymus (66). However, neither of these approaches addresses the most interesting and relevant question of whether DCs that might have picked up antigen in one tissue reenter the blood and home to thymus for antigen presentation. Further experiments in the same study were designed to probe whether endogenous, FITC antigen-bearing DCs can leave a tissue like skin, gain access to blood, and then home to the thymus. In these experiments, mice were treated epicutaneously with FITC. Subsequently, FITC+ CD11c+ DCs were found in the thymus, although at a frequency so low that fewer than 10 scattered events said to correspond with the labeled cells were typically detected by FACS (66). Moreover, the protocol of delivering FITC as antigen to the skin was unusual; the skin was tape-stripped prior to FITC application to remove the stratum corneum that largely absorbs most of the applied FITC (30), and a very large volume of FITC was applied. The investigators in the study also found FITC+ DCs in the spleen using this protocol, in contrast to others who have used epicutaneous FITC via a more standard protocol (61, 62). As a result, the use of FITC painting in conjunction with removal of the stratum corneum may be flawed, likely because it leads to systemic spread of the FITC label that may not require any DC transport from the skin. In any case, given the probability that only a very small number of DCs mobilize from tissues to thymus (66) and that only a very small fraction of those DCs bears significant self-antigens from tissues that may not be expressed in the thymus (antigens acquired by DC engulfment of apoptotic parenchymal cells), DC trafficking to the thymus from other tissues, even if it occurs, is most likely irrelevant for presentation of self-antigens and clonal deletion of lymphocytes.
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Anatomic Restrictions that May Affect Migration Routes from Tissue to Blood Versus Lymph In the context of transplantation, pDCs, conventional DCs, and cells closely resembling DCs can be found to leave tissues and reenter the bloodstream (56, 67–70). These observations may reveal a pattern of trafficking that is always ongoing but difficult to observe. Alternatively, the transplantation may have an impact on DC trafficking. In particular, because lymphatic vessels sometimes reanastomose slowly after transplantation, migratory cells may instead mobilize via atypical or normally less-favored routes. Indeed, accumulation of DCs or their precursors in tissues that for any reason have restricted access to lymphatics may provoke nonstandard routes of emigration. For example, priming of immune responses by DCs within lymph nodes is redirected to the spleen when emigration to lymph nodes is hindered by genetic deficiency in CCR7 ligands that normally mediate DC mobilization to lymph nodes (71). An example of naturally restricted access to lymphatics may be found in atherosclerosis. Early in this disease, monocyte-derived cells that can develop into macrophages or DCs accumulate beneath arterial endothelium in a position lumenal to the internal elastic lamina (72). Mononuclear phagocytes with a “veiled” morphological appearance akin to DCs have been observed to return across arterial endothelium in the ablumenal-to-lumenal direction (73), allowing their escape from atherosclerotic plaques by reentry into the bloodstream. Within atherosclerotic lesions, monocyte-derived cells that differentiate into would-be lymph-homing DCs are expected to have limited capacity to mobilize toward the lymphatic vessels, which are located in the periadventitial space of the artery, because they are separated from those lymphatics by the imposing arterial media lined with smooth muscle cells and elastic laminae. As mentioned, the internal elastic lamina provides a floor for developing atherosclerotic plaques,
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and this lamina acts as a barrier to transport of large molecules. After traversing the arterial endothelium, low-density lipoproteins, for example, travel beneath and laterally along the endothelium rather than passing through the elastic lamina (74). Likewise, the elastic laminae may impede cellular passage and possibly even perceptions of chemotactic signals that would support movement toward the periadventitia. Consistent with the possibility that cellular passage into and across the media is very limited are observations that herpes virus–infected smooth muscle cells within elastic arteries are inaccessible to clearance by phagocytes and lymphocytes (75). In the absence of an open pathway to lymphatics and without a physical barrier between them and the ablumenal surface of the endothelium, “veiled” mononuclear phagocytes that may be akin to DCs from atherosclerotic plaques return to blood (73, 77) using what is likely an alternative, secondary route.
SIGNALING CASCADES THAT GOVERN MIGRATION OF DENDRITIC CELLS Migratory cells use highly conserved mechanisms to sense and respond to small changes in the concentration of chemoattractants in their external milieu (78). Over the past few years, many key intracellular pathways and signaling molecules downstream of chemokine receptors in DCs have begun to be identified, and some signal transduction models have been proposed (79). Yet a global unified model encompassing the diversity of chemokine receptors, their complex downstream signaling cascades, and the remarkable heterogeneity of their biological effects is not achievable at this time. Most of the research on signaling during DC migration has been carried out using monocyte- or bone marrow–derived DCs. These DCs differ substantially from some DC subsets described above, but they do provide a valuable tool for researchers to develop a generic model of the proximal signals that govern DC motility and migration.
Before activation, conventional myeloid DCs found in peripheral organs can express CCR1, CCR2, CCR5, CCR6, CXCR1, CXCR2 and CXCR4, with these expression patterns differing somewhat among DC subsets. Upon stimulation by pathogenderived antigens and/or endogenously generated danger-associated signaling molecules, activated DCs acquire a migratory phenotype associated with the upregulation of CCR7 and express receptors linked with DC maturation, including CD40, CD80, CD86, and MHC class II. As mentioned above, the G protein–coupled receptor CCR7 is the dominant mediator of DC mobilization to the T cell compartment of lymphoid organs (19). CCR7 expression alone, however, is not sufficient to confer mobilization to the T cell zone of lymph nodes and spleen; additional DC receptors are required to positively regulate CCR7 function (79).
CCR7-Mediated Migration: A “Multimodule” Model DC signaling through CCR7 initiates and orchestrates a vast repertoire of molecular events that control chemotaxis and several other biological functions in these cells (reviewed in Reference 79). The CCR7 polyfunctional signal transduction apparatus exemplifies the complexity of the molecular events initiated upon ligation of most chemokine receptors. Various nonoverlapping signaling modules, rather than a single pathway, appear to regulate distinct DC migratory responses, such as chemotaxis or migratory speed, induced by the chemokine ligands for CCR7, CCL19, and CCL21. Similar to all G protein–coupled receptors, CCR7 interacts with G proteins to transmit intracellular signals. A classical G protein– dependent mechanism involves the use of the alpha (α) subunit and the release of the beta and gamma dimer (βγ) of the heterotrimeric G protein (80, 81) (Figure 2). Four families of α subunits are known: Gαs , Gαq , Gαi , and Gα12 . Each family is composed of several www.annualreviews.org • Migration of Dendritic Cell Subsets
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Figure 2 Various signaling pathway modules regulate distinct DC migratory responses induced by chemokines through CCR7. Upon agonist binding, trimeric G proteins are uncoupled, and a series of signal transduction events ensue that result in cell activation followed by enhanced motility. At least two nonoverlapping independent signaling modules are activated upon CCR7 ligation. One module is initiated by Gα12 activation, resulting in the release of the free βγ subunit, which in turn activates downstream effectors including Rho GTPases, the proline-rich tyrosine kinase 2 (Pyk2) and the actin-binding protein cofilin. This module may regulate the basal migratory speed of DCs, but not DC chemotaxis. Conversely, another signaling module engages upon Gαi stimulation, leading to mitogen-activated protein kinase (MAPK) activation, including p38, ERK1/2, and JNK. In addition, free βγ activates phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), and Akt-NF-κB pathways, which are important for activation and survival of the cells. Moreover, phospholipase Cβ2 (PLCβ2) breaks down plasma membrane lipids into diacylglycerol (DAG) and the calcium second messenger, inositol trisphosphate (IP3), which in turn induces the intracellular release of calcium ions (Ca2+ ) from IP3-gated stores on the endoplasmic reticulum (ER). This second module may regulate chemotaxis in most cellular systems. A third module appears to be required for CCR7-induced DC chemotaxis, and it would be sparked by sequential Gαi and Gαq activation. The free Gαq or βγ subunit would then activate PLCβ1,3 favoring the generation of IP3 and consequently intracellular Ca2+ release. The ectoenzyme CD38 may function as a coadjuvant of this module by converting NAD+ to cyclic ADP-ribose (cADPR), which may act at ryanodine receptors to expand release of Ca2+ from intracellular stores. This capacitates a calcium channel on the cell membrane, resulting in a sustained influx of extracellular Ca2+ required for DC migration.
members, thereby contributing to diversity in chemokine receptor–mediated signaling (82). Chemotaxis is thought to be regulated primarily through the Gαi subfamily, which contains three subunits, Gαi2 , β, and γ. The activation of Gαi , induced by the binding of GTP 304
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to Gαi2 and the release of free βγ, initiates the chemokine receptor signaling cascade (78) (Figure 2). The free βγ subunit subsequently activates downstream effectors such as PI3K which regulate the Akt pathway that plays a pivotal
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role in regulating chemotaxis in leukocytes, including DCs (83, 84). However, alternative pathways may also regulate chemotaxis in a PI3K/Akt-independent manner (85–88). Overall, it seems that PI3K/Akt and the transcription factor nuclear factor κB (NFκB) regulate CCR7-dependent DC survival, whereas PI3K/Akt-independent signaling pathways may be preferred, but not required, during chemokine receptor engagement in DCs (87, 88). In this model, the Gαi -proteinderived βγ subunit preferentially triggers signal transduction via mitogen-activated protein kinase (MAPK) family members p38, ERK1/2, and JNK (84, 87, 89), whereas Cdc42 and Rac, but not RhoA GTPases, coordinate actin polarization, cytoskeletal rearrangement, cell polarity, and ultimately motility (84, 87, 89). It is difficult to dissect the true importance of each kinase toward a specific biological endpoint because MAPKs play important roles in many DC functions, including maturation, migration, cell proliferation, cytokine production, and survival. The literature points to a critical role for MAPKs during the upstream events that lead to DC migration (90–93). Activity of the p38 MAPK regulates IL-12p40 production in macrophages and DCs (94, 95). Homodimers of IL-12p40 facilitate DC migration from the lung to the draining lymph nodes after Mycobacterium tuberculosis infection (96), and IL-12p40 also supports migration of adoptively transferred DCs to draining lymph nodes (40). Phosphorylation of p38 MAPK is required for DC maturation and the synthesis of cytokines (97–100), but DCs are at least partially competent to chemotax when p38 is inhibited (84, 88), suggesting that p38 MAPK in particular may support DC migration through production of cytokines that in turn participate in migration. When p38 MAPK is blocked, another MAPK may take over. Riol-Blanco and colleagues (87) recently proposed an integrated signaling module to regulate chemotaxis in CCR7-stimulated DCs. This pathway is ignited by Gαi -mediated activation of either
p38 or ERK1/2, and this activation is thought to be upstream of JNK. Interestingly, inhibition of all these kinases does not completely blunt CCR7-dependent chemotaxis (87, 88), suggesting that additional unidentified molecules or signaling pathways may also regulate chemotaxis of DCs. Although the pertussis toxin–sensitive Gαi subunit is known to be the nascent component regulating various independent signaling/functional arms during DC chemotaxis (101, 102), chemokine receptor coupling to other Gα subunit families has not been thoroughly examined. By using Gα subunit– deficient mice, we recently identified a novel alternative chemokine receptor signaling module that requires Gαi as well as Gαq for the in vitro chemotaxis of bone marrow– derived DCs to the ligands of CXCR4 and CCR7 (103). Gαq -coupled pathways directly activate PLCβ1 and PLCβ3, resulting in the generation of diacylglycerol and the subsequent activation of protein kinase C. This in turn leads to PI3K-dependent inositol trisphosphate production and calcium mobilization (81, 104). Immature or mature DCs from Gαq −/− mice have significantly reduced calcium fluxes in response to chemokine receptor stimulation and are unable to migrate to inflammatory sites or lymph nodes in vivo (103), indicating that signaling modules dependent on Gαi and Gαq are critical for DC migration. Strikingly, T cells, which also use CCR7 to migrate to CCR7 ligands, did not require Gαq , indicating unexpectedly that distinct signaling pathways are used by DCs and T cells to respond to the same chemokines (103). In addition to the Gαq pathway, another Gαi -independent signaling module via Rho/Pyk2/cofilin has been reported (87). Like the Gαq pathway, this signaling module is engaged by a pertussis toxin–insensitive class of G proteins, presumably G12 /G13 . However, unlike the Gαq pathway, this module was dispensable for chemotaxis and instead was found to control DC migratory speed (79, 87, 105) (Figure 2). Further understanding of www.annualreviews.org • Migration of Dendritic Cell Subsets
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the different signaling networks downstream of chemokine receptors and identification of the individual signaling components that regulate each pathway are needed. This knowledge may lead to improved DC vaccination protocols or application in other therapeutic settings where modulation of DC migration may be desirable.
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Signaling Through Cell Surface Enzymes and Nonchemokine Dendritic Cell Receptors A myriad of maturation and nonchemokine chemotactic factors, which can be rapidly produced within inflamed or damaged tissue, plays a central role in stimulating recruitment of DCs and preparing them for subsequent mobilization to lymph nodes (106–109). Immature DCs express several chemotactic receptors for nonchemokine agonists (110, 111). Several of these receptors promote DC activation and are upregulated by endogenous maturation signals such as IL-1, TNF-α, and CD40L or exogenous microbial products that activate Toll-like receptors (TLRs) (112– 114). Most of the aforementioned stimuli trigger downstream signaling pathways that activate NF-κB and induce proinflammatory gene expression (115, 116). Inflammatory and cellular stress–linked signals expand the array of signaling mechanisms that can directly affect DC migration. For example, the activating surface receptor TREM-2, which induces DC maturation by a mechanism independent of NF-κB, critically regulates CCR7-dependent DC chemotaxis (117, 118). TREM-2 associates with DAP12, an ITAM-containing adaptor molecule that also regulates DC migration (119, 120). Intriguingly, TREM-2-mediated upregulation of CCR7 does not correlate with a greater capacity of DCs for chemotaxis, consistent with the notion that CCR7 responses require additional extracellular signals (118). It is not yet understood how the TREM/DAP12 pathway may converge with other intracellular signals downstream of CCR7. Knockdown of 306
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the transmembrane adapter protein NTAL, a novel component of the TREM-1/DAP12 pathway, yields significantly reduced calcium influx (121), supporting the idea that NTAL may mediate calcium mobilization that is required for DC chemotaxis to a variety of chemokines and nonchemokine stimuli (122– 125). Chemoattractant-triggered DC chemotaxis is thought to be controlled, at least in part, by cADPR and ADPR calciummobilizing metabolites (126, 127) (Figure 2), both catalytic products of the nucleotidemetabolizing ectoenzyme CD38 and the NAD+ substrate. CD38-deficient neutrophils, monocytes, and DCs show impaired calcium and chemotactic responses to a variety of chemokines in vitro and in vivo (128, 129). CD38-derived metabolites have a broad impact on chemokine receptor–mediated signaling in myeloid cells, presumably by inducing calcium fluxes conducted through the cADPR- and ADPR-activated plasma membrane channel TRPM2 (130), a member of the transient receptor potential TRP channel superfamily (131, 132). TRPM2 is a nonselective cation channel widely expressed by leukocytes, including DCs (130, 133, 134). Other DC receptors that induce calcium mobilization may also rely on a CD38-generated calcium second messenger to transmit signals that promote migration. Inflammatory signals and bacterial products that induce DC maturation and CCR7 expression often induce upregulation of CD38 (128, 135–137). By contrast, activation of monocytes through TLR2, 4, and 5 induces CD38 downregulation (135), which is possibly linked to the observation that monocyte-derived cells can become impaired in their migration to lymph nodes by bacterial signals (138). TLR signaling triggers a cascade of events in DCs that includes modified chemokine and cytokine production, altered chemokine receptor expression, and changes in signaling through G protein–coupled receptors (112, 139–141). These changes may often
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synergistically support migration of DCs, but crosstalk between TLR-mediated signaling pathways in DCs may sometimes result in antagonistic effects. For example, engagement of TLR3 or TLR4 on monocyte-derived DCs markedly increases expression of regulator of G protein signaling 1 (RGS1) protein (101), which has been well documented as accelerating the intrinsic GTPase activity linked with Gαi subunits. Thus, increased levels of RSG1 inhibit DC migration to lymph nodes (101). How pathogen-derived signals, including but not limited to signals through TLRs, regulate DC migration needs more study. Clearly, some pathogens use mechanisms to arrest DC migration to protect themselves from the generation of potent adaptive immune responses. Schistosomal parasites produce prostaglandin D2 to inhibit DC migration to lymph nodes after an experimental infection through skin (142), and microbial antigens derived from Borrelia garinii, the causative agent of chronic Lyme disease, significantly downregulate CD38 and CCR7 expression in DCs, thereby hampering their migratory capacity (143).
Signals that Modulate Migration as Part of a Tissue Damage Response Under conditions of cell stress, inflammation, or tissue insult, ordinary metabolites that are otherwise maintained intracellularly may be released to the extracellular milieu. Such molecules may then target receptors present on the surface of DCs to modulate their maturation and/or migration. One cytokine-like molecule released in necrotic tissues or by some cells in response to TLR signals is high mobility group box 1 (HMGB1), which may regulate DC migration (144). Another class of metabolites released in injured tissues includes purine nucleotides, such as NAD, ATP, ADP, ADPR, and AMP (Figure 2). DCs express a variety of purine sensors on their surface; some, like CD38, work as ectoenzymes metabolizing purine nucleotides, whereas others are a class of
plasma membrane receptors ligated by extracellular nucleotides (145, 146). Two main types of purinoreceptors, P2YR and P2XR, have been identified. P2YRs are a family of G protein–coupled receptors that are abundantly expressed on DCs. Upon activation, they induce generation of inositol trisphosphate, release of calcium, and stimulation of adenylate cyclase via Gαi or Gαq proteins. Selective P2YR agonists (e.g., ATP, ADP, and UTP) are potent chemotactic stimuli for immature, but not mature, DCs (125, 147). P2YR-dependent, downstream signals mobilize calcium and couple to pertussis toxin–sensitive G proteins (125). Thus, purinoreceptors and NAD+ -ases such as CD38 may function in a concerted manner during inflammation or tissue damage to regulate DC recruitment and emigration. Given both that these signals may couple with CCR7 to optimize migration of DCs and that regulating the availability of extracellular nucleotides may be feasible pharmacologically, these pathways merit further attention in future research.
SUMMARY AND FUTURE DIRECTIONS As discussed herein, it is clear that trafficking patterns of DCs are highly regulated and differ greatly among different types of DCs (Figure 1). The variation in trafficking patterns sets the stage for the many roles different DC subsets play in immunity. For example, the slow arrival and distinct localization of Langerhans cells to lymph nodes in response to contact sensitizers naturally limits their importance in inducing immunity to sensitizers and suggests that they play a different role in the ensuing immune response than do the earlier arriving DCs. In some cases, the immunologic significance behind a particular pattern or restriction in trafficking seems obvious. For example, the retention of most DCs within the lymph node through limited circulation into efferent lymph concentrates antigen within www.annualreviews.org • Migration of Dendritic Cell Subsets
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the lymph node, thereby likely increasing the relative density of particular peptide-MHC complexes for improved antigen presentation to a cognate population of T cells. Furthermore, the relative sequestration of activated DCs in the lymphatic system, permitting only rare return of mature DCs to blood, may protect the host. Indeed, it has been argued that the passage of highly activated, cytokine-producing and procoagulant-prone macrophages and DCs in the circulation during Ebola virus infection contributes pivotally to the deadly nature of this pathogen (148). However, especially under conditions when DCs fail to access lymphatics appropriately, they can gain at least limited access to blood and go on to mediate immune responses in distal lymphoid organs. The migratory patterns of pDCs are in almost every way different from those of conventional DCs, as we discuss in this review (Figure 1). Any immunological advantage that may be conferred by the fact that pDCs take distinct routes to the lymph node that differ so greatly from the routes of conventional DCs remains unknown. It is unclear, in particular, if there is an underlying immunological advantage in their apparent failure to move from tissues to lymph nodes through lymphatics. Why do they enter lymph nodes primarily through HEVs? Leaving the tissue of transplant immunity aside, entry of pDCs through HEVs when viruses or other antigens enter lymph nodes through afferent lymph seems to put pDCs at a disadvantage in accessing relevant antigen for presen-
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tation. Their trafficking pattern seemingly fits best with the concept that in many instances pDCs support antigen presentation mediated by conventional DCs, rather than present themselves. Alternatively, the entry of pDCs into the lymph node through HEVs may set up an important backup system. Upon entry through HEVs, pDCs could acquire viral particles that may have escaped capture by conventional DCs and that may be freely available in lymph fluid. They may then process and present these antigens, such that their participation in presenting viral antigen in the lymph node may be a “second-tier” level of defense and depend on how well conventional DCs and other cells in tissues and the lymphatic system have managed to contain the virus. Obviously, we still have much to learn regarding how DC migration is regulated, why it is regulated the way it is, and what happens when normal migration and trafficking patterns are disrupted. In addition, much work remains to be done to explain how signaling pathways work together to coordinate DC migration. Recent findings discussed herein indicate that DCs employ distinct signaling cascades to respond to chemokines like CCR7 ligands, raising the possibility that DC migration could be manipulated by means that will not alter T cell migration. Ultimately, the goal is to integrate our understanding of the signals that regulate DC migration and the molecular changes within tissues where DC migration occurs with our knowledge of the overall trafficking patterns of different DC subsets in vivo.
DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS We thank Dr. Claudia Jakubzick for critical reading of the manuscript. G.J.R. is supported in part by NIH grants and an Established Investigator Award from the American Heart Associa´ y Ciencia, Spain (reference SAF2007tion, J.O. by a grant from the Ministerio de Educacion 63579), and S.P-S. by CCRI-175404. 308
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LITERATURE CITED 1. Trombetta ES, Mellman I. 2005. Cell biology of antigen processing in vitro and in vivo. Annu. Rev. Immunol. 23:975–1028 2. Jakubzick C, Tacke F, Llodra J, van Rooijen N, Randolph GJ. 2006. Modulation of dendritic cell trafficking to and from the airways. J. Immunol. 176:3578–84 3. Norbury CC, Malide D, Gibbs JS, Bennink JR, Yewdell JW. 2002. Visualizing priming of virus-specific CD8+ T cells by infected dendritic cells in vivo. Nat. Immunol. 3:265–71 4. Randolph GJ, Angeli V, Swartz MA. 2005. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat. Rev. Immunol. 5:617–28 5. Gretz JE, Anderson AO, Shaw S. 1997. Cords, channels, corridors and conduits: critical architectural elements facilitating cell interactions in the lymph node cortex. Immunol. Rev. 156:11–24 6. Sixt M, Kanazawa N, Selg M, Samson T, Roos G, et al. 2005. The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Immunity 22:19–29 7. Itano AA, McSorley SJ, Reinhardt RL, Ehst BD, Ingulli E, et al. 2003. Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity. Immunity 19:47–57 8. Mebius RE, Kraal G. 2005. Structure and function of the spleen. Nat. Rev. Immunol. 5:606–16 9. Liu K, Waskow C, Liu X, Yao K, Hoh J, Nussenzweig M. 2007. Origin of dendritic cells in peripheral lymphoid organs of mice. Nat. Immunol. 8:578–83 10. Shortman K, Naik SH. 2007. Steady-state and inflammatory dendritic-cell development. Nat. Rev. Immunol. 7:19–30 11. Reis e Sousa C, Hieny S, Scharton-Kersten T, Jankovic D, Charest H, et al. 1997. In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin 12 by dendritic cells and their redistribution to T cell areas. J. Exp. Med. 186:1819–29 12. Gunn MD, Kyuwa S, Tam C, Kakiuchi T, Matsuzawa A, et al. 1999. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J. Exp. Med. 189:451–60 13. Ato M, Stager S, Engwerda CR, Kaye PM. 2002. Defective CCR7 expression on dendritic cells contributes to the development of visceral leishmaniasis. Nat. Immunol. 3:1185–91 14. Kamath AT, Henri S, Battye F, Tough DF, Shortman K. 2002. Developmental kinetics and lifespan of dendritic cells in mouse lymphoid organs. Blood 100:1734–41 15. Varol C, Landsman L, Fogg DK, Greenshtein L, Gildor B, et al. 2007. Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J. Exp. Med. 204:171–80 16. Naik SH, Metcalf D, van Nieuwenhuijze A, Wicks I, Wu L, et al. 2006. Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. Nat. Immunol. 7:663–71 17. Pugh CW, MacPherson GG, Steer HW. 1983. Characterization of nonlymphoid cells derived from rat peripheral lymph. J. Exp. Med. 157:1758–79 18. MacPherson GG, Jenkins CD, Stein MJ, Edwards C. 1995. Endotoxin-mediated dendritic cell release from the intestine: characterization of released dendritic cells and TNF dependence. J. Immunol. 154:1317–22 ¨ ¨ 19. Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, et al. 1999. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99:23–33 www.annualreviews.org • Migration of Dendritic Cell Subsets
309
ARI
25 March 2008
22:6
20. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. 1999. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401:708–12 21. Villadangos JA, Heath WR. 2005. Life cycle, migration and antigen presenting functions of spleen and lymph node dendritic cells: limitations of the Langerhans cells paradigm. Semin. Immunol. 17:262–72 22. Merad M, Manz MG, Karsunky H, Wagers A, Peters W, et al. 2002. Langerhans cells renew in the skin throughout life under steady-state conditions. Nat. Immunol. 3:1135–41 23. Macatonia SE, Edwards AJ, Knight SC. 1986. Dendritic cells and the initiation of contact sensitivity to fluorescein isothiocyanate. Immunology 59:509–14 24. Valladeau J, Duvert-Frances V, Pin JJ, Dezutter-Dambuyant C, Vincent C, et al. 1999. The monoclonal antibody DCGM4 recognizes Langerin, a protein specific of Langerhans cells, and is rapidly internalized from the cell surface. Eur. J. Immunol. 29:2695–704 25. Kissenpfennig A, Henri S, Dubois B, Laplace-Builhe C, Perrin P, et al. 2005. Dynamics and function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells. Immunity 22:643–54 26. Kaplan DH, Jenison MC, Saeland S, Shlomchik WD, Shlomchik MJ. 2005. Epidermal langerhans cell-deficient mice develop enhanced contact hypersensitivity. Immunity 23:611–20 27. Allan RS, Smith CM, Belz GT, van Lint AL, Wakim LM, et al. 2003. Epidermal viral immunity induced by CD8α+ dendritic cells but not by Langerhans cells. Science 301:1925–28 28. Kimber I, Cumberbatch M. 1992. Stimulation of Langerhans cell migration by tumor necrosis factor α (TNF-α). J. Invest. Dermatol. 99:48S–50S 29. Cumberbatch M, Griffiths CE, Tucker SC, Dearman RJ, Kimber I. 1999. Tumour necrosis factor-α induces Langerhans cell migration in humans. Br. J. Dermatol. 141:192–200 30. Robbiani DF, Finch RA, Jager D, Muller WA, Sartorelli AC, Randolph GJ. 2000. The leukotriene C(4) transporter MRP1 regulates CCL19 (MIP-3β, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell 103:757–68 31. Cella M, Jarrossay D, Facchetti F, Alebardi O, Nakajima H, et al. 1999. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat. Med. 5:919–23 32. Diacovo TG, Blasius AL, Mak TW, Cella M, Colonna M. 2005. Adhesive mechanisms governing interferon-producing cell recruitment into lymph nodes. J. Exp. Med. 202:687– 96 33. Palframan RT, Jung S, Cheng G, Weninger W, Luo Y, et al. 2001. Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J. Exp. Med. 194:1361–73 34. Leon B, Lopez-Bravo M, Ardavin C. 2007. Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania. Immunity 26:519–31 35. Belz GT, Smith CM, Kleinert L, Reading P, Brooks A, et al. 2004. Distinct migrating and nonmigrating dendritic cell populations are involved in MHC class I-restricted antigen presentation after lung infection with virus. Proc. Natl. Acad. Sci. USA 101:8670–75 36. Allan RS, Waithman J, Bedoui S, Jones CM, Villadangos JA, et al. 2006. Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming. Immunity 25:153–62 37. Le Borgne M, Etchart N, Goubier A, Lira SA, Sirard JC, et al. 2006. Dendritic cells rapidly recruited into epithelial tissues via CCR6/CCL20 are responsible for CD8(+) T cell crosspriming in vivo. Immunity 24:191–201
Annu. Rev. Immunol. 2008.26:293-316. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-10
310
Randolph
·
Ochando
·
Partida-S´anchez
Annu. Rev. Immunol. 2008.26:293-316. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-10
ARI
25 March 2008
22:6
38. Smith AL, Fazekas de St Groth B. 1999. Antigen-pulsed CD8α+ dendritic cells generate an immune response after subcutaneous injection without homing to the draining lymph node. J. Exp. Med. 189:593–98 39. Randolph GJ, Inaba K, Robbiani DF, Steinman RM, Muller WA. 1999. Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 11:753–61 40. Reinhardt RL, Hong S, Kang SJ, Wang ZE, Locksley RM. 2006. Visualization of IL12/23p40 in vivo reveals immunostimulatory dendritic cell migrants that promote Th1 differentiation. J. Immunol. 177:1618–27 41. Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, et al. 2000. BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J. Immunol. 165:6037–46 42. Shortman K, Liu YJ. 2002. Mouse and human dendritic cell subtypes. Nat. Rev. Immunol. 2:151–61 43. Asselin-Paturel C, Brizard G, Pin JJ, Briere F, Trinchieri G. 2003. Mouse strain differences in plasmacytoid dendritic cell frequency and function revealed by a novel monoclonal antibody. J. Immunol. 171:6466–77 44. Blasius A, Vermi W, Krug A, Facchetti F, Cella M, Colonna M. 2004. A cell-surface molecule selectively expressed on murine natural interferon-producing cells that blocks secretion of interferon-α. Blood 103:4201–6 45. Zhang J, Raper A, Sugita N, Hingorani R, Salio M, et al. 2006. Characterization of Siglec-H as a novel endocytic receptor expressed on murine plasmacytoid dendritic cell precursors. Blood 107:3600–8 46. Nakano H, Yanagita M, Gunn MD. 2001. CD11c+ B220+ Gr-1+ cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells. J. Exp. Med. 194:1171–78 47. Vermi W, Riboldi E, Wittamer V, Gentili F, Luini W, et al. 2005. Role of ChemR23 in directing the migration of myeloid and plasmacytoid dendritic cells to lymphoid organs and inflamed skin. J. Exp. Med. 201:509–15 48. Zabel BA, Silverio AM, Butcher EC. 2005. Chemokine-like receptor 1 expression and chemerin-directed chemotaxis distinguish plasmacytoid from myeloid dendritic cells in human blood. J. Immunol. 174:244–51 49. Masten BJ, Olson GK, Tarleton CA, Rund C, Schuyler M, et al. 2006. Characterization of myeloid and plasmacytoid dendritic cells in human lung. J. Immunol. 177:7784–93 50. Imhof BA, Aurrand-Lions M. 2004. Adhesion mechanisms regulating the migration of monocytes. Nat. Rev. Immunol. 4:432–44 51. Woltman AM, de Fijter JW, Zuidwijk K, Vlug AG, Bajema IM, et al. 2007. Quantification of dendritic cell subsets in human renal tissue under normal and pathological conditions. Kidney Int. 71:1001–8 52. Jahnsen FL, Gran E, Haye R, Brandtzaeg P. 2004. Human nasal mucosa contains antigenpresenting cells of strikingly different functional phenotypes. Am. J. Respir. Cell Mol. Biol. 30:31–37 53. De Heer HJ, Hammad H, Soullie T, Hijdra D, Vos N, et al. 2004. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J. Exp. Med. 200:89–98 54. Wendland M, Czeloth N, Mach N, Malissen B, Kremmer E, et al. 2007. CCR9 is a homing receptor for plasmacytoid dendritic cells to the small intestine. Proc. Natl. Acad. Sci. USA 104:6347–52 www.annualreviews.org • Migration of Dendritic Cell Subsets
311
ARI
25 March 2008
22:6
55. Farkas L, Beiske K, Lund-Johansen F, Brandtzaeg P, Jahnsen FL. 2001. Plasmacytoid dendritic cells (natural interferon-α/β-producing cells) accumulate in cutaneous lupus erythematosus lesions. Am. J. Pathol. 159:237–43 56. Ochando JC, Homma C, Yang Y, Hidalgo A, Garin A, et al. 2006. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat. Immunol. 7:652– 62 57. Yrlid U, Jenkins CD, MacPherson GG. 2006. Relationships between distinct blood monocyte subsets and migrating intestinal lymph dendritic cells in vivo under steady state conditions. J. Immunol. 176:4155–62 58. Chackerian AA, Alt JM, Perera TV, Dascher CC, Behar SM. 2002. Dissemination of Mycobacterium tuberculosis is influenced by host factors and precedes the initiation of Tcell immunity. Infect. Immun. 70:4501–9 59. Vazquez-Torres A, Jones-Carson J, Baumler AJ, Falkow S, Valdivia R, et al. 1999. Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes. Nature 401:804–8 60. Cavanagh LL, Bonasio R, Mazo IB, Halin C, Cheng G, et al. 2005. Activation of bone marrow-resident memory T cells by circulating, antigen-bearing dendritic cells. Nat. Immunol. 6:1029–37 61. Angeli V, Ginhoux F, Llodra J, Quemeneur L, Frenette PS, et al. 2006. B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 24:203–15 62. Rennert PD, Hochman PS, Flavell RA, Chaplin DD, Jayaraman S, et al. 2001. Essential role of lymph nodes in contact hypersensitivity revealed in lymphotoxin-α-deficient mice. J. Exp. Med. 193:1227–38 63. Enioutina EY, Bareyan D, Daynes RA. 2007. Vitamin D3-mediated alterations to myeloid dendritic cell trafficking in vivo expand the scope of their antigen presenting properties. Vaccine 25:1236–49 64. Liu YJ. 2006. A unified theory of central tolerance in the thymus. Trends Immunol. 27:215– 21 65. Mathis D, Benoist C. 2004. Back to central tolerance. Immunity 20:509–16 66. Bonasio R, Scimone ML, Schaerli P, Grabie N, Lichtman AH, von Andrian UH. 2006. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat. Immunol. 7:1092–100 67. Larsen CP, Morris PJ, Austyn JM. 1990. Migration of dendritic leukocytes from cardiac allografts into host spleens. A novel pathway for initiation of rejection. J. Exp. Med. 171:307–14 68. Saiki T, Ezaki T, Ogawa M, Matsuno K. 2001. Trafficking of host- and donor-derived dendritic cells in rat cardiac transplantation: allosensitization in the spleen and hepatic nodes. Transplantation 71:1806–15 69. Llodra J, Angeli V, Liu J, Trogan E, Fisher EA, Randolph GJ. 2004. Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc. Natl. Acad. Sci. USA 101:11779–84 70. Ochando J, Krieger NR, Bromberg JS. 2006. Direct vs. indirect allorecognition: visualization of dendritic cell distribution and interactions during rejection and tolerization. Am. J. Transplant. 6:2488–96 71. Mori S, Nakano H, Aritomi K, Wang CR, Gunn MD, Kakiuchi T. 2001. Mice lacking expression of the chemokines ccl21-ser and ccl19 (plt mice) demonstrate delayed but enhanced T cell immune responses. J. Exp. Med. 193:207–18 72. Glass CK, Witztum JL. 2001. Atherosclerosis: the road ahead. Cell 104:503–16
Annu. Rev. Immunol. 2008.26:293-316. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-10
312
Randolph
·
Ochando
·
Partida-S´anchez
Annu. Rev. Immunol. 2008.26:293-316. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-10
ARI
25 March 2008
22:6
73. Gerrity RG. 1981. The role of the monocyte in atherogenesis: II. Migration of foam cells from atherosclerotic lesions. Am. J. Pathol. 103:191–200 74. Huang Y, Rumschitzki D, Chien S, Weinbaum S. 1994. A fiber matrix model for the growth of macromolecular leakage spots in the arterial intima. J. Biomech. Eng. 116:430– 45 75. Dal Canto AJ, Swanson PE, O’Guin AK, Speck SH, Virgin HW. 2001. IFN-γ action in the media of the great elastic arteries, a novel immunoprivileged site. J. Clin. Invest. 107:R15–22 76. Deleted in proof 77. Llodra J, Angeli V, Liu J, Trogan E, Fisher EA, Randolph GJ. 2004. Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc. Natl. Acad. Sci. USA 101:11779–84 78. Van Haastert PJ, Devreotes PN. 2004. Chemotaxis: signalling the way forward. Nat. Rev. Mol. Cell Biol. 5:626–34 79. Sanchez-Sanchez N, Riol-Blanco L, Rodriguez-Fernandez JL. 2006. The multiple personalities of the chemokine receptor CCR7 in dendritic cells. J. Immunol. 176:5153–9 80. Bourne HR. 1997. How receptors talk to trimeric G proteins. Curr. Opin. Cell Biol. 9:134– 42 81. Kuang Y, Wu Y, Jiang H, Wu D. 1996. Selective G protein coupling by C-C chemokine receptors. J. Biol. Chem. 271:3975–78 82. Wu D. 2005. Signaling mechanisms for regulation of chemotaxis. Cell Res. 15:52–56 83. Del Prete A, Vermi W, Dander E, Otero K, Barberis L, et al. 2004. Defective dendritic cell migration and activation of adaptive immunity in PI3Kγ-deficient mice. EMBO J. 23:3505–15 84. Shin EH, Lee HY, Bae YS. 2006. Leukotriene B4 stimulates human monocyte-derived dendritic cell chemotaxis. Biochem. Biophys. Res. Commun. 348:606–11 85. Andrew N, Insall RH. 2007. Chemotaxis in shallow gradients is mediated independently of PtdIns 3-kinase by biased choices between random protrusions. Nat. Cell Biol. 9:193– 200 86. Smith DF, Deem TL, Bruce AC, Reutershan J, Wu D, Ley K. 2006. Leukocyte phosphoinositide-3 kinase γ is required for chemokine-induced, sustained adhesion under flow in vivo. J. Leukoc. Biol. 80:1491–99 87. Riol-Blanco L, Sanchez-Sanchez N, Torres A, Tejedor A, Narumiya S, et al. 2005. The chemokine receptor CCR7 activates in dendritic cells two signaling modules that independently regulate chemotaxis and migratory speed. J. Immunol. 174:4070–80 88. Sanchez-Sanchez N, Riol-Blanco L, de la Rosa G, Puig-Kroger A, Garcia-Bordas J, et al. 2004. Chemokine receptor CCR7 induces intracellular signaling that inhibits apoptosis of mature dendritic cells. Blood 104:619–25 89. Iijima N, Yanagawa Y, Clingan JM, Onoe K. 2005. CCR7-mediated c-Jun N-terminal kinase activation regulates cell migration in mature dendritic cells. Int. Immunol. 17:1201– 12 90. Scandella E, Men Y, Legler DF, Gillessen S, Prikler L, et al. 2004. CCL19/CCL21triggered signal transduction and migration of dendritic cells requires prostaglandin E2. Blood 103:1595–601 91. Luft T, Maraskovsky E, Schnurr M, Knebel K, Kirsch M, et al. 2004. Tuning the volume of the immune response: strength and persistence of stimulation determine migration and cytokine secretion of dendritic cells. Blood 104:1066–74 www.annualreviews.org • Migration of Dendritic Cell Subsets
313
ARI
25 March 2008
22:6
92. Galgani M, De Rosa V, De Simone S, Leonardi A, D’Oro U, et al. 2004. Cyclic AMP modulates the functional plasticity of immature dendritic cells by inhibiting Src-like kinases through protein kinase A-mediated signaling. J. Biol. Chem. 279:32507–14 93. Sato K, Kawasaki H, Nagayama H, Enomoto M, Morimoto C, et al. 2001. Signaling events following chemokine receptor ligation in human dendritic cells at different developmental stages. Int. Immunol. 13:167–79 94. Kitanaka N, Owada Y, Okuyama R, Sakagami H, Nourani MR, et al. 2006. Epidermaltype fatty acid binding protein as a negative regulator of IL-12 production in dendritic cells. Biochem. Biophys. Res. Commun. 345:459–66 95. Nagayama H, Sato K, Kawasaki H, Enomoto M, Morimoto C, et al. 2000. IL-12 responsiveness and expression of IL-12 receptor in human peripheral blood monocyte-derived dendritic cells. J. Immunol. 165:59–66 96. Khader SA, Partida-S´anchez S, Bell G, Jelley-Gibbs DM, Swain S, et al. 2006. Interleukin 12p40 is required for dendritic cell migration and T cell priming after Mycobacterium tuberculosis infection. J. Exp. Med. 203:1805–15 97. Yanagawa Y, Onoe K. 2006. Distinct regulation of CD40-mediated interleukin-6 and interleukin-12 productions via mitogen-activated protein kinase and nuclear factor κBinducing kinase in mature dendritic cells. Immunology 117:526–35 98. Wang S, Hong S, Yang J, Qian J, Zhang X, et al. 2006. Optimizing immunotherapy in multiple myeloma: restoring the function of patients’ monocyte-derived dendritic cells by inhibiting p38 or activating MEK/ERK MAPK and neutralizing interleukin6 in progenitor cells. Blood 108:4071–77 99. Nakagawa S, Ohtani T, Mizuashi M, Mollah ZU, Ito Y, et al. 2004. p38 mitogen-activated protein kinase mediates dual role of UVB radiation in induction of maturation and apoptosis of monocyte-derived dendritic cells. J. Invest. Dermatol. 123:361–70 100. Aiba S, Manome H, Nakagawa S, Mollah ZU, Mizuashi M, et al. 2003. p38 mitogenactivated protein kinase and extracellular signal-regulated kinases play distinct roles in the activation of dendritic cells by two representative haptens, NiCl2 and 2,4dinitrochlorobenzene. J. Invest. Dermatol. 120:390–99 101. Shi GX, Harrison K, Han SB, Moratz C, Kehrl JH. 2004. Toll-like receptor signaling alters the expression of regulator of G protein signaling proteins in dendritic cells: implications for G protein-coupled receptor signaling. J. Immunol. 172:5175–84 102. Oppermann M. 2004. Chemokine receptor CCR5: insights into structure, function, and regulation. Cell. Signal. 16:1201–10 103. Shi G, Partida-Sanchez S, Misra RS, Tighe M, Borchers MT, et al. 2007. Identification of an alternative Gαq -dependent chemokine receptor signal transduction pathway in dendritic cells and granulocytes. J. Exp. Med. 204:2705–18 104. Klinker JF, Wenzel-Seifert K, Seifert R. 1996. G-protein-coupled receptors in HL-60 human leukemia cells. Gen. Pharmacol. 27:33–54 105. Riobo NA, Manning DR. 2005. Receptors coupled to heterotrimeric G proteins of the G12 family. Trends Pharmacol. Sci. 26:146–54 106. Schaerli P, Moser B. 2005. Chemokines: control of primary and memory T-cell traffic. Immunol. Res. 31:57–74 107. Weninger W, von Andrian UH. 2003. Chemokine regulation of naive T cell traffic in health and disease. Semin. Immunol. 15:257–70 108. Muller G, Hopken UE, Lipp M. 2003. The impact of CCR7 and CXCR5 on lymphoid organ development and systemic immunity. Immunol. Rev. 195:117–35 109. Muller G, Lipp M. 2003. Shaping up adaptive immunity: the impact of CCR7 and CXCR5 on lymphocyte trafficking. Microcirculation 10:325–34
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ANRV338-IY26-10
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110. Sozzani S. 2005. Dendritic cell trafficking: more than just chemokines. Cytokine Growth Factor Rev. 16:581–92 111. Kim CH. 2005. The greater chemotactic network for lymphocyte trafficking: chemokines and beyond. Curr. Opin. Hematol. 12:298–304 112. Steinman RM, Hemmi H. 2006. Dendritic cells: translating innate to adaptive immunity. Curr. Top. Microbiol. Immunol. 311:17–58 113. Crow MK. 2006. Modification of accessory molecule signaling. Springer Semin. Immunopathol. 27:409–24 114. Hemmi H, Akira S. 2005. TLR signalling and the function of dendritic cells. Chem. Immunol. Allergy 86:120–35 115. Ouaaz F, Arron J, Zheng Y, Choi Y, Beg AA. 2002. Dendritic cell development and survival require distinct NF-κB subunits. Immunity 16:257–70 116. Lindner I, Cejas PJ, Carlson LM, Torruellas J, Plano GV, Lee KP. 2007. Signal transduction in DC differentiation: winged messengers and Achilles’ heel. Adv. Exp. Med. Biol. 590:1–29 117. Colonna M. 2003. TREMs in the immune system and beyond. Nat. Rev. Immunol. 3:445– 53 118. Bouchon A, Hernandez-Munain C, Cella M, Colonna M. 2001. A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J. Exp. Med. 194:1111–22 119. Lanier LL, Bakker AB. 2000. The ITAM-bearing transmembrane adaptor DAP12 in lymphoid and myeloid cell function. Immunol. Today 21:611–14 120. Bakker AB, Hoek RM, Cerwenka A, Blom B, Lucian L, et al. 2000. DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming. Immunity 13:345–53 121. Tessarz AS, Weiler S, Zanzinger K, Angelisova P, Horejsi V, Cerwenka A. 2007. Non-T cell activation linker (NTAL) negatively regulates TREM-1/DAP12-induced inflammatory cytokine production in myeloid cells. J. Immunol. 178:1991–99 122. Bagley KC, Abdelwahab SF, Tuskan RG, Lewis GK. 2004. Calcium signaling through phospholipase C activates dendritic cells to mature and is necessary for the activation and maturation of dendritic cells induced by diverse agonists. Clin. Diagn. Lab. Immunol. 11:77–82 123. Aliberti J, Valenzuela JG, Carruthers VB, Hieny S, Andersen J, et al. 2003. Molecular mimicry of a CCR5 binding-domain in the microbial activation of dendritic cells. Nat. Immunol. 4:485–90 124. Yang D, Chen Q, Gertz B, He R, Phulsuksombati M, et al. 2002. Human dendritic cells express functional formyl peptide receptor-like-2 (FPRL2) throughout maturation. J. Leukoc. Biol. 72:598–607 125. Idzko M, Dichmann S, Ferrari D, Di Virgilio F, la Sala A, et al. 2002. Nucleotides induce chemotaxis and actin polymerization in immature but not mature human dendritic cells via activation of pertussis toxin-sensitive P2y receptors. Blood 100:925–32 126. Partida-S´anchez S, Rivero-Nava L, Shi G, Lund FE. 2007. CD38: an ecto-enzyme at the crossroads of innate and adaptive immune responses. Adv. Exp. Med. Biol. 590:171–83 127. Lund FE. 2006. Signaling properties of CD38 in the mouse immune system: enzymedependent and -independent roles in immunity. Mol. Med. 12:328–33 128. Partida-S´anchez S, Goodrich S, Kusser K, Oppenheimer N, Randall TD, Lund FE. 2004. Regulation of dendritic cell trafficking by the ADP-ribosyl cyclase CD38: impact on the development of humoral immunity. Immunity 20:279–91 129. Partida-S´anchez S, Randall TD, Lund FE. 2003. Innate immunity is regulated by CD38, an ecto-enzyme with ADP-ribosyl cyclase activity. Microbes Infect. 5:49–58 www.annualreviews.org • Migration of Dendritic Cell Subsets
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130. Partida-Sanchez S, Gasser A, Fliegert R, Siebrands CC, Dammermann W, et al. 2007. Chemotaxis of mouse bone marrow neutrophils and dendritic cells is controlled by ADPribose, the major product generated by the CD38 enzyme reaction. J. Immunol. 179:7827– 39 131. Fliegert R, Gasser A, Guse AH. 2007. Regulation of calcium signalling by adenine-based second messengers. Biochem. Soc. Trans. 35:109–14 132. Perraud AL, Schmitz C, Scharenberg AM. 2003. TRPM2 Ca2+ permeable cation channels: from gene to biological function. Cell Calcium 33:519–31 133. Massullo P, Sumoza-Toledo A, Bhagat H, Partida-Sanchez S. 2006. TRPM channels, calcium and redox sensors during innate immune responses. Semin. Cell Dev. Biol. 17:654– 66 134. Fonfria E, Murdock PR, Cusdin FS, Benham CD, Kelsell RE, McNulty S. 2006. Tissue distribution profiles of the human TRPM cation channel family. J. Recept. Signal. Transduct. Res. 26:159–78 135. Farina C, Theil D, Semlinger B, Hohlfeld R, Meinl E. 2004. Distinct responses of monocytes to Toll-like receptor ligands and inflammatory cytokines. Int. Immunol. 16:799–809 136. Iqbal J, Zaidi M. 2007. CD38 is required for priming by TNF-α: a mechanism for extracellular coordination of cell fate. Am. J. Physiol. Renal Physiol. 292:F1283–90 137. Guerrero-Plata A, Casola A, Suarez G, Yu X, Spetch L, et al. 2006. Differential response of dendritic cells to human metapneumovirus and respiratory syncytial virus. Am. J. Respir. Cell Mol. Biol. 34:320–29 138. Rotta G, Edwards EW, Sangaletti S, Bennett C, Ronzoni S, et al. 2003. Lipopolysaccharide or whole bacteria block the conversion of inflammatory monocytes into dendritic cells in vivo. J. Exp. Med. 198:1253–63 139. Watts C, Zaru R, Prescott AR, Wallin RP, West MA. 2007. Proximal effects of Toll-like receptor activation in dendritic cells. Curr. Opin. Immunol. 19:73–78 140. Pasare C, Medzhitov R. 2005. Toll-like receptors: linking innate and adaptive immunity. Adv. Exp. Med. Biol. 560:11–18 141. Krutzik SR, Tan B, Li H, Ochoa MT, Liu PT, et al. 2005. TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells. Nat. Med. 11:653–60 142. Angeli V, Staumont D, Charbonnier AS, Hammad H, Gosset P, et al. 2004. Activation of the D prostanoid receptor 1 regulates immune and skin allergic responses. J. Immunol. 172:3822–29 143. Hartiala P, Hytonen J, Pelkonen J, Kimppa K, West A, et al. 2007. Transcriptional response of human dendritic cells to Borrelia garinii–defective CD38 and CCR7 expression detected. J. Leukoc. Biol. 82:33–43 144. Dumitriu IE, Bianchi ME, Bacci M, Manfredi AA, Rovere-Querini P. 2007. The secretion of HMGB1 is required for the migration of maturing dendritic cells. J. Leukoc. Biol. 81:84– 91 145. la Sala A, Ferrari D, Di Virgilio F, Idzko M, Norgauer J, Girolomoni G. 2003. Alerting and tuning the immune response by extracellular nucleotides. J. Leukoc. Biol. 73:339–43 146. Di Virgilio F, Chiozzi P, Ferrari D, Falzoni S, Sanz JM, et al. 2001. Nucleotide receptors: an emerging family of regulatory molecules in blood cells. Blood 97:587–600 147. la Sala A, Sebastiani S, Ferrari D, Di Virgilio F, Idzko M, et al. 2002. Dendritic cells exposed to extracellular adenosine triphosphate acquire the migratory properties of mature cells and show a reduced capacity to attract type 1 T lymphocytes. Blood 99:1715–22 148. Bray M, Geisbert TW. 2005. Ebola virus: the role of macrophages and dendritic cells in the pathogenesis of Ebola hemorrhagic fever. Int. J. Biochem. Cell Biol. 37:1560–66
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:293-316. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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Contents
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu1 and Warner C. Greene1,2 1
Gladstone Institute of Virology and Immunology, San Francisco, California 94158
2
Departments of Medicine and of Microbiology and Immunology, University of California, San Francisco, California 94143; email:
[email protected],
[email protected] Annu. Rev. Immunol. 2008. 26:317–53
Key Words
First published online as a Review in Advance on December 3, 2007
Alu, APOBEC3G, HIV-1, LINE-1, retrotransposition, Vif
The Annual Review of Immunology is online at immunol.annualreviews.org This article’s doi: 10.1146/annurev.immunol.26.021607.090350 c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0317$20.00
Abstract All retroviruses, including HIV-1, display species-specific patterns of infection. The impaired growth of these retroviruses in foreign and sometimes even in their natural hosts often stems from the action of potent host-encoded “viral restriction factors” that form important protective components of the innate immune system. The discovery of APOBEC3G and related cytidine deaminases as one class of host restriction factors and of the action of HIV-1 Vif as a specific APOBEC3G antagonist have stimulated intense scientific interest. This Vif-APOBEC3G axis now forms a very attractive target for development of an entirely new class of anti-HIV drugs. In this review, we summarize current understanding of the mechanism of action of the APOBEC3 family of enzymes, their intriguing regulation within cells, the impact of these enzymes on viral evolution and disease progression, and their roles in controlling not only the replication of exogenous retroviruses but also the retrotransposition of endogenous retroelements.
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DISCOVERY OF APOBEC3G AS AN ANTI-RETROVIRAL FACTOR
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APOBEC: apolipoprotein B mRNA-editing enzyme, catalytic polypeptide
The HIV-1 Vif Phenotype
APOBEC proteins: a family of DNA or RNA cytidine deaminases, enzymes that have the hallmark deaminase motif (Cys/His)Xaa-Glu-Xaa23∼28 Pro-Cys-Xaa2∼4 -Cys Retroviruses: enveloped RNA viruses with positive-sense single-stranded RNA genomes that undergo reverse transcription and integration as obligatory steps in their life cycle Human immunodeficiency virus (HIV): a retrovirus with two types (1 and 2) belonging to the lentivirus family that causes AIDS Virion infectivity factor (Vif ): an HIV-1 accessory protein essential for efficient viral replication in primary CD4 T cells and macrophages
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The identification of human APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G, or hA3G) and related cytidine deaminases as potent innate inhibitors of a wide range of exogenous retroviruses emerged from studies of the HIV-1 protein Vif (virion infectivity factor). HIV-1 is a member of the primate lentivirus family of retroviruses. In contrast to simple retroviruses, which encode only Gag, Pol, and Env, HIV-1 encodes six additional auxiliary proteins (Tat, Rev, Nef, Vif, Vpr, and Vpu) that play pivotal roles in orchestrating the pathogenic interplay of HIV-1 with its human host. Vif itself, a basic 23-kDa phosphoprotein, is expressed late in the retroviral life cycle and is conserved among all of the primate lentiviruses, except for equine infectious anemia virus. Viruses lacking a functional vif gene (vif ) fail to mount a spreading infection in “nonpermissive” cells, which include biologically relevant primary CD4 T cells and macrophages (Figure 1). Vif is required for viral spread in cultures of some T cell leukemia lines, such as H9, HuT78, and MT2. Conversely, many “permissive” T cell lines (e.g., Jurkat and SupT1) and nonhematopoietic cell
lines (e.g., HeLa, 293T, and COS) fully support HIV spread in the absence of Vif (1– 3). Despite the early recognition of permissive and nonpermissive cell types supporting or not supporting the spread of vif HIV-1 respectively, the molecular basis for these cellular differences remained elusive for many years. Similarly, the mechanism by which Vif allowed wild-type HIV-1 to spread readily in cultures of nonpermissive cells was unclear.
Identifying the Vif-Sensitive Anti-HIV Factor Produced by Nonpermissive Cells Of note, nonpermissive cells support the normal production of vif HIV-1 virions, but these virions are unable to productively infect the next target cell (1–3). These findings suggest that Vif either overcomes the effects of a negative factor produced in nonpermissive cells or, alternatively, that permissive cells express a Vif-like host factor that positively influences virion infectivity. This issue was resolved in experiments in which heterokaryons formed between permissive and nonpermissive cells were infected with vif HIV-1 (4, 5). Progeny virions from these heterokaryons proved noninfectious, promoting the argument that nonpermissive cells express an inhibitory factor whose function is somehow defeated by Vif (Figure 1). This
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→ Figure 1 Nonpermissive cells produce an anti-HIV factor that is neutralized by Vif. (a) The HIV-1 Vif phenotype. Viruses lacking a functional vif gene (vif ) fail to mount a spreading infection in “nonpermissive” cells, which include biologically relevant primary CD4 T cells and macrophages. Conversely, many “permissive” T cell lines (e.g., Jurkat and SupT1) and nonhematopoietic cell lines (e.g., HeLa, 293T, and COS) fully support HIV spread in the absence of Vif. Note that permissive and nonpermissive cells produce the same amount of progeny virions, but virions derived from nonpermissive cells are unable to infect the next target cell. (b) Nonpermissivity is dominant in heterokaryons formed between permissive and nonpermissive cells. Nonpermissive T cells (HuT78 or CEM-SS) were initially infected with HIV-1vifenv viruses pseudotyped with VSV-G. Heterokaryons were formed by incubation of these nonpermissive cells with permissive cells expressing HIV Env. The presence of CD4/CXCR4 receptors on the nonpermissive cells mediated fusion and heterokaryon formation. When progeny virions (HIV-1vif ) were tested for their ability to infect the next target cell, no spread was detected. However, in the presence of Vif, effective spread occurred. These findings indicated that nonpermissive cells produce an inhibitor of HIV infectious spread and that the action of this inhibitor is circumvented by Vif. This host inhibitory factor was subsequently identified as APOBEC3G. Chiu
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Vif-sensitive inhibitory factor remained uncharacterized until Sheehy et al. used subtractive hybridization techniques with two near-isogenic cell lines, CEM-S (permissive) and CEM-SS (nonpermissive) (6). One clone identified in this screen was hA3G (initially named CEM15), a known cytidine deami-
nase. Strikingly, permissive cells lacked hA3G expression, and the introduction of hA3G cDNA into permissive cells proved sufficient to convert these cells into nonpermissive hosts. Additionally, virions budding from nonpermissive cells were shown to contain hA3G, providing an explanation for how viral
a Nonpermissive cell
Permissive cell
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HIV-1∆Vif Infectious
Infectious
Noninfectious
Infectious
b Infectious VSVG-pseudotyped HIV-1∆Env∆Vif virus CXCR4 CD4 LTR
HIV-1 Env
LTR
HIV-1∆Env ∆Vif
Nonpermissive cell
LTR
Permissive cell
LTR
Noninfectious HIV-1∆Vif virus HIV-1∆Env ∆Vif
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Cytidine deamination: the conversion of a cytidine to uridine by the hydrolytic substitution of an amine group
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replication might be altered in the next set of target cells. The mechanism by which Vif overcomes the effects of hA3G remained unexplained.
Functional Clues from Related Enzymes: APOBEC1 and Activation-Induced Deaminase
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Human A3G is a member of a much larger family of tissue-restricted cytidine deaminases (7) that exhibit RNA editing and/or DNA mutating activity (8, 9). In humans, the APOBEC family of enzymes includes activation-induced deaminase (AID), APOBEC1, APOBEC2, APOBEC3A–H, and APOBEC4 (7, 10– 12). Their active sites are characterized by the presence of a conserved zinc-binding motif (Cys/His)-Xaa-Glu-Xaa23∼28 -Pro-CysXaa2∼4 -Cys, a key glutamate involved in the proton shuttling that occurs during deamination, and two critical aromatic residues involved in nucleic acid substrate binding (7). These enzymes mediate hydrolytic deamination at the C4 position of the C (or dC) base, converting C to U (or dC to dU). These changes are often referred to as RNA or DNA editing (Figure 2). Two well-studied members of this enzyme family are APOBEC1 and AID, which are located in tandem on human chromosome 12 (13, 14). Initially identified in 1993, APOBEC1 is primarily expressed in gastrointestinal tissue (8), where it is the central component of
an RNA editosome complex mediating the deamination of cytosine-6666 in apolipoprotein B mRNA (15). This action of APOBEC1 converts a glutamine at this position to an inframe stop codon, resulting in the expression of a truncated version of the apoB protein (8). These two forms of apoB protein serve different functions. The longer apoB100 protein mediates the transport of endogenously produced cholesterol and triglycerides, while the shorter apoB48 regulates the absorption and transport of exogenous dietary lipids. Of note, forced expression of APOBEC1 as a transgene in the livers of mice consistently leads to hepatic dysplasia and hepatocellular carcinoma, possibly owing to promiscuous RNA editing of tumor suppressors or oncogenes (16). Such activity likely reflects the formation of nonphysiological RNA editosomes whose normally exquisite substrate specificity is lost. APOBEC1 appears to be the only member of the APOBEC superfamily of enzymes whose principal nucleic acid substrate is RNA rather than DNA. In contrast to APOBEC1’s role in lipid metabolism, AID is required for the normal evolution of the humoral immune response. AID is selectively expressed in germinal center B cells (17), where it catalyzes dC-to-dU deamination at the DNA level and thus promotes immunoglobulin-gene diversification via somatic hypermutation and class switch recombination (18). These events are critically required for the natural maturation of
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→ Figure 2 A family of APOBEC3 cytidine deaminases. The APOBEC3 gene locus containing seven related but distinct APOBEC3 genes is located on chromosome 22 in humans. This multigene family stands in sharp contrast to the single APOBEC3 gene present on syntenic chromosome 15 in mice. This genetic expansion reflects tandem duplication and unequal crossover resulting in a head to tail arrangement of the human APOBEC3 genes. Four genes (hA3B, hA3DE, hA3F, and hA3G) exhibit additional duplications of the cytidine deaminase domain (CD), as well as the intervening linker and pseudoactive domains. The length of these double domain enzymes varies somewhat as indicated, although each of the CDs are similar in size. The active sites of these enzymes catalyze hydrolytic deamination at the C4 position of 2 -deoxycytidine requiring the presence of cysteine (Cys) residues coordinating a single zinc ion and a key glutamate involved in proton shuttling. In this reaction, 2 -deoxycytidine is converted to 2 -deoxyuridine as a result of the removal of an amine group in the presence of water. 320
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Mouse chromosome 15 mA3
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Human chromosome 22 A3B
A3A
A3C
1
aa: 1
1
A3DE
1
A3F
A3G
A3H
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1
1
Catalytic domain
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Deaminase Active Site Consensus
-Pr -Glu-Xaa23–28 o-Cys-Xaa2– -C -Xaa 4 ys s i H NH2 N O
O
O
P
O H
O H
NH3
O HN
Deamination
N
P
O
O H H
O– H
2'-deoxycytidine
N
O
O O
O H H
O–
H2O
H
O H
H
2'-deoxyuridine
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the antibody response. Uracil DNA glycosylase, a DNA repair enzyme that removes uracil from single- and double-stranded DNA, is required for all AID-dependent processes (19). Mutations within the AID are linked to the Hyper-IgM syndrome, as well as aberrant activity linked with the development of various large B cell lymphomas and non-Hodgkin’s lymphomas (20). Like transgenic expression of APOBEC1, the constitutive and ubiquitous transgenic expression of AID in mice uniformly results in the development of various cancers, specifically T cell lymphomas, micro-adenomas, and lung adenocarcinomas (21). This link of APOBEC1 and AID to cancer emphasizes how tight intracellular regulation of these cytidine deaminases is likely required to avoid harmful transforming events within cells. When expressed in Escherichia coli, hA3G, AID, and even APOBEC1 catalyze the deamination of dC residues in single-stranded DNA (9, 22), suggesting that single-stranded DNA is the favored substrate for hA3G. This finding provides a ready explanation for how viral replication might be blocked in the next target cell via the inherent deaminase activity of hA3G acting on the nascent reverse transcribed cDNAs of the virus.
MULTIFACETED ANTIVIRAL ACTIONS OF APOBEC3G Retroviruses as a Target for the Inherent Deaminase Activity of APOBEC3G In the absence of Vif, hA3G is effectively incorporated into budding HIV-1 virions (23, 24). This encapsidation reaction involves interaction with the nucleocapsid region of the HIV-1 Gag polyprotein (25–27). This interaction is further strengthened by A3G’s propensity to bind single-stranded nucleic acids, particularly viral RNA at the plasma membrane site of virion budding (28–34). The incorporation of only 7 ± 4 molecules of hA3G into vif HIV virions produced from 322
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human peripheral blood mononuclear cells appears sufficient to inhibit HIV-1 replication during the next round of infection (35). The virion-incorporated hA3G is bound to the viral core (32) and thus is effectively introduced into the target cell as a result of virion fusion. The enzyme then mediates extensive dC-todU mutations of the minus-strand viral DNA formed during reverse transcription (36, 37). These mutated viral minus-strand DNAs containing excessive dUs may then be destroyed by the action of two virion-associated DNA base repair enzymes, uracil DNA glycosylase and apurinic-apyrimidinic endonuclease (38, 39), although uracil DNA glycosylase 2 appears dispensable for this antiviral action of hA3G (40, 41). A few viral minus strands appear to survive this attack and serve as templates for plus-strand synthesis, where the dU promotes dA misincorporation. The resultant dG-to-dA mutations, which can exceed 10% of all dG residues, likely further negate HIV1 replication by altering viral open reading frames and introducing inappropriate translation termination codons (42–45) (Figure 3). HIV reverse transcription is initiated by extension from the tRNALys3 primer that anneals to the primer binding site of the viral genomic RNA generating minus-strand strong-stop DNA. This minus-strand strongstop DNA is translocated to the 3 end of the genome and further extended to complete the minus-strand cDNA. As the minusstrand cDNA is synthesized, the RNA template is degraded by the RNase H activity of the reverse transcriptase, exposing the singlestranded minus-strand DNA. Two RNase H– resistant RNA polypurine tracts (PPT), cPPT and 3 PPT, remain associated with the minusstrand cDNA to serve as initiation sites for subsequent plus-strand cDNA synthesis. As such, hA3G’s single-stranded DNA specificity (36, 37) accounts for two highly polarized (5 -to-3 ) mutational gradients within the viral genome, each with maxima just 5 to the cPPT and the 3 PPT. These gradients are in remarkable agreement with the time these regions of the minus-strand DNA
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Figure 3 Multifaceted antiviral actions of virion-incorporated hA3G. In the absence of Vif, hA3G present in the cytoplasm of virus-producing cells is effectively incorporated into budding virions and thus is carried forward into the next target cells, where it is available to act as a potent inhibitor of HIV-1 replication. These results explain how nonpermissive cells can produce normal levels of progeny virions, but the virions emanating from nonpermissive cells fail to replicate effectively in the next target cells. These inhibitory effects involve both deaminase-independent and deaminase-dependent antiviral actions of hA3G. Human A3G bound to HIV-1 RNA may physically impede reverse transcriptase movement on the viral RNA template, resulting in a deaminase-independent decrease in the production of early reverse transcripts (1). However, this inhibition is frequently incomplete, and minus-strand viral DNA is generated. This single-stranded DNA forms the target for hA3G’s deaminase-dependent antiviral attack. Human A3G mediates extensive deamination of deoxycytidine residues in the minus-stranded viral DNA. This action effectively halts HIV-1 replication either due to the accumulation of dG-to-dA hypermutations in the subsequently synthesized plus-strand DNA of the virus or because the uracil-containing minus-strand DNA is destroyed by the combined actions of uracil DNA glycosylase and apurinic-apyrimidinic endonuclease (2). Additionally, diminished chromosomal integration of the double-stranded viral DNA required for provirus formation may occur owing to defects in tRNALys3 primer cleavage leading to the formation of viral DNA with aberrant ends (3).
remain single-stranded, awaiting the commencement of plus-strand synthesis (36, 46). These gradients could also result from a processive directional attack leveled by hA3G on its single-stranded cDNA substrate (47). Human A3G binds randomly to single-stranded DNA, then jumps and/or slides processively for at least 100 nucleotides to deaminate target motifs. This intrinsic “slide-and-jump” cat-
alytic activity of hA3G exhibits a clear bias favoring 5 dCs over 3 dCs. Thus deamination occurs predominantly 3 to 5 on the minus-strand viral DNA without requiring hydrolysis of a nucleotide cofactor (47). Rarely, hA3G also modifies the viral plusstrand in the 5 U3 region and primer-binding site (36). Of note, the 5 U3 region becomes briefly single-stranded when displaced
www.annualreviews.org • The APOBEC3 Cytidine Deaminases
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MLV: murine leukemia virus HTLV: human T cell leukemia virus Hepatitis B virus (HBV): a DNA virus belonging to the hepadnavirus family that replicates via an RNA intermediate and requires reverse transcription
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from the minus-strand during plus-strand synthesis; the primer-binding site in the plus-strand similarly becomes single-stranded when RNase H degrades the tRNALys3 primer bound at this site. These findings strongly support the notion that single-stranded DNA is the physiological substrate of hA3G. The editing activity of hA3G exerts broad antiretroviral effects, blocking the replication of HIV-1 and other lentiviruses, including simian immunodeficiency virus (SIV) and equine infectious anemia virus, and even distantly related retroviruses, such as murine leukemia virus (MLV) and foamy viruses (23, 42, 44, 48–50). The common use of DNA deamination by hA3G and AID emphasizes an intriguing biological strategy whereby both the innate and adaptive immune defenses commonly exploit DNA editing for defense of the host.
Deaminase-Independent Antiviral Activity of APOBEC3G In contrast to APOBEC1 and AID, which have single catalytic domains, hA3G contains two cytidine deaminase domains (CDs), as well as duplicated intervening linker and pseudoactive domains (7) (Figure 2). Despite their homology, these two CDs display quite distinct functional properties; the N-terminal CD1 mediates RNA binding and virion encapcidation (51–53), whereas the C-terminal CD2 confers deoxycytidine deaminase activity (51–54) and sequence specificity for modification of the single-stranded DNA substrate. A3G preferentially deaminates 5 -CC dinucleotides at the 3 dC (42, 44, 45, 55–57). The ensuing degradation of the dU-containing viral minus-strands and the massive dG-to-dA hypermutation in the surviving viral plusstrand represent important events that centrally contribute to the antiviral properties of hA3G. Additionally, the accumulation of dUs in minus-strand DNA may lead to decreased plus-strand synthesis by HIV-1 reverse transcriptase owing to aberrant initiation at the PPT sites (58).
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Despite this clear link between the deoxycytidine deaminase activity of hA3G and its antiviral activity, emerging evidence suggests that A3G exerts additional antiviral effects independent of its enzymatic activity. Specifically, hA3G analogs containing disabling mutations in the C-terminal CD continue to substantially reduce the infectivity of vif HIV-1 virions. The RNA binding activity of the N-terminal CD appears critically involved in this nonenzymatic form of inhibition, which likely involves physical impairment of reverse transcriptase activity (52, 59). Additionally, the presence of hA3G in vif HIV-1 virions results in a 50% or greater reduction in the ability of tRNALys3 primers to initiate reverse transcription (60). Whether this inhibition reflects decreased tRNALys3 annealing to viral RNA or an altered configuration of the tRNALys3 /viral RNA hybrid in the presence of hA3G remains unclear. Finally, hA3G may also cause defects in tRNALys3 cleavage during plus-strand DNA transfer, leading to the formation of aberrant viral DNA ends that could interfere with subsequent chromosomal integration of the double-stranded viral DNA required for provirus formation (41) (Figure 3). Of note, the N-terminal linker region of hA3G has been implicated as a docking site for the C-terminal domain of HIV-1 integrase. The association of hA3G with components of the preintegration complex (PIC) such as integrase might interfere with the structural integrity of the PIC and consequently inhibit nuclear import of the PIC, thereby further impairing the successful integration of the viral DNA (61). Human A3G also mediates deaminaseindependent antiviral activity against human T cell leukemia virus type-1 (HTLV-1), although the effects are more modest than those occurring with HIV-1. Hypermutations are also not abundant in most of the HTLV-1 viral DNA (62, 63). Furthermore, hA3G also blocks the replication of hepatitis B virus (HBV) in a manner that does not require deamination. The HBV life cycle involves an obligatory reverse transcription
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step during which pregenomic RNA intermediates within nucleocapsids in the cytoplasm of virus-producer cells are converted to DNA before being packaged into budding virions. Human A3G appears to inhibit viral pregenome packaging, thereby destabilizing the reverse transcription complex and preventing HBV DNA accumulation in virions (64, 65). Only limited dG-to-dA mutations can be detected in HBV DNA, and these effects are only observed in selected hepatoma cell lines (65–67). All these studies support the notion that A3G’s antiviral activity is far more complex than previously thought. However, the precise mechanisms underlying these deaminase-independent antiviral actions of hA3G remain incompletely characterized.
Nuances of Intracellular Regulation of APOBEC3G Reveal a Novel Postentry Antiviral Activity A central question highly relevant to normal cell function is how the potentially promiscuous mutagenic activity of the hA3G enzymes is controlled. One possibility was immediately suggested by subcellular localization studies, which indicated that hA3G is chiefly cytoplasmic and does not appear to shuttle like APOBEC1 and AID. Rather hA3G is strongly retained in the cytoplasm (12, 42, 68–71). However, such localization is unlikely to represent the sole mechanism for limiting promiscuous editing of genomic DNA, especially because nuclear and cytoplasmic components are admixed in dividing cells after breakdown of the nuclear membrane. Indeed, subsequent studies revealed that endogenous hA3G expressed in the cytoplasm of H9 T cell lines and mitogen-activated CD4 T cells is assembled in 5–15 MDa high-molecularmass (HMM) ribonucleoprotein (RNP) complexes and that the deoxycytidine deaminase activity of hA3G is greatly inhibited in these complexes. Interestingly, these HMM hA3G complexes can be artificially converted to an enzymatically active low-molecular-mass (LMM) form by treatment with RNase A, sug-
gesting that RNA components play an important role in the assembly of HMM A3G complexes (72). This discovery of different forms of hA3G ultimately provided pivotal information bearing on the question of why resting CD4 T cells in lymphoid tissue are permissive to HIV1 infection, whereas CD4 T cells circulating in the peripheral blood are not, even though A3G is expressed in both cell types. The answer is that hA3G is expressed in two very different forms in these two populations of CD4 T cells. Circulating resting CD4 T cells are distinguished by the presence of LMM hA3G (72) and are refractory to HIV-1 infection at least in part because of an early postentry block during or soon after the reverse transcription step (73, 74). In sharp contrast, in lymphoid tissue–resident resting CD4 T cells, which display increased permissiveness to HIV-1 infection (75), hA3G is predominantly found in the HMM complexes (76). The formation of these complexes reflects, at least in part, the action of various cytokines, including IL-2 and IL-15, that are present in the lymphoid tissue microenvironment. These cytokines induce the assembly of HMM A3G complexes (76) (Figure 4). When RNA interference is used to knock down expression of the LMM hA3G present in peripheral blood– derived resting CD4 T lymphocytes, these cells are rendered permissive to HIV infection. This finding provides direct evidence that LMM hA3G functions as a potent postentry restriction factor that inhibits the replication of incoming HIV-1 virions (72). LMM hA3G can be converted to an HMM complex when CD4 T cells are activated with various mitogens (anti-CD3/CD28 and phorbol myristate acetate) and cytokines (IL-2, IL-7, and IL-15) (72, 77). The assembly of HMM A3G complexes appears to require entry into the G1b phase of the cell cycle (72), a stage characterized by RNA synthesis (78). These events result in HMM A3G complex assembly thereby removing the LMM hA3G postentry block and creating a favorable environment for productive HIV-1 infection www.annualreviews.org • The APOBEC3 Cytidine Deaminases
HMM: high molecular mass LMM: low molecular mass
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Peripheral blood
Lymphoid organs IL-2 IL-15 Other cytokines
HIV
HMM APOBEC3G LMM APOBEC3G
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Post-entry block
Resting g CD4 4 T celll
Resting CD4 T cell
Permissive for infection Nonpermissive for infection
Figure 4 APOBEC3G also functions as a potent postentry restriction factor for HIV-1 in resting CD4 T cells present in peripheral blood. Human A3G exists exclusively in LMM forms in peripheral blood–derived resting CD4 T cells. LMM hA3G functions as a postentry restriction factor blocking the replication of incoming HIV-1 viral particles. Of note, this action does not strictly depend on editing but rather appears to involve significant delays in the accumulation of viral reverse transcripts. Strikingly and in sharp contrast to their cellular counterparts isolated from peripheral blood, resting CD4 T cells residing in human lymphoid tissues are permissive to HIV-1 infection. In these cells, hA3G is predominantly detected in HMM complexes and as such is unable to exert the postentry restricting activity characteristic of LMM hA3G. Induction of HMM hA3G complex assembly in these tissue-derived resting CD4 T cells appears to reflect the action of various cytokines including IL-2 and IL-15, which are present in this lymphoid tissue microenvironment. Additional inductive signals may occur as a result of cell-cell contacts in these tissues. However, though sufficient to induce HMM hA3G complex assembly, these signals do not induce full-fledged lymphocyte activation.
(72, 77). Of note, the action of LMM A3G is not antagonized by Vif because virions contain little or no Vif (79), and the virus has not progressed far enough through its life cycle to produce new Vif. Thus, this postentry restricting activity of LMM A3G is equally effective against wild-type HIV-1 and vif HIV-1 virions. Vif springs into action much later in the viral replication cycle when its synthesis is triggered by Rev, and it prevents hA3G incorporation into progeny virions budding from productively infected cellular hosts. 326
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The identification of LMM forms of hA3G in primary resting CD4 T cells isolated from peripheral blood provided the first evidence that hA3G can exert antiviral effects in target cells independently of its prior incorporation into virions. Interestingly, this HIV-1 postentry replication block by cellular LMM hA3G does not depend strictly on editing. Instead, it involves significant delays in the accumulation of late reverse transcription products. Over 90% of the reverse transcripts that slowly form in infected blood-derived resting CD4 T cells contain no evidence of
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dG-to-dA hypermutation, arguing for an antiviral action of hA3G independent of cytidine deamination (72). However, the possibility that many transcripts are in fact hypermutated, but rapidly degraded, cannot be completely ruled out. The status of HMM hA3G complex formation also correlates well with the susceptibility or resistance of cells within the monocyte lineage to infection with HIV-1 (72, 80– 82). Specifically, freshly isolated monocytes are highly refractory to infection in vitro (83– 85) and are distinguished by the presence of LMM hA3G (72). Differentiation of these cells into macrophages promotes the HMM hA3G complex assembly (72), a transition that correlates with a sharp increase in permissiveness to HIV-1 infection (83–85). HMM hA3G complexes also are observed in the CD16+ subset of monocytes, which are more permissive than other monocytes. These cells may form a reservoir for viral persistence during antiretroviral therapy (80). Immature dendritic cells contain low levels of hA3G that is assembled into HMM complexes. Maturation of these cells is associated with a sharp increase in hA3G expression and the additional expression of LMM hA3G forms (77, 81). Mature dendritic cells are less permissive than immature dendritic cells to HIV infection (81).
DIVERSE RETROVIRAL STRATEGIES FOR CIRCUMVENTING APOBEC3G ANTIVIRAL ACTIVITY The Vif-APOBEC3G Paradigm Human A3G poses a significant threat to the successful replication and spread of HIV-1. One of the nine gene products of HIV1, Vif, is specifically utilized to counter this threat. Vif binds to hA3G and promotes its accelerated degradation by the 26S proteasome. The resulting depletion of the intracellular stores of hA3G prevents effective virion encapsidation of hA3G and ensures high infectivity of the progeny virions
(Figure 5). Vif uses multiple protein interaction regions to orchestrate proteasomemediated degradation of hA3G. The Nterminal region of Vif binds to the N-terminal region of hA3G (amino acids 54–124) (68, 86–88). The SLQ(Y/F)LA motif (amino acids 144–150) of Vif, which resembles a conserved sequence in the BC-box of the suppressors of cytokine signaling (SOCS) proteins, binds to Elongin C (87, 89–92). Finally, a novel zincbinding motif, His-Xaa5 -Cys-Xaa17−18 -CysX3−5 -His (HCCH, amino acids 108–139), interacts with Cullin5 (93–95). Through these interactions, Vif effectively recruits an active ubiquitin ligase (E3) complex composed of Elongin C, Elongin B, Cullin5, Nedd8, and Rbx1 (89, 92), which mediates polyubiquitylation of hA3G—a posttranslational modification that targets proteins for destruction by the proteasome (24, 86, 87, 96). Mutation of the BC-box domain (SLQ motif) or the HCCH motif in Vif or overexpression of Cullin5 mutants that fail to engage Nedd8 or Rbx1 all result in a loss of hA3G polyubiquitylation and the preservation of hA3G’s antiviral activity (89, 91–93). Two additional Vif domains, the central hydrophilic EWRKKR domain (amino acids 88–93) and the prolinerich PPLP domain (amino acids 161–164), are important respectively for enhancing steadystate levels of Vif and for interaction with tyrosine kinases (97, 98). Mutation of these domains also compromises Vif activity. In addition to accelerating proteasomal degradation of hA3G, Vif partially impairs the translation of hA3G mRNA (24), although the mechanism remains undefined. Nevertheless, the combined effects of accelerated degradation and diminished synthesis result in a striking depletion of intracellular hA3G and thus forfeiture of its antiviral activity (23, 24) (Figure 5). Additional mechanistic insights have emerged from interspecies studies. HIV-1 and HIV-2 represent the products of independent cross-species (zoonotic) transmission events of related but distinct lentiviruses (SIVs) that naturally infect nonhuman www.annualreviews.org • The APOBEC3 Cytidine Deaminases
Zoonotic transmissions: The cross-species transfer of an infectious agent from one animal species to another that is not regarded as a natural host for the pathogen
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primates in sub-Saharan Africa (99). One lentivirus, SIVcpz, present in chimpanzees (Pan troglodytes) in western equatorial Africa represents the precursor of pandemic HIV-1. Similarly, SIVsm from sooty mangabeys (Cercocebus atys) is the immediate source of HIV-2. Unlike HIV-1, HIV-2 infection remains largely restricted to western Africa.
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Other lentiviruses, such as SIV from African green monkeys (SIVagm), have not been transmitted to humans. Additionally, rhesus macaques strongly resist experimental infection with HIV-1, reflecting the action of TRIM5α, a second and distinct type of postentry restriction factor (100). Such species-specific barriers to infection not only
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oppose zoonotic infections but provide an important resource for better understanding virus-host interactions. In contrast to the broad antiviral action of A3G, Vif’s counterattack occurs in a highly species-specific manner (23). For example, Vif from SIVagm effectively triggers the degradation of African green monkey A3G but fails to neutralize either human or chimpanzee A3G. Similarly, HIV-1 Vif cannot induce degradation of African green monkey or rhesus macaque A3G. These species-specific limitations in Vif activity likely form an important barrier that minimizes successful zoonotic transmission of many primate lentiviruses. Of note, the fact that the Vif gene products of SIVsm and SIVcpz successfully degrade hA3G (23, 101, 102) provides a compelling explanation for how these viruses were able to spawn the HIV-1 and HIV-2 epidemics in humans. Species specificity is governed by a single amino acid at position 128 in A3G (aspartic acid in human and lysine in African green monkey) (101, 103–105) and amino acids 14–17 in Vif (106). Introduction of a D128K substitution in hA3G renders this protein sensitive to SIVagm Vif and resistant to HIV-1 Vif (101, 103–105). Corresponding mutations introduced into Vif similarly alter its species-specific effects. For example, replacement of D14 RMR17 in HIV-
1 Vif with SERQ or SEMQ, the equivalent residues in SIVagm Vif, allows functional interactions of HIV-1 Vif with rhesus macaque A3G and African green monkey A3G, as well as D128K-A3G. This loss of species restriction is likely linked to overall increase in the negative charge of amino acids 14–17 in HIV1 Vif that promotes effective interaction with the positively charged lysine present at residue 128 in African green monkey and rhesus A3G (106). Although Vif-induced degradation of hA3G plays an important role in overcoming the antiviral effects of hA3G, nondegradative mechanisms of Vif action have also been proposed. One study indicates that Vif can enhance virion infectivity even under conditions where it only moderately reduces steadystate levels of hA3G. Further, an S144A mutation in Vif that prevents phosphorylation at this site leads to progeny virions with poor infectivity. Nevertheless, this mutant effectively depletes hA3G (90). Additional complexity in Vif’s mechanism of action is highlighted by a recent report showing that Vif inhibits virion encapsidation and the antiviral activity of a hA3G variant, C97A, which is intrinsically resistant to degradation (107). Possible alternative mechanisms of Vif action include the physical exclusion of hA3G from sites of viral assembly and budding or inhibition of A3G encapsidation by competing for binding
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Figure 5 The interplay of Vif and APOBEC3G. (a) Neutralization of hA3G in virus-producing cells by HIV Vif. Vif defeats the antiviral activity of hA3G principally by both binding to hA3G and recruiting an E3 ligase complex that mediates polyubiquitylation (Ubn) of hA3G. This posttranslational modification of hA3G promotes its accelerated degradation in 26S proteasomes (1). Vif also partially impairs the translation of hA3G mRNA (2). These dual effects of Vif effectively deplete hA3G in the virus-producing cells; thus, hA3G is not available for incorporation into virions budding from these cells. Other auxiliary functions of Vif have been proposed, including physical exclusion of hA3G from virion encapsidation in the absence of degradation, perhaps owing to sequestration of hA3G away from the sites of viral assembly/budding (3). (b) Model of the Vif-Cul5-Elongin BC complex. Vif employs multiple protein interaction domains to orchestrate hA3G degradation. The N-terminal region of Vif has been implicated in its binding to an N-terminal region of hA3G (amino acids 54–124). The SLQ(Y/F)LA motif (amino acids 144–150) of Vif mediates binding to the Elongin C component of the E3 ligase complex. Finally, a novel zinc-binding motif (HCCH, amino acids 108–139) within Vif containing two conserved cysteines mediates a second interaction with the Cullin5 component. The Cul5-Vif E3 ubiquitin ligase binds hA3G and brings it into close proximity to the E2 ubiquitin-conjugating enzyme. www.annualreviews.org • The APOBEC3 Cytidine Deaminases
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to viral components like the nucleocapsid component of Gag or viral genomic RNA, which play central roles in A3G incorporation into virions (23, 107, 108) (Figure 5). Additionally, both Vif and a second viral accessory protein, Vpr, induce G2 cell-cycle arrest, which may play a role in the T cell cytopathicity induced by HIV infection (109, 110). These findings suggest that Vif may play a larger biological role beyond its function as a hA3G antagonist. Indeed, due to the limited size of the HIV genome, many viral proteins perform multiple functions, thereby achieving remarkable genetic economy.
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Viron Exclusion of APOBEC3G as a Common Strategy Although lentiviral Vif efficiently fends off A3G’s attack at least in part through proteasome-mediated degradation of the enzyme, other retroviruses have evolved rather different counterstrikes. These different strategies unambiguously highlight the importance of virion exclusion as a way to circumvent the antiviral activity of A3G. Primate foamy viruses and a distantly related feline foamy virus resist the inhibitory effects of hA3G through the action of the accessory protein Bet. Bet binds to hA3G and prevents its packaging into virus particles, but these effects do not involve degradation of hA3G in virionproducing cells (48, 49). HTLV-1 utilizes a very different strategy. Within the C-terminal region of its nucleocapsid domain, HTLV-1 encodes a peptide motif that impairs hA3G from interacting with viral genomic RNA and thus inhibits hA3G packaging into budding virions (111). This motif is highly conserved among the primate T cell leukemia viruses but is absent in all other retroviral nucleocapsid proteins. MLV replicates effectively in murine APOBEC3 (mA3)-expressing cells and survives because its Gag protein has been evolutionarily selected neither to bind nor to package the cognate mA3 enzyme. However, MLV infectivity is effectively restricted by hA3G, which continues to bind to MLV Gag (112– 330
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114). Similarly, Mason-Pfizer monkey virus (MPMV) escapes inhibition by A3G in its natural host, the rhesus macaque, by failing to incorporate rhesus A3G into budding virions. However, this virus is highly susceptible to inhibition by mA3, which efficiently forms a complex with MPMV Gag and is effectively encapsidated into virions (115). The finding that two essentially unrelated retroviruses (MLV and MPMV) employ similar strategies to escape inhibition by APOBEC3 proteins in their normal host species suggests that the selective exclusion of APOBEC3 proteins from virion particles represents a general mechanism employed by simple mammalian retroviruses. Although the specific virion exclusion of cognate APOBEC3 protein has been attributed to an inability to bind MLV Gag, MLV may also utilize additional strategies to prevent A3G encapsidation. Specifically, MLV viral RNA also blocks the binding of mA3 to Gag, contributing to the exclusion of mA3 from MLV virions (114). Finally, even if mA3 is successfully packaged, this antiviral enzyme may be inactivated by cleavage by the MLV protease (114).
RIBONUCLEOPROTEIN COMPLEXES INVOLVED IN REGULATING APOBEC3G ANTIVIRAL ACTIVITY Molecular Assemblies Involved in Cellular APOBEC3G Complexes Several laboratories joined in efforts to characterize the protein and RNA components of the HMM hA3G RNP complexes (71, 116, 117). Tandem affinity purification and mass spectrometry have led to the identification of at least 95 different proteins as participants in HMM hA3G complexes. Numerous cellular RNA binding proteins with diverse roles in RNA function, metabolism, and fate determination are present in these HMM hA3G complexes, but most are present owing to their binding to resident RNAs rather than
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their direct assembly with hA3G (71, 116, 117). These complexes actually correspond to three well-characterized multisubunit RNPs present in human cells: (a) Staufencontaining, polysome-associated RNA granules, (b) Ro RNPs, and (c) prespliceosomes plus reservoirs for transcriptional regulators (116). Of note, the protein cofactors in the latter class are multifunctional, and many participate in Staufen-containing RNA granules or function as cytoplasmic regulators of translation. Staufen, a double-stranded RNA-binding protein, is best known for its role in the localization of specific mRNAs during Drosophila oogenesis. Mammalian homologs of Staufen (Staufen1 and Staufen2) have been implicated in the function of neuronal granules within dendrites of hippocampal neurons. After synaptic stimulation, these granules are transported to the synapse, where their mRNA cargoes are rapidly translated. The resultant protein products contribute to orchestrating changes in synaptic plasticity (118, 119). In general, RNA granules are >10 MDa macromolecular RNP complexes containing more than 100 proteins, including ribosomal subunits, scaffold proteins, translation machinery, RNA-binding proteins, helicases, and various decay enzymes (i.e., Staufen; Purα; Purβ; DbpA and DbpB; nucleolin; RNA binding motif protein 3; NFAR; FMR1; FXR1; FXR2; PABP; CBP80; CBP20; EF1α; Hsp70; Upf1; 60S and 40S ribosomal proteins; DDX1; DDX3; p68 RNA helicases; RNA helicase A; and hnRNP A/B, A0, A, D, and U) (118–121). Ro RNPs are the major RNP autoantigens recognized by sera from patients with various connective tissue diseases, although their normal function remains incompletely understood. In human cells, Ro RNPs contain one of the four human small Y (hY) RNAs (hY1, hY3, hY4, and hY5) and two core proteins (60-kDa Ro and 50-kDa La) (122). Almost all of the proteins mentioned above that participate in the formation of Staufen-containing RNA granules and Ro RNPs are readily de-
tectable in the purified HMM hA3G RNP complexes. An association of hA3G with stress granules (SGs) and processing bodies (PBs) instead of RNA granules has also been proposed (69, 71, 117). RNA granules, SGs, and PBs are in fact related, dynamic cytoplasmic RNA structures that control the localization, translation, and stability of their resident mRNA cargoes. However, RNA granules harbor highly specific mRNA sequences, whereas SG and PB are less discriminating. In addition to differing in their mRNA selectivity, RNA granules contain both the 60S and 40S ribosomal subunits, whereas SGs contain only small ribosomal subunits and PBs lack both subunits (118, 119). Staufen proteins are present in all three types of cytoplasmic RNA structures (118, 119). However, the RNA granules that associate with HMM hA3G contain both the 60S and 40S ribosomal subunits and harbor highly specific mRNA cargos including hA3G mRNA (116, 117); thus, they are more reminiscent of Staufen-containing, polysome-associated RNA granules rather than of SGs or PBs. Further, an association of endogenous proteins that are characteristic components of SGs (i.e., TIA-1) and PBs (i.e., Ago2 and decapping enzymes) has not been demonstrated in HMM hA3G complexes. Nevertheless, exogenously expressed components of SGs and PBs can be copurified with HMM hA3G complexes (69, 71). Under these conditions of forced expression, confocal microscopy further supports substantial colocalization of hA3G with cytoplasmic SGs and PBs (69, 71). Indeed, hA3G complexes are shifted reversibly between polysomes and dormant pools (likely, SGs) in response to translational inhibitors (117). Stressing the cells also induces the rapid redistribution of hA3G and a number of PB proteins (Ago1 and Ago2) to SGs (71). These findings imply that the dynamic spatial organizations between RNA granules and related cytoplasmic RNA complexes could affect the status of hA3G complexes, control A3G’s antiviral activity, and www.annualreviews.org • The APOBEC3 Cytidine Deaminases
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regulate translation/decay of mRNAs encoding this innate antiretroviral factor. Intriguingly, delineation of the RNA components in HMM hA3G complexes identified human Alu (Sx, Sp, Ya5, Ya8, and Yb8 subfamily) and small hY (hY1–5) endogenous retroelement RNA sequences (116). Activation of CD4 T cells with PHA and IL-2 induces high-level expression of these endogenous retroelement RNAs. Conversely, almost all of the protein cofactors that participate in the HMM A3G complexes are constitutively expressed in resting CD4 T cells but are not assembled into complexes (116). These findings raise the distinct possibility that the induced expression of Alu and hY RNAs forms the driving force for HMM hA3G complex assembly. The hA3G-dependent recruitment and specific enrichment of Alu and hY RNAs into Staufen-containing RNA granules further suggest a potential physiological function for these complexes (116). Specifically, endogenous nonautonomous retroelements (i.e., Alu and hY RNAs) (123, 124) likely form the natural cellular targets of hA3G (see below).
Intravirion APOBEC3G Complexes: Unexpected Interplay Between Host and Virus The fact that cellular hA3G principally resides in 5–15-MDa HMM RNP complexes in activated, virus-producing T cells prompted studies to determine which form of hA3G is actually incorporated into budding virions. Three models seemed possible: (a) Although unlikely, the entire HMM hA3G complex might be incorporated into budding virions; (b) hA3G residing in HMM complexes might be selectively extracted via interactions with HIV Gag and genomic RNA; and (c) newly synthesized hA3G not yet assembled into HMM complexes might be preferentially recruited into virions. When virions are examined for proteins that compose the HMM A3G complex, most are undetectable; those that are present do not appear to be recruited 332
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into virions in an hA3G-dependent manner (32, 117). These findings argue strongly against model a. In pulse-chase radiolabeling and size fractionation studies, hA3G is rapidly assembled (5 on single-stranded DNA. Nat. Struct. Mol. Biol. 13:392–99 52. Michael N, Shen HM, Longerich S, Kim N, Longacre A, Storb U. 2003. The E box motif CAGGTG enhances somatic hypermutation without enhancing transcription. Immunity 19:235–42 53. Nambu Y, Sugai M, Gonda H, Lee CG, Katakai T, et al. 2003. Transcription-coupled events associating with immunoglobulin switch region chromatin. Science 302:2137–40 54. Unniraman S, Schatz DG. 2007. Strand-biased spreading of mutations during somatic hypermutation. Science 317:1227–30 55. Rada C, Di Noia JM, Neuberger MS. 2004. Mismatch recognition and uracil excision provide complementary paths to both Ig switching and the A/T-focused phase of somatic mutation. Mol. Cell 16:163–71 56. Shen HM, Tanaka A, Bozek G, Nicolae D, Storb U. 2006. Somatic hypermutation and class switch recombination in Msh6−/− Ung−/− double-knockout mice. J. Immunol. 177:5386–92 57. Ronai D, Iglesias MD, Fan M, Li Z, Martin A, Scharff MD. 2007. Single-stranded DNAprotein complexes in regions targeted for somatic hypermutation. J. Exp. Med. 2007:181– 90
Annu. Rev. Immunol. 2008.26:481-511. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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58. Apel TW, Mautner J, Polack A, Bornkamm GW, Eick D. 1992. Two antisense promoters in the immunoglobulin mu-switch region drive expression of c-myc in the Burkitt’s lymphoma cell line BL67. Oncogene 7:1267–71 59. Bolland DJ, Wood AL, Afshar R, Featherstone K, Oltz EM, Corcoran AE. 2007. Antisense intergenic transcription precedes Igh D-to-J recombination and is controlled by the intronic enhancer Eμ. Mol. Cell. Biol. 27:5523–33 60. Bolland DJ, Wood AL, Johnston CM, Bunting SF, Morgan G, et al. 2004. Antisense intergenic transcription in V(D)J recombination. Nat. Immunol. 5:630–37 61. Shen HM, Ratnam S, Storb U. 2005. Targeting of the activation-induced cytosine deaminase is strongly influenced by the sequence and structure of the targeted DNA. Mol. Cell. Biol. 25:10815–21 62. Durandy A, Peron S, Taubenheim N, Fischer A. 2006. Activation-induced cytidine deaminase: structure-function relationship as based on the study of mutants. Hum. Mutat. 27:1185–91 63. Ta VT, Nagaoka H, Catalan N, Durandy A, Fischer A, et al. 2003. AID mutant analyses indicate requirement for class-switch-specific cofactors. Nat. Immunol. 4:843–48 64. Barreto V, Reina-San-Martin B, Ramiro AR, McBride KM, Nussenzweig MC. 2003. C-terminal deletion of AID uncouples class switch recombination from somatic hypermutation and gene conversion. Mol. Cell 12:501–8 65. Shinkura R, Ito S, Begum NA, Nagaoka H, Muramatsu M, et al. 2004. Separate domains of AID are required for somatic hypermutation and class-switch recombination. Nat. Immunol. 5:707–12 66. Prochnow C, Bransteitter R, Klein MG, Goodman MF, Chen XS. 2007. The APOBEC-2 crystal structure and functional implications for the deaminase AID. Nature 445:447–51 67. Deleted in proof 68. Basu U, Chaudhuri J, Alpert C, Dutt S, Ranganath S, et al. 2005. The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation. Nature 438:508– 11 69. McBride KM, Gazumyan A, Woo EM, Barreto VM, Robbiani DF, et al. 2006. Regulation of hypermutation by activation-induced cytidine deaminase phosphorylation. Proc. Natl. Acad. Sci. USA 103:8798–803 70. Pasqualucci L, Kitaura Y, Gu H, Dalla-Favera R. 2006. PKA-mediated phosphorylation regulates the function of activation-induced deaminase (AID) in B cells. Proc. Natl. Acad. Sci. USA 103:395–400 71. Chaudhuri J, Khuong C, Alt FW. 2004. Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature 430:992–98 72. Noguchi E, Shibasaki M, Inudou M, Kamioka M, Yokouchi Y, et al. 2001. Association between a new polymorphism in the activation-induced cytidine deaminase gene and atopic asthma and the regulation of total serum IgE levels. J. Allergy Clin. Immunol. 108:382–86 73. Greeve J, Philipsen A, Krause K, Klapper W, Heidorn K, et al. 2003. Expression of activation-induced cytidine deaminase in human B-cell non-Hodgkin lymphomas. Blood 101:3574–80 74. Oppezzo P, Dumas G, Lalanne AI, Payelle-Brogard B, Magnac C, et al. 2005. Different isoforms of BSAP regulate expression of AID in normal and chronic lymphocytic leukemia B cells. Blood 105:2495–503 75. Oppezzo P, Vuillier F, Vasconcelos Y, Dumas G, Magnac C, et al. 2003. Chronic lymphocytic leukemia B cells expressing AID display dissociation between class switch recombination and somatic hypermutation. Blood 101:4029–32 www.annualreviews.org • Somatic Hypermutation
505
ARI
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76. McCarthy H, Wierda WG, Barron LL, Cromwell CC, Wang J, et al. 2003. High expression of activation-induced cytidine deaminase (AID) and splice variants is a distinctive feature of poor-prognosis chronic lymphocytic leukemia. Blood 101:4903–8 77. Albesiano E, Messmer BT, Damle RN, Allen SL, Rai KR, Chiorazzi N. 2003. Activationinduced cytidine deaminase in chronic lymphocytic leukemia B cells: expression as multiple forms in a dynamic, variably sized fraction of the clone. Blood 102:3333–39 78. Jansen JG, Langerak P, Tsaalbi-Shtylik A, Van Den Berk P, Jacobs H, de Wind N. 2006. Strand-biased defect in C/G transversions in hypermutating immunoglobulin genes in Rev1-deficient mice. J. Exp. Med. 203:319–23 79. Masuda K, Ouchida R, Hikida M, Kurosaki T, Yokoi M, et al. 2007. DNA polymerases η and θ function in the same genetic pathway to generate mutations at A/T during somatic hypermutation of Ig genes. J. Biol. Chem. 282:17387–94 80. Imai K, Slupphaug G, Lee WI, Revy P, Nonoyama S, et al. 2003. Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat. Immunol. 4:1023–28 81. Bardwell PD, Martin A, Wong E, Li Z, Edelmann W, Scharff MD. 2003. Cutting edge: the G-U mismatch glycosylase methyl-CpG binding domain 4 is dispensable for somatic hypermutation and class switch recombination. J. Immunol. 170:1620–24 82. Di Noia JM, Rada C, Neuberger MS. 2006. SMUG1 is able to excise uracil from immunoglobulin genes: insight into mutation versus repair. EMBO J. 25:585–95 83. Krokan HE, Drablos F, Slupphaug G. 2002. Uracil in DNA–occurrence, consequences and repair. Oncogene 21:8935–48 84. Almeida KH, Sobol RW. 2007. A unified view of base excision repair: lesion-dependent protein complexes regulated by post-translational modification. DNA Repair 6:695–711 85. Fortini P, Dogliotti E. 2007. Base damage and single-strand break repair: mechanisms and functional significance of short- and long-patch repair subpathways. DNA Repair 6:398–409 86. Simpson LJ, Ross AL, Szuts D, Alviani CA, Oestergaard VH, et al. 2006. RAD18independent ubiquitination of proliferating-cell nuclear antigen in the avian cell line DT40. EMBO Rep. 7:927–32 87. Bachl J, Ertongur I, Jungnickel B. 2006. Involvement of Rad18 in somatic hypermutation. Proc. Natl. Acad. Sci. USA 103:12081–86 88. Arakawa H, Moldovan GL, Saribasak H, Saribasak NN, Jentsch S, Buerstedde JM. 2006. A role for PCNA ubiquitination in immunoglobulin hypermutation. PLoS Biol. 4:e366 89. Langerak P, Nygren AO, Krijger PH, Van Den Berk PC, Jacobs H. 2007. A/T mutagenesis in hypermutated immunoglobulin genes strongly depends on PCNAK164 modification. J. Exp. Med. 204:1989–98 90. Rada C, Williams GT, Nilsen H, Barnes DE, Lindahl T, Neuberger MS. 2002. Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Curr. Biol. 12:1748–55 91. Bennett SE, Sung JS, Mosbaugh DW. 2001. Fidelity of uracil-initiated base excision DNA repair in DNA polymerase beta-proficient and -deficient mouse embryonic fibroblast cell extracts. J. Biol. Chem. 276:42588–600 92. Larson ED, Cummings WJ, Bednarski DW, Maizels N. 2005. MRE11/RAD50 cleaves DNA in the AID/UNG-dependent pathway of immunoglobulin gene diversification. Mol. Cell 20:367–75 93. Yabuki M, Fujii MM, Maizels N. 2005. The MRE11-RAD50-NBS1 complex accelerates somatic hypermutation and gene conversion of immunoglobulin variable regions. Nat. Immunol. 6:730–36
Annu. Rev. Immunol. 2008.26:481-511. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-16
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ANRV338-IY26-16
ARI
16 February 2008
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94. Poltoratsky V, Prasad R, Horton JK, Wilson SH. 2007. Down-regulation of DNA polymerase β accompanies somatic hypermutation in human BL2 cell lines. DNA Repair 6:244–53 95. Wu X, Stavnezer J. 2007. DNA polymerase β is able to repair breaks in switch regions and plays an inhibitory role during immunoglobulin class switch recombination. J. Exp. Med. 204:1677–89 96. Parlanti E, Locatelli G, Maga G, Dogliotti E. 2007. Human base excision repair complex is physically associated to DNA replication and cell cycle regulatory proteins. Nucleic Acids Res. 35:1569–77 97. Iyer RR, Pluciennik A, Burdett V, Modrich PL. 2006. DNA mismatch repair: functions and mechanisms. Chem. Rev. 106:302–23 98. Jiricny J. 2006. The multifaceted mismatch-repair system. Nat. Rev. Mol. Cell Biol. 7:335– 46 99. Kadyrov FA, Dzantiev L, Constantin N, Modrich P. 2006. Endonucleolytic function of MutLα in human mismatch repair. Cell 126:297–308 100. Jungnickel B. 2006. False moves for survival: error-prone DNA repair in adaptive immunity. Cell Cycle 5:2856–61 101. Woo CJ, Martin A, Scharff MD. 2003. Induction of hypermutation is associated with modifications of variable region chromatin in BL2 cells. Immunity 19:479–89 102. Li Z, Zhao C, Iglesias-Ussel MD, Polonskaya Z, Zhuang M, et al. 2006. The mismatch repair protein Msh6 influences the in vivo AID targeting to the Ig locus. Immunity 24:393– 403 103. Wiesendanger M, Kneitz B, Edelmann W, Scharff MD. 2000. Somatic mutation in MutS homologue (MSH)3-, MSH6-, and MSH3/MSH6-deficient mice reveals a role for the MSH2-MSH6 heterodimer in modulating the base substitution pattern. J. Exp. Med. 191:579–84 104. Li Z, Scherer SJ, Ronai D, Iglesias-Ussel MD, Peled JU, et al. 2004. Examination of Msh6- and Msh3-deficient mice in class switching reveals overlapping and distinct roles of MutS homologues in antibody diversification. J. Exp. Med. 200:47–59 105. Martomo SA, Yang WW, Gearhart PJ. 2004. A role for Msh6 but not Msh3 in somatic hypermutation and class switch recombination. J. Exp. Med. 200:61–68 106. Warren JJ, Pohlhaus TJ, Changela A, Iyer RR, Modrich PL, Beese LS. 2007. Structure of the human MutSα DNA lesion recognition complex. Mol. Cell 26:579–92 107. Park K, Kim J, Kim HS, Shin HS. 1998. Isolated human germinal center centroblasts have an intact mismatch repair system. J. Immunol. 161:6128–32 108. Li Z, Peled JU, Zhao C, Svetlanov A, Ronai D, et al. 2006. A role for Mlh3 in somatic hypermutation. DNA Repair 5:675–82 109. Zeng X, Winter DB, Kasmer C, Kraemer KH, Lehmann AR, Gearhart PJ. 2001. DNA polymerase η is an A-T mutator in somatic hypermutation of immunoglobulin variable genes. Nat. Immunol. 2:537–41 110. Delbos F, Aoufouchi S, Faili A, Weill JC, Reynaud CA. 2007. DNA polymerase η is the sole contributor of A/T modifications during immunoglobulin gene hypermutation in the mouse. J. Exp. Med. 204:17–23 111. Faili A, Aoufouchi S, Flatter E, Gueranger Q, Reynaud CA, Weill JC. 2002. Induction of somatic hypermutation in immunoglobulin genes is dependent on DNA polymerase iota. Nature 419:944–47 112. Zan H, Komori A, Li Z, Cerrutti M, Flajnik MF, et al. 2001. The translesional polymerase zeta plays a major role in Ig and Bcl-6 somatic mutation. Immunity 14:643–53 www.annualreviews.org • Somatic Hypermutation
507
ARI
16 February 2008
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113. Diaz M, Verkoczy LK, Flajnik MF, Klinman NR. 2001. Decreased frequency of somatic hypermutation and impaired affinity maturation but intact germinal center formation in mice expressing antisense RNA to DNA polymerase zeta. J. Immunol. 167:327–36 114. Garg P, Burgers PM. 2005. Ubiquitinated proliferating cell nuclear antigen activates translesion DNA polymerases η and REV1. Proc. Natl. Acad. Sci. USA 102:18361–66 115. Ulrich HD. 2006. Deubiquitinating PCNA: a downside to DNA damage tolerance. Nat. Cell Biol. 8:303–5 116. Friedberg EC. 2006. Reversible monoubiquitination of PCNA: a novel slant on regulating translesion DNA synthesis. Mol. Cell 22:150–52 117. Goodman MF. 2002. Error-prone repair DNA polymerases in prokaryotes and eukaryotes. Annu. Rev. Biochem. 71:17–50 118. Moldovan GL, Pfander B, Jentsch S. 2007. PCNA, the maestro of the replication fork. Cell 129:665–79 119. Mao C, Jiang L, Melo-Jorge M, Puthenveetil M, Zhang X, et al. 2004. T cell-independent somatic hypermutation in murine B cells with an immature phenotype. Immunity 20:133– 44 120. Han JH, Akira S, Calame K, Beutler B, Selsing E, Imanishi-Kari T. 2007. Class switch recombination and somatic hypermutation in early mouse B cells are mediated by B cell and Toll-like receptors. Immunity 27:64–75 121. Cattoretti G, Buttner M, Shaknovich R, Kremmer E, Alobeid B, Niedobitek G. 2006. Nuclear and cytoplasmic AID in extrafollicular and germinal center B cells. Blood 107:3967– 75 122. Crouch EE, Li Z, Takizawa M, Fichtner-Feigl S, Gourzi P, et al. 2007. Regulation of AID expression in the immune response. J. Exp. Med. 204:1145–56 123. Martin A, Bardwell PD, Woo CJ, Fan M, Shulman MJ, Scharff MD. 2002. Activationinduced cytidine deaminase turns on somatic hypermutation in hybridomas. Nature 415:802–6 124. Martin A, Scharff MD. 2002. Somatic hypermutation of the AID transgene in B and non-B cells. Proc. Natl. Acad. Sci. USA 99:12304–8 125. Okazaki IM, Hiai H, Kakazu N, Yamada S, Muramatsu M, et al. 2003. Constitutive expression of AID leads to tumorigenesis. J. Exp. Med. 197:1173–81 126. Ito S, Nagaoka H, Shinkura R, Begum N, Muramatsu M, et al. 2004. Activation-induced cytidine deaminase shuttles between nucleus and cytoplasm like apolipoprotein B mRNA editing catalytic polypeptide 1. Proc. Natl. Acad. Sci. USA 101:1975–80 127. McBride KM, Barreto V, Ramiro AR, Stavropoulos P, Nussenzweig MC. 2004. Somatic hypermutation is limited by CRM1-dependent nuclear export of activation-induced deaminase. J. Exp. Med. 199:1235–44 128. Gordon MS, Kanegai CM, Doerr JR, Wall R. 2003. Somatic hypermutation of the B cell receptor genes B29 (Igβ, CD79b) and mb1 (Igα, CD79a). Proc. Natl. Acad. Sci. USA 100:4126–31 129. Shen HM, Peters A, Baron B, Zhu X, Storb U. 1998. Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 280:1750–52 130. Muschen M, Re D, Jungnickel B, Diehl V, Rajewsky K, Kuppers R. 2000. Somatic mutation of the CD95 gene in human B cells as a side-effect of the germinal center reaction. J. Exp. Med. 192:1833–40 131. Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, et al. 2001. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412:341–46
Annu. Rev. Immunol. 2008.26:481-511. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-16
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Peled et al.
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ANRV338-IY26-16
ARI
16 February 2008
15:33
132. Pasqualucci L, Migliazza A, Fracchiolla N, William C, Neri A, et al. 1998. BCL-6 Mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci. Proc. Natl. Acad. Sci. USA 95:11816–21 133. Yoshikawa K, Okazaki IM, Eto T, Kinoshita K, Muramatsu M, et al. 2002. AID enzymeinduced hypermutation in an actively transcribed gene in fibroblasts. Science 296:2033–36 134. Parsa JY, Basit W, Wang CL, Gommerman JL, Carlyle JR, Martin A. 2007. AID mutates a nonimmunoglobulin transgene independent of chromosomal position. Mol. Immunol. 44:567–75 135. Wang CL, Harper RA, Wabl M. 2004. Genome-wide somatic hypermutation. Proc. Natl. Acad. Sci. USA 101:7352–56 136. Petersen S, Casellas R, Reina-San-Martin B, Chen HT, Difilippantonio MJ, et al. 2001. AID is required to initiate Nbs1/gamma-H2AX focus formation and mutations at sites of class switching. Nature 414:660–65 137. Okazaki IM, Kotani A, Honjo T. 2007. Role of AID in tumorigenesis. Adv. Immunol. 94:245–73 138. Yang SY, Schatz DG. 2007. Targeting of AID-mediated sequence diversification by cisacting determinants. Adv. Immunol. 94:109–25 139. Li Z, Luo Z, Ronai D, Kuang FL, Peled JU, et al. 2007. Targeting AID to the Ig genes. Adv. Exp. Med. Biol. 596:93–109 140. Fraenkel S, Mostoslavsky R, Novobrantseva TI, Pelanda R, Chaudhuri J, et al. 2007. Allelic ‘choice’ governs somatic hypermutation in vivo at the immunoglobulin kappachain locus. Nat. Immunol. 8:715–22 141. Odegard VH, Kim ST, Anderson SM, Shlomchik MJ, Schatz DG. 2005. Histone modifications associated with somatic hypermutation. Immunity 23:101–10 142. Larijani M, Frieder D, Sonbuchner TM, Bransteitter R, Goodman MF, et al. 2005. Methylation protects cytidines from AID-mediated deamination. Mol. Immunol. 42:599– 604 143. Li Z, Luo Z, Scharff MD. 2004. Differential regulation of histone acetylation and generation of mutations in switch regions is associated with Ig class switching. Proc. Natl. Acad. Sci. USA 101:15428–33 144. Wang L, Whang N, Wuerffel R, Kenter AL. 2006. AID-dependent histone acetylation is detected in immunoglobulin S regions. J. Exp. Med. 203:215–26 145. Odegard VH, Schatz DG. 2006. Targeting of somatic hypermutation. Nat. Rev. Immunol. 6:573–83 146. Bachl J, Wabl M. 1996. Enhancers of hypermutation. Immunogenetics 45:59–64 147. Lin MM, Green NS, Zhang W, Scharff MD. 1998. The effects of Em, 3 α (hs 1,2) and 3 κ enhancers on mutation of an Ig-VDJ-Cγ2a immunoglobulin heavy gene in cultured B cells. Int. Immunol. 10:1121–29 148. Yang SY, Fugmann SD, Schatz DG. 2006. Control of gene conversion and somatic hypermutation by immunoglobulin promoter and enhancer sequences. J. Exp. Med. 203:2919– 28 149. Perlot T, Alt FW, Bassing CH, Suh H, Pinaud E. 2005. Elucidation of IgH intronic enhancer functions via germ-line deletion. Proc. Natl. Acad. Sci USA 102:14362–67 150. Morvan CL, Pinaud E, Decourt C, Cuvillier A, Cogne M. 2003. The immunoglobulin heavy-chain locus hs3b and hs4 3 enhancers are dispensable for VDJ assembly and somatic hypermutation. Blood 102:1421–27 151. Garrett FE, Emelyanov AV, Sepulveda MA, Flanagan P, Volpi S, et al. 2005. Chromatin architecture near a potential 3 end of the IgH locus involves modular regulation of www.annualreviews.org • Somatic Hypermutation
509
ANRV338-IY26-16
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152.
153.
154.
Annu. Rev. Immunol. 2008.26:481-511. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
155.
156. 157. 158. 159. 160.
161.
162.
163.
164.
165. 166. 167.
168.
510
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histone modifications during B-cell development and in vivo occupancy of CTCF sites. Mol. Cell. Biol. 25:1511–25 Ronai D, Iglesias-Ussel MD, Fan M, Shulman MJ, Scharff MD. 2005. Complex regulation of somatic hypermutation by cis-acting sequences in the endogenous IgH gene in hybridoma cells. Proc. Natl. Acad. Sci. USA 102:11829–34 Komori A, Xu Z, Wu X, Zan H, Casali P. 2006. Biased dA/dT somatic hypermutation as regulated by the heavy chain intronic iEμ enhancer and 3 Eα enhancers in human lymphoblastoid B cells. Mol. Immunol. 43:1817–26 Kodama M, Hayashi R, Nishizumi H, Nagawa F, Takemori T, Sakano H. 2001. The PU.1 and NF-EM5 binding motifs in the Igκ 3 enhancer are responsible for directing somatic hypermutations to the intrinsic hotspots in the transgenic Vκ gene. Int. Immunol. 13:1415–22 Duquette ML, Pham P, Goodman MF, Maizels N. 2005. AID binds to transcriptioninduced structures in c-MYC that map to regions associated with translocation and hypermutation. Oncogene 24:5791–98 Yu K, Lieber MR. 2003. Nucleic acid structures and enzymes in the immunoglobulin class switch recombination mechanism. DNA Repair 2:1163–74 Kinoshita K, Honjo T. 2001. Linking class-switch recombination with somatic hypermutation. Nat. Rev. Mol. Cell Biol. 2:493–503 Wright BE, Schmidt KH, Minnick MF. 2004. Mechanisms by which transcription can regulate somatic hypermutation. Genes Immun. 5:176–82 Wu X, Geraldes P, Platt JL, Cascalho M. 2005. The double-edged sword of activationinduced cytidine deaminase. J. Immunol. 174:934–41 MacDuff DA, Neuberger MS, Harris RS. 2006. MDM2 can interact with the C-terminus of AID but it is inessential for antibody diversification in DT40 B cells. Mol. Immunol. 43:1099–108 Faili A, Aoufouchi S, Gueranger Q, Zober C, Leon A, et al. 2002. AID-dependent somatic hypermutation occurs as a DNA single-strand event in the BL2 cell line. Nat. Immunol. 3:815–21 Yang G, Obiakor H, Sinha RK, Newman BA, Hood BL, et al. 2005. Activation-induced deaminase cloning, localization, and protein extraction from young VH-mutant rabbit appendix. Proc. Natl. Acad. Sci. USA 102:17083–88 Kosak ST, Skok JA, Medina KL, Riblet R, Le Beau MM, et al. 2002. Subnuclear compartmentalization of immunoglobulin loci during lymphocyte development. Science 296:158– 62 Reina-San-Martin B, Difilippantonio S, Hanitsch L, Masilamani RF, Nussenzweig A, Nussenzweig MC. 2003. H2AX is required for recombination between immunoglobulin switch regions but not for intra-switch region recombination or somatic hypermutation. J. Exp. Med. 197:1767–78 Osborne CS, Chakalova L, Mitchell JA, Horton A, Wood AL, et al. 2007. Myc dynamically and preferentially relocates to a transcription factory occupied by Igh. PLoS Biol. 5:e192 Neuberger MS, Rada C. 2007. Somatic hypermutation: activation-induced deaminase for C/G followed by polymerase η for A/T. J. Exp. Med. 204:7–10 Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, et al. 2005. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood 105:1851–61 Shaffer AL, Wright G, Yang L, Powell J, Ngo V, et al. 2006. A library of gene expression signatures to illuminate normal and pathological lymphoid biology. Immunol. Rev. 210:67–85
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169. Ranuncolo SM, Polo JM, Dierov J, Singer M, Kuo T, et al. 2007. Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR. Nat. Immunol. 8:705–14 170. Phan RT, Dalla-Favera R. 2004. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 432:635–39 171. Reynaud CA, Aoufouchi S, Faili A, Weill JC. 2003. What role for AID: mutator, or assembler of the immunoglobulin mutasome? Nat. Immunol. 4:631–38 172. Kavli B, Otterlei M, Slupphaug G, Krokan HE. 2007. Uracil in DNA—general mutagen, but normal intermediate in acquired immunity. DNA Repair 6:505–16
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RELATED RESOURCES Stavnezer, J, Guikema JEJ, Schrader CE, 2008. Mechanism and regulation of class switch recombination. Annu. Rev. Immunol. 26:261–92 Database of HIGM Type II causing mutations: http://bioinf.uta.fi/AICDAbase
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:481-511. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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Contents
Supplemental Material: Annu. Rev. Immunol. 2008. 26: 481-511 doi: 10.1146/annurev.immunol.26.021607.090236 The Biochemistry of Somatic Hypermutation Peled et al.
Supplemental Table Interactions that occur amongst the proteins involved in somatic hypermutation
Protein
Select Functions
Effect in SHM
AID
Cytidine deaminase: deaminates dC into dU on ssDNA (1, 2).
Abolished, both in patients with mutations in AID (3) and in knock-out mice (4).
PKA
RPA
MDM2
Phosphorylates AID at serine 38 and tyrosine 184 (8) -DNA replication, recombination and repair. -ssDNA binding protein. -NER: hRPA binds to the undamaged strand and directs incisions to the damaged strand. DNA damage: is a ring finger E3 ubiquitin ligase that promotes ubiquitination and proteasomal degradation of p53.
Select protein–protein interactions -RNA pol II: by co-IP (5). -RPA (32 kDa subunit): by cloning a complementing factor required for AID activity in vitro (6). -MDM2: through C-terminus of AID (7). -PKA: by coIP and co-purification (8). -DNA-PKcs: (through C-terminal AID domain): by IP followed by MALDITOF (9).
AIDS38A has diminished SHM activity on artificial and physiological DNA targets (10)
-AID: by coIP and co-purification (8) in the cytoplasm of B cells (11).
AID–RPA complexes may preferentially bind to ssDNA of small transcription bubbles at SHM hotspots (6).
-Phosphorylated AID: (8) unphosphorylated AID from 293 cells does not interact with RPA (6). -PCNA: by affinity chromatography and mass spectrometry (12). -hUNG2: interacts with RPA2 (34KDa subunit) by two hybrid (13). -XPG: by gel retardation assays (14). -ATR: ATR and RPA colocalize to nuclear foci after DNA damage and RPA is required for the recruitment of ATR to sites of DNA damage (15).
_
-AID: through C-terminus of AID (7). -MRE11, RAD50 and NBS1: by co-IP in HeLa cell lysates (16).
Supplemental Material: Annu. Rev. Immunol. 2008. 26: 481-511 doi: 10.1146/annurev.immunol.26.021607.090236 The Biochemistry of Somatic Hypermutation Peled et al.
MSH2
MSH3
MMR: -Recognition of point mutations or short mismatches (in complex with MSH6) and large mismatches, insertions or deletions (with MSH3). -Scaffolding: recruits accessory proteins involved in processing of the mismatch. MMR: mediates repair of large mismatches, insertions and deletions (in complex with MSH2). MMR: recognition of point mutations and short mismatches (in complex with MSH2).
MSH6 In complex with MSH2 physically recognizes dU:dG mismatches (36). PMS2
MMR
In Msh2 -/- mice: *5-fold reduction in mutation frequency. *Reduced mutations at A:T. *Increase in hotspot targeting. (17-19)
-MSH3: by co-IP with human proteins (20). Contact regions have been mapped (21). -MSH6: by co-IP with human proteins (20). Contact regions have been mapped (21). -MLH1 and PMS1: Msh2-Msh6 forms a ternary complex with MLH1-PMS1 on DNA substrate containing a mismatch. (22). -EXO1: by GST fusion pull-down (23). -PMS2: interacts with MSH2-MSH6 (24). -Controversial interaction with PCNA: not detected by co-IP but found to interact in yeast two-hybrid assay (25). PCNA binds to MSH2 when MSH2 is in a heterodimer with MSH6 (26) (27) or with MSH3 (28). -RAD50: in a complex (29). -POL η: in cell extracts (30). -EXO I: by GST pull-down analysis (23). -ATR: by co-IP in HeLa and sf9 cells (31).
In Msh3 -/-: No effect (32, 33) or slight decrease in mutations at G/C basepairs and slight decrease in mutations at A:T bases in JH2-JH4 regions (34)
-MSH2: by co-IP with human proteins (20). Contact regions have been mapped (21). -PCNA: by GST pull-down (27). -EXO I: by GST/IVTT bait-prey interaction assay (35).
In Msh6 -/- mice: *Decrease in mutation frequency. *Reduced mutations at A/T. *Increase in Ts mutations at G/C. *Increase in hotspot targeting. (32-34)
-MSH2: by co-IP with human proteins (20). Contact regions have been mapped (21). -MLH1: by co-IP (29). -PCNA by GST pull-down (27). -EXO I: weak interaction by GST/IVTT bait-prey interaction assay (35). -ATR: by co-IP in sf9 cells (31).
In Pms2 -/- mice: *2-4 fold reduction in mutation frequency (37-39) *6-22-fold reduction in mutation frequency (40). *High frequency of dinucleotide mutations (39). *Slight increase in mutations at G:C (37).
-MSH2 in complex with MSH6: (24). -MLH1: by coIP (41) (42) (24). -PCNA: by co-IP (43). -EXO I: weak interaction by GST/IVTT bait-prey interaction system (35).
Supplemental Material: Annu. Rev. Immunol. 2008. 26: 481-511 doi: 10.1146/annurev.immunol.26.021607.090236 The Biochemistry of Somatic Hypermutation Peled et al.
MLH1
MLH3
MMR
In Mlh1 -/- mice: normal to ∼2-fold reduction in frequency of mutation and altered patterns of mutation in a nonselectable Ig-κ gene with an artificial insert in the V region with a preference for targeting G and C nucleotides (37).
-MSH2: in the presence of DNA (homoduplex or heteroduplex), Mg2+ and ATP (24, 43). -MLH3: by yeast two-hybrid assay (44). -MSH6: by co-IP (29). -PMS2: by co-IP (41-43). -PCNA: MLH1 interacts with PCNA (26). Human MLH1 and PCNA coimmunoprecipitate (43). Yeast PCNA interacts with yeast MLH1 in a two hybrid system (25). -MRN complex: by IP anti RAD50 and mass spectrometry (29). -EXO I: by GST/IVTT bait-prey interaction system (35).
MMR
In Mlh3 -/-: Slight decrease in the frequency of mutations in the intronic DNA downstream of the rearranged JH4 gene (45) or increase in the frequency of mutations in the intronic DNA downstream of the rearranged JH4 gene (46).
-MLH1: by yeast two-hybrid assay (44).
Since PCNA -/- is embryonic lethal PCNA K164R (that prevents ubiquitination, but does not interfere with its function in replication) has been used to study the effect of PCNA ubiquitylation in SHM: *PCNA K164R knock-in in DT40 cells shown reduction frequency of mutations at the lightchain VJ segment. Although all types of mutations are reduced the most pronounced decreases seen are C-to-G and G-to-C Tv (48). *PCNA K164R knock-in mice: altered mutation spectrum of at variable Ig region (JH4 intronic region), strong reduction of mutations at A/T basepairs associated with a compensatory increase at G/C (49). *Transgenic mice expressing a PCNA-/- + Tg K164R: decrease in mutations per sequence and at A/T basepairs in the VH 186.2 region (S. Roa et al. unpublished results).
-RPA: by affinity chromatography and mass spectrometry (12) -Controversial interaction with MSH2: not detected by co-IP but found to interact in yeast two-hybrid assay (25). PCNA binds to MSH2 when MSH2 is in a heterodimer with MSH6 (26) (27) or with MSH3 (28). - MSH3 and MSH6: from human and yeast, by GST pull-down (27). -MSH2-MSH6 heterodimer: by glycerol gradient (26) and by GST pull-down (27). -MSH2-MSH3 heterodimer (28). -PMS2: by co-IP (43). -MLH1: interaction between human proteins by co-IP (43) and yeast proteins by two-hybrid assay (25). -RAD18: by two-hybrid (50). -RFC: in complex with CHL12 (12). -hUNG2: physical and fuctional interaction (51, 52). -APE1: by co-IP (53). -POL μ: detected both with yeast and human proteins, in vitro (by gel filtration) and in vivo by yeast two-hybrid analysis (54). -POL η: physical and fuctional interaction and mutations in the PCNA binding motif of hPol η inactivate this interaction (55). -POL ι: physical interaction (56). -REV1: binds PCNA (through the BRCT domain located near the N terminus of REV1) and monoubiquitylation of PCNA enhances this interaction (57). -XPG: interaction between human proteins by co-IP (58).
-MMR: DNA replication and DNA re-synthesis. -Long-patch BER.
PCNA
Monoubiquitination of PCNA at Lys 164 triggers switching from a damage sensitive, high fidelity DNA polymerase (δ, ε) to one of the damage tolerant, low fidelity TLS polymerases (47). High fidelity replication over U favors Ts (C to T and G to A), whereas low fidelity replication over abasic sites favors Tv (C to G/A or G to C/T).
Supplemental Material: Annu. Rev. Immunol. 2008. 26: 481-511 doi: 10.1146/annurev.immunol.26.021607.090236 The Biochemistry of Somatic Hypermutation Peled et al.
RAD18
RFC
Ubiquitination of PCNA
Long-patch BER: loads PCNA onto DNA
Inactivation of Rad18 in DT-40 cell line: *In a hypermutation reporter construct: Impaired SHM (59). *In the endogenous Ig locus: decrease in the mutation frequency and decrease in all types of mutations at dG/dC residues, as well as an increase in deletions (59) _
Transcription factors that regulates immunoglobulin gene expression.
Base substitutions in the 3’ enhancer in the PU.1 binding motif cause reduction in the mutation rate and in hotspot mutations in an Igκ transgene (60).
BER: Removal of uracil bases by deglycosylation: hydrolizes the Nglycosidic bond between the nucleotide base and the deoxyribose phosphate creating an AP site.
-In Ung -/- mice: mutations at G/C are shifted toward Ts (95%), indicating inhibition in the generation of abasic sites (that introduce Tv at C/G) and the pattern of mutations at A/T remains unaffected (61). -In patients: recessive mutations in ung (hyper-IgM syndrome type 5) cause a partial disturbance in the SHM pattern in the a VH3-23 region of IgM+ B (CD19+) memory (CD27+) cell populations, such that mutations at G/C baispairs are biased toward Ts, whereas at A/T residues the ratio of Ts/Tv remains unaffected (62).
APE (1 and 2 )
Short-patch BER: excises AP sites at 5’, generating a ssDNA break.
Not determined in SHM. Involved in CSR (Stavnezer et al, this volume)
MRE11/ RAD50/ NBS1 (MRN) complex
Long-patch BER: DNA break repair.
PU1
UNG
Overexpression of NBS1 (nibrin) in a hypermutating B cell line increases mutation (65)
-PCNA: physical interaction by two-hybrid (50).
-PCNA: in complex with CHL12 (12).
-RPA2 (34KDa subunit): by two-hybrid (13). -PCNA: physical and fuctional interaction (51, 52).
-PCNA: by co-IP (53). -POL β: by two-hybrid assay (63). Fail to detect this interaction using affinity chromatography (64) might indicate that this interaction occurs in the context of DNA. -MSH2: interacts with RAD50 in a complex (29). -MLH1: by IP antiRAD50 and mass spectrometry (29). -MDM2 interacts with MRE11, RAD50 and NBS1: by co-IP in HeLa cell lysates (16).
Supplemental Material: Annu. Rev. Immunol. 2008. 26: 481-511 doi: 10.1146/annurev.immunol.26.021607.090236 The Biochemistry of Somatic Hypermutation Peled et al.
POL β (beta, B)
POL η (eta, H)
REV1
POL ι (iota, I):
Short-patch BER: processes ssDNA breaks with high fidelity.
TLS
TLS: -Possible role in shortpatch BER
TLS:
-Correlation between pol β expression and SHM in various hypermutating BL2 cell line subclones: pol β expression is downregulated in SHM-proficient clones and upregulated in SHM-deficient subclones (66) -No direct effect in SHM (67). -Pol η is downregulated in mutating human B cells (68). -Pol η -/- mice show an 80% reduction of mutations at A/T base pairs and increase of mutations at G/C base pairs in the JH4 intron (69, 70) (71) -In patients with xeroderma pigmentosum variant disease (with a defect in pol η) the frequency of SHM is normal but mutations at A/T basepairs is decreased (72) in WA (A/T, A) motifs (73). -In Rev1 -/- mice: C to G Tv are absent (and A to T, C to A, and T to C increased) in the nontranscribed (coding) strand and reduced in the transcribed strand. In addition, loss of REV1 causes compensatory increase in mutagenesis by other TLS polymerases (77). -In REV1-deficient DT40: reduced level of immunoglobulin gene mutation, indicating a defect in translesion bypass (78). Controversial: -When the Pol ι gene is knocked out in BL2 cell line: no detectable increase in mutation frequency after induction for hypermutation (80). -Mice from the 129 strain (which have an inactivating nonsense mutation in exon 2 that abrogates production of POL ι) have normal SHM (81).
-APE1: by two-hybrid assay (63). Fail to detect this interaction using affinity chromatography (64) might indicate that this interaction occurs in the context of DNA.
-MSH2: in cell extracts (30). -PCNA: physical and fuctional (55). -REV1: (through C-terminal region of Rev1): by yeast two-hybrid and co-IP in mouse (74) and human (75). Interaction between human proteins is strong (76) .
-PCNA: REV1 binds PCNA (through the BRCT domain located near the N terminus of REV1) and monoubiquitylation of PCNA enhances this interaction (57). -POL ζ: Interaction between hREV1 and hREV7 (subunit of DNA polymerase ζ) proteins by yeast two-hybrid, GST pull-down assays, and co-IP (79). -POL ι: (through C-terminal region of Rev1): by yeast two-hybrid system and co-IP in mouse (74). -POL η: (through C-terminal region of Rev1): by yeast two-hybrid co-IP using in mouse (74).
-PCNA: physical interaction (56). -REV1: (through C-terminal region of Rev1): by yeast two-hybrid system and co-IP in mouse (74). Interaction between human proteins is interaction (76).
Supplemental Material: Annu. Rev. Immunol. 2008. 26: 481-511 doi: 10.1146/annurev.immunol.26.021607.090236 The Biochemistry of Somatic Hypermutation Peled et al.
POL θ (theta, Q)
TLS
POL ζ (zeta, Z):
TLS
POL μ (mu, M)
NHEJ. Is an error prone polymerase.
EXOI
MMR: exonuclease that creates a ssDNA break.
Somewhat controversial: -In mice carrying a gene disruption that completely eliminates the POLQ enzyme: 60-80% reduction in overall frequency of SHM, pattern of mutations moderately shifted towards more Ts at both A/T and C/G basepairs, but no overall change in the proportion of events at A/T and C/G positions (82). -In mice carrying an in-frame deletion of part of the DNA polymerase domain, so that a catalytically inactive POLQ protein is still produced: slight reduction in the overall mutation frequency, unaffected % of mutations at A/T, significant decrease in % of mutations at C/G particularly at hotspots and both Ts and Tv are similarly reduced at JH4 intronic sequences. Partial impairment in the production of high-affinity specific antibodies. (83). -POL ζ is upregulated in mutating human B cells (68). -Antisense RNA (in mice)/oligos (in cell line) to a portion of mouse REV3: *In mice: decreased frequency of mutation but no effect in pattern of mutations (84). *In the mutating CL-01 cell line: moderate reduction of both A:T and G:C mutations (68). Overexpression of hPOL μ in Ramos cells increases SHM in the IgVH4–34 gene, mutations occur preferably at C and G residues in hotspots rather than in A/T residues. More C G Tv (34%) than C T Ts (23%) (85)
ExoI -/- mice have: increase in Ts at G/C, reduced mutations at A/T and increase in hotspot targeting (86).
-REV1: Interaction between hREV1 and hREV7 (subunit of DNA polymerase ζ) proteins was detected by yeast two-hybrid assay, GST pull-down and co-IP (79). Interaction also reported between mouse proteins (74). Interaction between human proteins is strong (76).
-PCNA: detected both with yeast and human proteins, in vitro (by gel filtration) and in vivo by yeast two-hybrid analysis (54). Mutations in the PCNA binding motif of hPol μ inactivate this interaction (55). -MSH2: by yeast two-hybrid (87) and between human proteins (23). -hExo1 binds to hMLH1: by the GST/IVTT bait-prey interaction assay (35). -hExo1 binds to hMSH3: by the GST/IVTT bait-prey interaction assay (35). -hExo1 binds weakly to MSH6: by the GST/IVTT bait-prey interaction assay (35). -hExo1 binds weakly to PMS2: by the GST/IVTT bait-prey interaction assay (35). -hExoI forms an immunoprecipitable complex with hMLH1/hPMS2 in vivo (35).
Supplemental Material: Annu. Rev. Immunol. 2008. 26: 481-511 doi: 10.1146/annurev.immunol.26.021607.090236 The Biochemistry of Somatic Hypermutation Peled et al.
DNA-PKcs
DSB repair by NHEJ.
XPG
NER endonuclease
ATR
-DNA damage signaling during Sphase (90). -DNA replication (S/M) checkpoint (91).
GANP/ MCM3AP
Inhibitor of DNA replication
BACH2
THO complex
B-cell-specific transcription repressor highly expressed before the plasma cell stage Co-transcriptional recruitment of export factors to package mRNA into an exportable mRNA ribonucleoprotein.
Small to no effect (88). xpg deficient mice have 3-fold increase in mutation frequency and increase of mutations at A/T pairs, particularly A/T to C/G Tv in a supF shuttle vector (89). Patients with mutations in the ATR gene have a normal-to-slightly-elevated frequency of SHM and an altered pattern of mutations at VH3-23-C transcripts, with fewer mutations at A and more mutations at T residues and more Ts at T residues (92). Ganp–/– mice have decreased affinity maturation: decrease in overall mutation in VH186.2 region after NP-CG immunization and severe decrease in highaffinity type W33L, mutations biased to known SHM hotspots (93) Bach2-/- mice have impaired SHM (94)
THO mutants (in yeast) that generate suboptimal mRNP formation strongly increase hypermutation in a transcription-dependent manner and preferentially at the non transcribed strand (95).
AID: activation-induced cytidine deaminase AP sites: apurinic/apyrimidinic or abasic sites, where a nucleotide base has been removed APE: apurinic/apyrimidinic endonuclease ATR: ataxia telangiectasia and Rad3-related protein BER: Base excision repair Co-IP: coimmunoprecipitation DNA-PKcs: DNA-dependent protein kinase catalytic subunit EXO1: exonuclease 1 GANP: Germinal center-associated nuclear protein MLH1: MutL homologue 1 MMR: mismatch repair MSH: MutS homologue NER: Nucleotide excision repair NHEJ: non homologous end joining
-AID (C-terminal domain): Showed by transient expression of mouse AID in HeLa doing AID IP followed by MALDI-TOF (9). -RPA: on 3'-protruding substrates the 5'- oriented side of hRPA is positioned toward the DNA junction allows specific interaction with XPG, which cleaves the strand opposite the one that is bound by hRPA (14). -PCNA: interaction detected between human proteins by co-IP (58). -RPA: ATR and RPA colocalize to nuclear foci after DNA damage and RPA is required for the recruitment of ATR to sites of DNA damage (15). -MSH2: by co-IP in HeLa and sf9 cells (31). -MSH6: by co-IP in sf9 cells (31).
Supplemental Material: Annu. Rev. Immunol. 2008. 26: 481-511 doi: 10.1146/annurev.immunol.26.021607.090236 The Biochemistry of Somatic Hypermutation Peled et al. PCNA: Proliferating cell nuclear antigen PKA: protein kinase A PMS2: postmeiotic segregation 2 POL: polymerase RFC: Replication Factor Chaperone like complex RPA: replication protein A ssDNA: single stranded DNA TLS: translesion DNA synthesis Ts: transition mutations Tv: transversion mutations UNG: uracil DNA glycosylase XPG: xeroderma pigmentosum complementation group G
Supplementary Table Legend Interactions among proteins implicated in somatic hypermutation are summarized. A brief description of their known cellular functions and the effect on SHM when those proteins are deficient, overexpressed, or otherwise altered are provided. Early references and evidence that support those interactions are listed. Supplementary Table Literature Cited 1. 2. 3.
4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
Bransteitter R, Pham P, Scharff MD, Goodman MF. 2003. Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase. Proc Natl Acad Sci U S A 100: 4102-7 Pham P, Bransteitter R, Petruska J, Goodman MF. 2003. Processive AID-catalysed cytosine deamination on single-stranded DNA simulates somatic hypermutation. Nature 424: 103-7 Revy P, Muto T, Levy Y, Geissmann F, Plebani A, Sanal O, Catalan N, Forveille M, Dufourcq-Labelouse R, Gennery A, Tezcan I, Ersoy F, Kayserili H, Ugazio AG, Brousse N, Muramatsu M, Notarangelo LD, Kinoshita K, Honjo T, Fischer A, Durandy A. 2000. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 102: 565-75 Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T. 2000. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102: 553-63 Nambu Y, Sugai M, Gonda H, Lee CG, Katakai T, Agata Y, Yokota Y, Shimizu A. 2003. Transcription-coupled events associating with immunoglobulin switch region chromatin. Science 302: 2137-40 Chaudhuri J, Khuong C, Alt FW. 2004. Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature 430: 992-8 MacDuff DA, Neuberger MS, Harris RS. 2006. MDM2 can interact with the C-terminus of AID but it is inessential for antibody diversification in DT40 B cells. Mol Immunol 43: 1099-108 Basu U, Chaudhuri J, Alpert C, Dutt S, Ranganath S, Li G, Schrum JP, Manis JP, Alt FW. 2005. The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation. Nature 438: 508-11 Wu X, Geraldes P, Platt JL, Cascalho M. 2005. The double-edged sword of activation-induced cytidine deaminase. J Immunol 174: 934-41 McBride KM, Gazumyan A, Woo EM, Barreto VM, Robbiani DF, Chait BT, Nussenzweig MC. 2006. Regulation of hypermutation by activation-induced cytidine deaminase phosphorylation. Proc Natl Acad Sci U S A 103: 8798-803 Pasqualucci L, Kitaura Y, Gu H, Dalla-Favera R. 2006. PKA-mediated phosphorylation regulates the function of activation-induced deaminase (AID) in B cells. Proc Natl Acad Sci U S A 103: 395-400 Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T. 2002. A proteomics approach to identify proliferating cell nuclear antigen (PCNA)-binding proteins in human cell lysates. Identification of the human CHL12/RFCs2-5 complex as a novel PCNA-binding protein. J Biol Chem 277: 40362-7 Nagelhus TA, Haug T, Singh KK, Keshav KF, Skorpen F, Otterlei M, Bharati S, Lindmo T, Benichou S, Benarous R, Krokan HE. 1997. A sequence in the N-terminal region of human uracil-DNA glycosylase with homology to XPA interacts with the C-terminal part of the 34-kDa subunit of replication protein A. J Biol Chem 272: 6561-6 de Laat WL, Appeldoorn E, Sugasawa K, Weterings E, Jaspers NG, Hoeijmakers JH. 1998. DNA-binding polarity of human replication protein A positions nucleases in nucleotide excision repair. Genes Dev 12: 2598-609 Zou L, Elledge SJ. 2003. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300: 1542-8 Alt JR, Bouska A, Fernandez MR, Cerny RL, Xiao H, Eischen CM. 2005. Mdm2 binds to Nbs1 at sites of DNA damage and regulates double strand break repair. J Biol Chem 280: 18771-81
Supplemental Material: Annu. Rev. Immunol. 2008. 26: 481-511 doi: 10.1146/annurev.immunol.26.021607.090236 The Biochemistry of Somatic Hypermutation Peled et al. 17. Phung QH, Winter DB, Cranston A, Tarone RE, Bohr VA, Fishel R, Gearhart PJ. 1998. Increased Hypermutation at G and C Nucleotides in Immunoglobulin Variable Genes from Mice Deficient in the MSH2 Mismatch Repair Protein. The Journal of Experimental Medicine 187: 1745-51 18. Rada C, Ehrenstein MR, Neuberger MS, Milstein C. 1998. Hot Spot Focusing of Somatic Hypermutation in MSH2-Deficient Mice Suggests Two Stages of Mutational Targeting. Immunity 9: 135-41 19. Martin A, Li Z, Lin D, Bardwell PD, Iglesias-Ussel MD, Edelmann W, Scharff MD. 2003. Msh2 ATPase Activity is Essential for Somatic Hypermutation at A-T Basepairs and for Efficient Class Switch Recombination. J. Exp. Med. 198: 1171-8 20. Acharya S, Wilson T, Gradia S, Kane MF, Guerrette S, Marsischky GT, Kolodner R, Fishel R. 1996. hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proc Natl Acad Sci U S A 93: 13629-34 21. Guerrette S, Wilson T, Gradia S, Fishel R. 1998. Interactions of human hMSH2 with hMSH3 and hMSH2 with hMSH6: examination of mutations found in hereditary nonpolyposis colorectal cancer. Mol Cell Biol 18: 6616-23 22. Habraken Y, Sung P, Prakash L, Prakash S. 1998. ATP-dependent assembly of a ternary complex consisting of a DNA mismatch and the yeast MSH2-MSH6 and MLH1-PMS1 protein complexes. J Biol Chem 273: 9837-41 23. Schmutte C, Marinescu RC, Sadoff MM, Guerrette S, Overhauser J, Fishel R. 1998. Human exonuclease I interacts with the mismatch repair protein hMSH2. Cancer Res 58: 4537-42 24. Plotz G, Raedle J, Brieger A, Trojan J, Zeuzem S. 2003. N-terminus of hMLH1 confers interaction of hMutLalpha and hMutLbeta with hMutSalpha. Nucleic Acids Res 31: 3217-26 25. Umar A, Buermeyer AB, Simon JA, Thomas DC, Clark AB, Liskay RM, Kunkel TA. 1996. Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Cell 87: 65-73 26. Flores-Rozas H, Clark D, Kolodner RD. 2000. Proliferating cell nuclear antigen and Msh2p-Msh6p interact to form an active mispair recognition complex. Nat Genet 26: 375-8 27. Clark AB, Valle F, Drotschmann K, Gary RK, Kunkel TA. 2000. Functional interaction of proliferating cell nuclear antigen with MSH2-MSH6 and MSH2-MSH3 complexes. J Biol Chem 275: 36498-501 28. Johnson RE, Kovvali GK, Guzder SN, Amin NS, Holm C, Habraken Y, Sung P, Prakash L, Prakash S. 1996. Evidence for involvement of yeast proliferating cell nuclear antigen in DNA mismatch repair. J Biol Chem 271: 27987-90 29. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. 2000. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 14: 927-39 30. Wilson TM, Vaisman A, Martomo SA, Sullivan P, Lan L, Hanaoka F, Yasui A, Woodgate R, Gearhart PJ. 2005. MSH2-MSH6 stimulates DNA polymerase eta, suggesting a role for A:T mutations in antibody genes. J Exp Med 201: 637-45 31. Wang Y, Qin J. 2003. MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation. Proc Natl Acad Sci U S A 100: 15387-92 32. Wiesendanger M, Kneitz B, Edelmann W, Scharff MD. 2000. Somatic mutation in MSH3, MSH6, and MSH3/MSH6-deficient mice reveals a role for the MSH2-MSH6 heterodimer in modulating the base substitution pattern. J. Exp. Med. 191: 579-84 33. Martomo SA, Yang WW, Gearhart PJ. 2004. A role for Msh6 but not Msh3 in somatic hypermutation and class switch recombination. J Exp Med 200: 61-8 34. Li Z, Scherer SJ, Ronai D, Iglesias-Ussel MD, Peled JU, Bardwell PD, Zhuang M, Lee K, Martin A, Edelmann W, Scharff MD. 2004. Examination of Msh6- and Msh3-deficient mice in class switching reveals overlapping and distinct roles of MutS homologues in antibody diversification. J Exp Med 200: 47-59 35. Schmutte C, Sadoff MM, Shim KS, Acharya S, Fishel R. 2001. The interaction of DNA mismatch repair proteins with human exonuclease I. J Biol Chem 276: 33011-8 36. Warren JJ, Pohlhaus TJ, Changela A, Iyer RR, Modrich PL, Beese LS. 2007. Structure of the human MutSalpha DNA lesion recognition complex. Mol Cell 26: 579-92 37. Kim N, Bozek G, Lo JC, Storb U. 1999. Different mismatch repair deficiencies all have the same effects on somatic hypermutation: intact primary mechanism accompanied by secondary modifications. J Exp Med 190: 21-30 38. Kong Q, Maizels N. 1999. PMS2-deficiency diminishes hypermutation of a lambda1 transgene in young but not older mice. Mol Immunol 36: 83-91 39. Winter DB, Phung QH, Umar A, Baker SM, Tarone RE, Tanaka K, Liskay RM, Kunkel TA, Bohr VA, Gearhart PJ. 1998. Altered Spectra of Hypermutation in Antibodies from Mice Deficient for the Mismatch Repair Protein PMS2. Proceedings of the National Academy of Sciences USA 95: 6953-8 40. Cascalho M, Wong J, Steinberg C, Wabl M. 1998. Mismatch repair co-opted by hypermutation. Science 279: 1207-10 41. Guerrette S, Acharya S, Fishel R. 1999. The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer. J Biol Chem 274: 6336-41 42. Brieger A, Trojan J, Raedle J, Plotz G, Zeuzem S. 2002. Transient mismatch repair gene transfection for functional analysis of genetic hMLH1 and hMSH2 variants. Gut 51: 677-84 43. Gu L, Hong Y, McCulloch S, Watanabe H, Li GM. 1998. ATP-dependent interaction of human mismatch repair proteins and dual role of PCNA in mismatch repair. Nucleic Acids Res 26: 1173-8 44. Kondo E, Horii A, Fukushige S. 2001. The interacting domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2. Nucleic Acids Res 29: 1695-702 45. Wu X, Tsai CY, Patam MB, Zan H, Chen JP, Lipkin SM, Casali P. 2006. A role for the MutL mismatch repair Mlh3 protein in immunoglobulin class switch DNA recombination and somatic hypermutation. J Immunol 176: 5426-37 46. Li Z, Peled JU, Zhao C, Svetlanov A, Ronai D, Cohen PE, Scharff MD. 2006. A role for Mlh3 in somatic hypermutation. DNA Repair (Amst) 5: 675-82 47. Plosky BS, Woodgate R. 2004. Switching from high-fidelity replicases to low-fidelity lesion-bypass polymerases. Curr Opin Genet Dev 14: 113-9 48. Arakawa H, Moldovan GL, Saribasak H, Saribasak NN, Jentsch S, Buerstedde JM. 2006. A role for PCNA ubiquitination in immunoglobulin hypermutation. PLoS Biol 4: e366 49. Langerak P, Nygren AO, Krijger P, van den Berk P, Jacobs H. 2007. A/T mutagenesis in hypermutated immunoglobulin genes strongly depends on PCNA K164 modification. J Exp Med 204 50. Hoege C, Pfander B, Moldovan GL, Pyrowolakis G, Jentsch S. 2002. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419: 135-41 51. Ko R, Bennett SE. 2005. Physical and functional interaction of human nuclear uracil-DNA glycosylase with proliferating cell nuclear antigen. DNA Repair (Amst) 4: 1421-31
Supplemental Material: Annu. Rev. Immunol. 2008. 26: 481-511 doi: 10.1146/annurev.immunol.26.021607.090236 The Biochemistry of Somatic Hypermutation Peled et al. 52. Otterlei M, Warbrick E, Nagelhus TA, Haug T, Slupphaug G, Akbari M, Aas PA, Steinsbekk K, Bakke O, Krokan HE. 1999. Post-replicative base excision repair in replication foci. Embo J 18: 3834-44 53. Dianova, II, Bohr VA, Dianov GL. 2001. Interaction of human AP endonuclease 1 with flap endonuclease 1 and proliferating cell nuclear antigen involved in long-patch base excision repair. Biochemistry 40: 12639-44 54. Haracska L, Kondratick CM, Unk I, Prakash S, Prakash L. 2001. Interaction with PCNA is essential for yeast DNA polymerase eta function. Mol Cell 8: 407-15 55. Haracska L, Johnson RE, Unk I, Phillips B, Hurwitz J, Prakash L, Prakash S. 2001. Physical and functional interactions of human DNA polymerase eta with PCNA. Mol Cell Biol 21: 7199-206 56. Haracska L, Johnson RE, Unk I, Phillips BB, Hurwitz J, Prakash L, Prakash S. 2001. Targeting of human DNA polymerase iota to the replication machinery via interaction with PCNA. Proc Natl Acad Sci U S A 98: 14256-61 57. Guo C, Sonoda E, Tang TS, Parker JL, Bielen AB, Takeda S, Ulrich HD, Friedberg EC. 2006. REV1 protein interacts with PCNA: significance of the REV1 BRCT domain in vitro and in vivo. Mol Cell 23: 265-71 58. Gary R, Ludwig DL, Cornelius HL, MacInnes MA, Park MS. 1997. The DNA repair endonuclease XPG binds to proliferating cell nuclear antigen (PCNA) and shares sequence elements with the PCNAbinding regions of FEN-1 and cyclin-dependent kinase inhibitor p21. J Biol Chem 272: 24522-9 59. Bachl J, Ertongur I, Jungnickel B. 2006. Involvement of Rad18 in somatic hypermutation. Proc Natl Acad Sci U S A 103: 12081-6 60. Kodama M, Hayashi R, Nishizumi H, Nagawa F, Takemori T, Sakano H. 2001. The PU.1 and NF-EM5 binding motifs in the Igkappa 3' enhancer are responsible for directing somatic hypermutations to the intrinsic hotspots in the transgenic Vkappa gene. Int Immunol 13: 1415-22 61. Rada C, Williams GT, Nilsen H, Barnes DE, Lindahl T, Neuberger MS. 2002. Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Curr Biol 12: 1748-55 62. Imai K, Slupphaug G, Lee WI, Revy P, Nonoyama S, Catalan N, Yel L, Forveille M, Kavli B, Krokan HE, Ochs HD, Fischer A, Durandy A. 2003. Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat Immunol 4: 1023-8 63. Bennett RA, Wilson DM, 3rd, Wong D, Demple B. 1997. Interaction of human apurinic endonuclease and DNA polymerase beta in the base excision repair pathway. Proc Natl Acad Sci U S A 94: 71669 64. Prasad R, Singhal RK, Srivastava DK, Molina JT, Tomkinson AE, Wilson SH. 1996. Specific interaction of DNA polymerase beta and DNA ligase I in a multiprotein base excision repair complex from bovine testis. J Biol Chem 271: 16000-7 65. Yabuki M, Fujii MM, Maizels N. 2005. The MRE11-RAD50-NBS1 complex accelerates somatic hypermutation and gene conversion of immunoglobulin variable regions. Nat Immunol 6: 730-6 66. Poltoratsky V, Prasad R, Horton JK, Wilson SH. 2007. Down-regulation of DNA polymerase beta accompanies somatic hypermutation in human BL2 cell lines. DNA Repair (Amst) 6: 244-53 67. Esposito G, Texido G, Betz UA, Gu H, Muller W, Klein U, Rajewsky K. 2000. Mice reconstituted with DNA polymerase beta-deficient fetal liver cells are able to mount a T cell-dependent immune response and mutate their Ig genes normally. Proc Natl Acad Sci U S A 97: 1166-71 68. Zan H, Komori A, Li Z, Cerrutti M, Flajnik MF, Diaz M, Casali P. 2001. The translesional polymerase zeta plays a major role in Ig and Bcl-6 somatic mutation. Immunity 14: 643-53 69. Delbos F, De Smet A, Faili A, Aoufouchi S, Weill JC, Reynaud CA. 2005. Contribution of DNA polymerase eta to immunoglobulin gene hypermutation in the mouse. J Exp Med 201: 1191-6 70. Masuda K, Ouchida R, Hikida M, Kurosaki T, Yokoi M, Masutani C, Seki M, Wood RD, Hanaoka F, J OW. 2007. DNA polymerases eta and theta function in the same genetic pathway to generate mutations at A/T during somatic hypermutation of Ig genes. J Biol Chem 282: 17387-94 71. Martomo SA, Yang WW, Wersto RP, Ohkumo T, Kondo Y, Yokoi M, Masutani C, Hanaoka F, Gearhart PJ. 2005. Different mutation signatures in DNA polymerase eta- and MSH6-deficient mice suggest separate roles in antibody diversification. Proc Natl Acad Sci U S A 102: 8656-61 72. Zeng X, Winter DB, Kasmer C, Kraemer KH, Lehmann AR, Gearhart PJ. 2001. DNA polymerase eta is an A-T mutator in somatic hypermutation of immunoglobulin variable genes. Nat Immunol 2: 53741 73. Yavuz S, Yavuz AS, Kraemer KH, Lipsky PE. 2002. The role of polymerase eta in somatic hypermutation determined by analysis of mutations in a patient with xeroderma pigmentosum variant. J Immunol 169: 3825-30 74. Guo C, Fischhaber PL, Luk-Paszyc MJ, Masuda Y, Zhou J, Kamiya K, Kisker C, Friedberg EC. 2003. Mouse Rev1 protein interacts with multiple DNA polymerases involved in translesion DNA synthesis. Embo J 22: 6621-30 75. Ohashi E, Murakumo Y, Kanjo N, Akagi J, Masutani C, Hanaoka F, Ohmori H. 2004. Interaction of hREV1 with three human Y-family DNA polymerases. Genes Cells 9: 523-31 76. Tissier A, Kannouche P, Reck MP, Lehmann AR, Fuchs RP, Cordonnier A. 2004. Co-localization in replication foci and interaction of human Y-family members, DNA polymerase pol eta and REVl protein. DNA Repair (Amst) 3: 1503-14 77. Jansen JG, Langerak P, Tsaalbi-Shtylik A, van den Berk P, Jacobs H, de Wind N. 2006. Strand-biased defect in C/G transversions in hypermutating immunoglobulin genes in Rev1-deficient mice. J Exp Med 203: 319-23 78. Simpson LJ, Sale JE. 2003. Rev1 is essential for DNA damage tolerance and non-templated immunoglobulin gene mutation in a vertebrate cell line. Embo J 22: 1654-64 79. Murakumo Y, Ogura Y, Ishii H, Numata S, Ichihara M, Croce CM, Fishel R, Takahashi M. 2001. Interactions in the error-prone postreplication repair proteins hREV1, hREV3, and hREV7. J Biol Chem 276: 35644-51 80. Faili A, Aoufouchi S, Flatter E, Gueranger Q, Reynaud CA, Weill JC. 2002. Induction of somatic hypermutation in immunoglobulin genes is dependent on DNA polymerase iota. Nature 419: 944-7 81. McDonald JP, Frank EG, Plosky BS, Rogozin IB, Masutani C, Hanaoka F, Woodgate R, Gearhart PJ. 2003. 129-derived strains of mice are deficient in DNA polymerase iota and have normal immunoglobulin hypermutation. J Exp Med 198: 635-43
Supplemental Material: Annu. Rev. Immunol. 2008. 26: 481-511 doi: 10.1146/annurev.immunol.26.021607.090236 The Biochemistry of Somatic Hypermutation Peled et al. 82. Zan H, Shima N, Xu Z, Al-Qahtani A, Evinger Iii AJ, Zhong Y, Schimenti JC, Casali P. 2005. The translesion DNA polymerase theta plays a dominant role in immunoglobulin gene somatic hypermutation. Embo J 24: 3757-69 83. Masuda K, Ouchida R, Takeuchi A, Saito T, Koseki H, Kawamura K, Tagawa M, Tokuhisa T, Azuma T, J OW. 2005. DNA polymerase theta contributes to the generation of C/G mutations during somatic hypermutation of Ig genes. Proc Natl Acad Sci U S A 102: 13986-91 84. Diaz M, Verkoczy LK, Flajnik MF, R. KN. 2001. Decreased Frequency of Somatic Hypermutation and Impaired Affinity Maturation but Intact Germinal Center Formation in Mice Expressing Antisense RNA to DNA Polymerase zeta. J Immunol 167: 327-35. 85. Ruiz JF, Lucas D, Garcia-Palomero E, Saez AI, Gonzalez MA, Piris MA, Bernad A, Blanco L. 2004. Overexpression of human DNA polymerase mu (Pol mu) in a Burkitt's lymphoma cell line affects the somatic hypermutation rate. Nucleic Acids Res 32: 5861-73 86. Bardwell PD, Woo CJ, Wei K, Li Z, Martin A, Sack SZ, Parris T, Edelmann W, Scharff MD. 2004. Altered somatic hypermutation and reduced class-switch recombination in exonuclease 1-mutant mice. Nat Immunol 5: 224-9 87. Tishkoff DX, Boerger AL, Bertrand P, Filosi N, Gaida GM, Kane MF, Kolodner RD. 1997. Identification and characterization of Saccharomyces cerevisiae EXO1, a gene encoding an exonuclease that interacts with MSH2. Proc Natl Acad Sci U S A 94: 7487-92 88. Bemark M, Sale JE, Kim H-J, Berek C, Cosgrove RA, Neuberger MS. 2000. Somatic hypermutation in the absence of DNA-PK or Rag1 activity. J. Exp. Med. 192: 1509-14 89. Shiomi N, Hayashi E, Sasanuma S, Mita K, Shiomi T. 2001. Disruption of Xpg increases spontaneous mutation frequency, particularly A:T to C:G transversion. Mutat Res 487: 127-35 90. Dart DA, Adams KE, Akerman I, Lakin ND. 2004. Recruitment of the cell cycle checkpoint kinase ATR to chromatin during S-phase. J Biol Chem 279: 16433-40 91. Cliby WA, Roberts CJ, Cimprich KA, Stringer CM, Lamb JR, Schreiber SL, Friend SH. 1998. Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. Embo J 17: 159-69 92. Pan-Hammarstrom Q, Lahdesmaki A, Zhao Y, Du L, Zhao Z, Wen S, Ruiz-Perez VL, Dunn-Walters DK, Goodship JA, Hammarstrom L. 2006. Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation. J Exp Med 203: 99-110 93. Kuwahara K, Fujimura S, Takahashi Y, Nakagata N, Takemori T, Aizawa S, Sakaguchi N. 2004. Germinal center-associated nuclear protein contributes to affinity maturation of B cell antigen receptor in T cell-dependent responses. Proc Natl Acad Sci U S A 101: 1010-5 94. Muto A, Tashiro S, Nakajima O, Hoshino H, Takahashi S, Sakoda E, Ikebe D, Yamamoto M, Igarashi K. 2004. The transcriptional programme of antibody class switching involves the repressor Bach2. Nature 429: 566-71 95. Gomez-Gonzalez B, Aguilera A. 2007. Activation-induced cytidine deaminase action is strongly stimulated by mutations of the THO complex. Proc Natl Acad Sci U S A 104: 8409-14
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ANRV338-IY26-17
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16 February 2008
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Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn1 and Jeffrey V. Ravetch2 1
Laboratory of Experimental Immunology and Immunotherapy, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen-Nuremberg, 91054 Erlangen, Germany; email:
[email protected] 2
Laboratory for Molecular Genetics and Immunology, Rockefeller University, New York, New York 10021; email:
[email protected] Annu. Rev. Immunol. 2008. 26:513–33
Key Words
The Annual Review of Immunology is online at immunol.annualreviews.org
Fc receptor, inflammation, glycosylation, autoimmunity, autoantibody, sialic acid, IVIG
This article’s doi: 10.1146/annurev.immunol.26.021607.090232 c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0513$20.00
Abstract The remarkable success story of the therapeutic application of pooled immunoglobulin G (IgG) preparations from thousands of donors, the so-called intravenous IgG (IVIG) therapy, to patients with a variety of hematological and immunological disorders began more than half a century ago. Since then, the use of this primary blood product has increased constantly, resulting in the serious danger of shortages in supply. Despite its widespread use and therapeutic success, the mechanisms of action, especially of the antiinflammatory activity, are only beginning to be understood. In this review, we summarize the clinical use of IVIG for different diseases and discuss recent data on the molecular mechanisms that might explain how this potent drug mediates its activity in vivo.
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INTRODUCTION IgG: immunoglobulin G IVIG: intravenous IgG therapy
Annu. Rev. Immunol. 2008.26:513-533. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ITP: idiopathic thrombocytopenic purpura
Table 1
Immunoglobulins together with T cells are the key mediators of adaptive immunity, and deficiencies in either of these two arms of the adaptive immune system can result in a heightened susceptibility to bacterial, fungal, or viral infections. A variety of situations can lead to a constant or transient deficiency in immunoglobulins, including primary immunodeficiencies, such as several X-linked agammaglobulinemias and common variable immunodeficiencies (CVID) (1–3). In addition, hypogammaglobulinemic phenotypes can be caused by viral infections (for example with HIV), in the course of B cell malignancies, or after bone marrow transplantation (4–9). Thus, replacement of immunoglobulin levels, especially of the immunoglobulin G (IgG) isotype, by administration of pooled serum from healthy donors—IVIG (intravenous IgG) as a therapeutic agent—occurred more than 50 years ago. Since then, IVIG use has increased exponentially, although its therapeutic effectiveness in most of these different diseases has not been rigorously addressed, in part because of the variety of diseases it is used to treat and
in part because extant studies include low patient numbers. The popularity of IVIG in the clinic and in research is exemplified by the 360 hits that a PubMed search for IVIG yielded in 2007, when we wrote this review. The two major clinical indications for which IVIG is used are IgG replacement therapy and antiinflammation therapy in a variety of acute and chronic autoimmune diseases (Table 1). This latter approach is based on an early observation that a child with idiopathic thrombocytopenic purpura (ITP) showed an attenuated platelet clearance after IVIG administration, which was confirmed in adult patients shortly thereafter (10, 11). Since then, IVIG administration has been included in the therapy of many chronic autoimmune diseases affecting a wide range of tissues and target organs, such as the skin, joints, central nervous system, and hematopoietic system (6). Aside from immunoglobulin replacement therapy, currently licensed applications for IVIG administration include Guillain-Barr`e syndrome, Kawasaki disease, and chronic inflammatory demyelinating polyneuropathy
Examples for the clinical use of IVIG (see text for details) Anti-inflammatory (high-dose therapy)
Replacement (low-dose therapy) Primary immunodeficiencies (CVID and others) HIV infection Bone marrow transplantation B cell lymphocytic leukemia Multiple myeloma
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Ravetch
Licensed
Off-label
Idiopathic thrombocytopenia purpura Guillain-Barr´e syndrome Kawasaki disease Chronic inflammatory demyelinating polyneuropathy (CIDP)
Autoimmune neutropenia Autoimmune hemolytic anemia Anti–Factor VIII autoimmune disease Multiple sclerosis Myesthenia gravis Stiff person syndrome Multifocal neuropathy Systemic vasculitis (ANCA positive) Polymyositis Dermatomyositis Rheumatoid arthritis Systemic lupus erythematosus Antiphospholipid syndrome Toxic epidermal necrolysis Autoimmune skin blistering diseases Steroid-dependent atopic dermatitis Graft-vs-host disease Sepsis syndrome
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(CIDP). Licensed indications, however, only account for approximately 40%–50% of the worldwide IVIG sales, as most IVIG administrations are “off-label” (8, 12). Although in many instances positive results have been reported, well-controlled clinical studies addressing the beneficial effects of IVIG therapy are lacking for most of these diseases. One distinguishing feature between the use of IVIG as a replacement therapy and its use as an anti-inflammatory agent is the therapeutically active dose. If used as an IgG replacement, a dose of 300–500 mg/kg body weight of IVIG is recommended to achieve serum levels of approximately 500 mg/dl, which is sufficient to prevent or substantially reduce pulmonary infections, one of the major complications in immunocompromised patients; a dose in this range is considered low-dose therapy. Consistent with the serum half-life of IgG, this treatment must be repeated every 3–4 weeks to maintain a protective serum level (6). To achieve the anti-inflammatory effect, however, doses in the range of 1–3 g/kg body weight are required repeatedly (high-dose therapy) (13). Whereas the mechanism of IVIG activity in IgG replacement therapy may be readily explained by the presence of so-called natural antibodies that have an intrinsic capacity to recognize foreign antigens or by the presence of common pathogen-specific IgG anti-
Table 2
bodies derived from previously immunized or vaccinated serum donors, the explanation of the anti-inflammatory activity is more complicated and a matter of much debate. The difficulty is to explain how a polyclonal mixture of IgG molecules can suppress the activity of the very same class of molecules, that is, other IgG antibodies recognizing autoantigens. A diverse array of mechanisms, including the blockade of cellular receptors for immunoglobulins (Fc receptors, or FcRs), inhibition of the complement cascade, modulation of cytokine production, neutralization of autoantibodies, and the modulation of inhibitory FcR expression, have been suggested as being responsible for the anti-inflammatory activity of IVIG (Table 2) (6, 8, 14, 15). Considering the heterogeneous array of diseases treated with IVIG, one might expect a similarly complex number of mechanisms of action. In this review, we discuss these different possible mechanisms, with an emphasis on results obtained in in vivo model systems. Owing to space limitations, we do not include the immunoglobulin replacement aspect of IVIG therapy, which has been covered in several excellent recent reviews (16, 17). We start with a brief description of the drug IVIG and an introduction into IgG-mediated effector responses, and we follow with a detailed discussion of the different potential mechanisms
Proposed mechanisms for IVIG activity
Replacement therapy
Anti-inflammatory therapy
Preventing infection with pathogenic microorganisms and improving quality of life Reducing risk of graft-vs-host disease after bone marrow transplantation
a b
Autoantibody neutralizationa Modulation of antibody productiona Modulating signaling pathwaysa Modulation of cytokine expression and functiona,b Modulating DC maturation and functiona,b Complement inhibitiona,b Enhancing autoantibody clearance by blocking the FcRnb Functional blockade of activating FcγRsb Upregulation of the inhibitory FcγRIIBb Restoring an anti-inflammatory milieub
F(ab)2 -mediated activity. Fc fragment–mediated activity.
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that might explain the therapeutic activity of IVIG in vivo. FcRn: neonatal Fc receptor FcγR: Fcγ receptor
IVIG: PRODUCTION PROCESS, PRODUCT SAFETY, AND SIDE EFFECTS
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IVIG is produced by many different companies and a variety of nonprofit organizations such as the American Red Cross (13). With such diverse providers, the compositions of the different IVIG preparations vary in the purity of the IgG preparation, pH, osmolarity, and sodium and sugar content (8, 13). The other most dominant immunoglobulin isotype, IgA, ranges from trace amounts up to 1–2 mg/ml in the different IVIG preparations. IVIG is a primary blood product and must be manufactured according to World Health Organization guidelines. The careful selection and testing of donors for blood transmittable viral diseases, such as HIV, HBV, and HCV, and the incorporation of virus-inactivating steps in the production process are of utmost importance (18). Similarly, the concentration step to obtain a highly enriched IgG preparation has to be selected carefully to prevent loss of biological activity and to minimize unwanted side effects such as the formation of protein aggregates. Most of the currently used techniques were developed in the 1940s and 1950s and only slightly modified since. Thus, either a cold ethanol precipitation step or the more recently developed caprylate precipitation followed by anion exchange chromatography are used (18). With the optimization of these methods and strict quality control measures, the side effects of IVIG administration are relatively minor today, but they may include a transient headache, nausea, fever, cough, and sore throat (13, 19). In many instances, not the IgG preparation itself but rather product stabilizers such as sugar or salt content or denatured aggregated proteins are responsible for adverse effects (13). Therefore, one quality check is to prevent the presence of significant amounts of multimeric IgG aggregates that 516
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may trigger activating FcRs unspecifically. Ultimately, replacing IVIG with a recombinant product would be advantageous to circumvent these side effects and to prevent supply shortages. For this, however, we must know the molecular mechanism of IVIG activity, which is the focus of the following section.
IgG ACTIVITY IN VIVO As indicated above, both the therapeutically active molecule in the IVIG preparation and the pathology-causing agent in autoimmune diseases are IgG molecules. Thus, we give a brief overview of how IgG antibodies are thought to mediate their activity in vivo. IgG and other immunoglobulin isotypes are composed of an amino acid backbone that contains a sugar moiety attached to an asparagine residue in the antibody constant region (N297) (20, 21). Mice and humans have four different IgG subclasses, denominated IgG1, 2a, 2b, and 3 in mice and IgG1–4 in humans. These are present in the mg/ml range in the serum and have a relatively long halflife, in the range of one week (22). In contrast to other serum proteins, the half-life of the different IgG subclasses is not regulated by the hepatic asialo receptor, which purges the blood of nonfunctional proteins. For IgG molecules, the neonatal Fc receptor, FcRn, plays a crucial role in keeping IgG levels constant. FcRn belongs to the family of major histocompatibility class I (MHC class I) molecules, and mice deficient in this protein or its associated β2-microglobulin (β2M) chain have a dramatically reduced IgG serum concentration and half-life (23, 24). IgG molecules’ proinflammatory activity requires recruiting secondary effector functions via their Fc fragment. Cytotoxic or proinflammatory pathways that can be activated via the Fc fragment include the complement pathway and crosslinking of cellular FcRs for IgG (Fcγ receptors, FcγR) on innate immune effector cells (25, 26). The family of FcγRs consists of several activating members and one inhibitory member that are
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Figure 1 Activating and inhibitory Fcγ receptors set a threshold for immune effector cell activation. (a) Immune complex (IC) binding to activating FcγRs results in the ITAM phosphorylation of the receptor-associated γc -chain, creating docking sites for Syk kinases. Syk activates several downstream kinases such as the phosphatidylinositol-3 kinase (PI3K), leading to the recruitment of Bruton’s tyrosine kinase (BTK) and phospholipase Cγ (PLCγ) to the plasma membrane, and ultimately leading to calcium influx into the cytosol from intracellular and extracellular sources. (b) The inhibitory FcγRIIB interferes with these activating signaling pathways by recruiting phosphatases such as SHIP (SH2-containing inositide phosphatase) that hydrolyze phosphatidylinositol signaling intermediates necessary for recruitment of BTK and PLCγ, thus limiting cell activation. [Reprinted from Springer Seminars in Immunopathology (2006), 28:305–19, Copyright 2006 with kind permission of Springer Science and Business Media.]
usually coexpressed on the same cell, thereby setting a threshold for cell activation by simultaneously triggering counteracting signaling pathways (Figure 1b) (27). Crosslinking of activating FcγRs leads to the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) present in receptorassociated signaling adaptor proteins such as the common γ-chain (γc -chain) by Src family kinases. This phosphorylation induces several downstream signaling pathways, resulting in an increase in intracellular calcium levels and cell activation (Figure 1a). Simultaneous triggering of FcγRIIB leads to phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM) in the cytosolic domain of this receptor, which in turn recruits phosphatases such as the SH2-domain containing inositol polyphosphate 5 phosphatase
(SHIP) that interfere with these activating signaling pathways at several stages (Figure 1). The individual receptors differ in their affinity and specificity for the different IgG subclasses. In mice and humans, there is one high-affinity receptor, FcγRI, which is the only FcγR that can bind to monomeric IgG. All other family members have a low to medium affinity, in the micromolar range, and exclusively bind to antibodies bound to their respective antigen, including soluble proteins, microorganisms, and malignant or virus-infected cells in the form of immune complexes (IC). Thus, the relative expression level and affinities of these different family members are important for regulating antibody activity in vivo (26). This ratio can be influenced by several cytokines and other pro- or anti-inflammatory stimuli, such www.annualreviews.org • Mechanism of IVIG Activity
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as lipopolysaccharide (LPS), several interleukins, transforming growth factor β (TGFβ), tumor necrosis factor α (TNF-α), and C5a (26). Effector functions that are triggered upon IC binding to FcγRs and regulated by balanced FcγR expression include phagocytosis, degranulation, antigen presentation, release of proinflammatory cytokines, and antibody-dependent cellular cytotoxicity (ADCC) (27–29). Although several IgG subclasses can efficiently activate the complement pathway and mediate target cell lysis in vitro, experimental evidence from in vivo model systems argues against an important role of the complement pathway for these antibody-mediated effector functions (26, 30). Because IVIG and the autoantibodies responsible for chronic inflammation and tissue destruction can bind to the same effector cells and molecules, one attractive possibility of IVIG activity is simply to compete for the same effector pathways as the pathogenic autoantibodies. This important point is addressed below.
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MECHANISMS OF IVIG ACTIVITY Several different models explain IVIG activity in various diseases and in vivo model systems. Most currently available in vivo data in mice and humans clearly point to a dominant role of the antibody Fc fragment as responsible for the anti-inflammatory activity of IVIG. There are, however, instances in which the Fab fragment may be involved in IVIG’s therapeutic activity. In many of these cases, whether both Fab and Fc fragments contribute to the antiinflammatory activity has not been addressed.
F(ab)2 -Dependent Effects Two main mechanisms for the Fab fragment’s anti-inflammatory function have been described in the literature. First, the F(ab)2 antibody portion may bind to and neutralize the potent proinflammatory activity of the C3aand C5a-anaphylatoxins in a mouse model of 518
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asthma and in a C5a-mediated shock model in pigs (31). However, allergic diseases are quite different from other autoimmune diseases, and IVIG treatment has not demonstrated beneficial effects in two out of three randomized controlled studies with asthma patients. Furthermore, IVIG therapy is not recommended for patients with severe asthma by the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology (32). Thus, it remains to be seen whether this is a relevant mechanism of action in other autoimmune diseases for which beneficial effects of high-dose IVIG therapy have been described. Second, a number of studies have addressed whether antibodies with distinct specificities are present in the IVIG preparation. Indeed, several groups identified significant binding to a variety of proteins and cell surface receptors that may explain the therapeutic activity of IVIG. These include anti-idiotypic, TCRα/β, Siglec-9, CD5, antiintegrin, Fas, cytokines, and cytokine receptor specificities (6, 33–38). It is beyond our scope to discuss all these possibilities, as in vivo evidence is not yet available to demonstrate a significant contribution of many of these antigen-specific antibodies in the IVIG preparation. For special instances in which certain receptor-ligand interactions are the main cause for the disease, such as in myasthenia gravis or toxic epidermal necrolysis (TEN), these (auto-) antibody specificities may have an important therapeutic function (39, 40). TEN, for example, is the result of an adverse drug reaction and is characterized by the detachment of large sections of the epidermis from the dermis caused by widespread death of keratinocytes (40). The CD95- or Fas-mediated pathway of apoptosis is of central importance for keratinocyte death, and CD95-specific antibodies within the IVIG preparation can block this interaction by binding to CD95 (41). Depletion of the CD95-specific antibodies within the IVIG preparation results in a loss of activity, as measured in an in vitro assay with human
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keratinocytes. It is unclear, however, whether this is the sole mode of action of IVIG in TEN in vivo or if other Fc fragment–dependent activities are involved as well. Further complicating this scenario are reports that both agonistic and blocking anti-Fas antibodies are present in IVIG preparations (34, 42). Thus, apoptosis was induced upon incubation of human lymphocytes and monocytes with therapeutic preparations of IVIG, which may be responsible for eliminating or reducing effector cells involved in causing chronic inflammation (34). More studies are necessary to define the role of these antigen-specific antibodies in the IVIG preparation in suitable in vivo model systems.
Fc-Dependent Effects In contrast to the role of the Fab fragment, considerable evidence suggests that many autoimmune diseases for which IVIG has beneficial effects involve the Fc fragment as playing the central role in IVIG’s anti-inflammatory activity. In a clinical trial with ITP patients and in many mouse autoimmune models, such as arthritis, nephrotoxic nephritis (NTN), and ITP, the Fc fragment was as effective as the whole IVIG preparation (43–46). The potential mechanisms for this activity are mirrored by the different effector pathways or receptors/ligands that can interact with the Fc fragment (Figure 2), including the complement pathway, FcRn, and classical activating and inhibitory FcγRs (23, 25, 26). As is now well established, the complement pathway is not significantly involved in the activity of different cytotoxic and autoantibodies in most mouse in vivo model systems; therefore, we do not cover this topic in depth, although IVIG does bind to activated C3b and C4b and prevents the tissue deposition of these activated complement proteins (47–49). However, tissue deposition of activated complement proteins is not necessarily predictive of complementmediated tissue destruction. Indeed, in many mouse models of antibody-mediated inflammation, autoantibody activity and tissue de-
struction are abrogated in the absence of cellular FcγRs, although activated complement components are still present in high amounts in noninflamed tissues (50, 51). Similar results were reported for many other in vivo models of antibody-mediated inflammation in vivo (30). Direct evidence against a role for complement in the mechanism of IVIG activity comes from studies in which complement inactivation by injection of cobra venom factor had no impact on IVIG activity (52, 53). In addition to these well-described Fc fragment– dependent effector pathways, recent evidence points to a novel anti-inflammatory function of the Fc fragment–associated sugar moiety, which is discussed at the end of this review. IVIG-mediated saturation of FcRn. The FcRn is the crucial regulator of IgG half-life (Figure 2a). Therefore, one rationale to block autoantibody activity is to interfere with their interaction with FcRn, thus shortening their half-life and clearing them from the circulation before they can cause major damage. Indeed, a generation of antibody mutants with enhanced affinity for FcRn or for blocking the IgG-FcRn interaction by antibodies specific for FcRn or its β2M subunit competes with serum antibodies for binding to FcRn and inducing their accelerated clearance (54– 56). One attractive possibility is that IVIG, by means of its high dose, may also mediate its anti-inflammatory activity by competing with autoantibodies for FcRn binding (Figure 2b) (57–61). Antibody half-life studies in ITP models in mice and rats demonstrated that IVIG at a dose of 1 g/kg can shorten the half-life of a platelet-specific autoantibody from 79 to 54 h (58). Importantly, however, the maximal levels of platelet depletion and of IVIG-mediated protection essentially occur immediately after autoantibody injection (within the first 1–4 h) in mice and rats, which makes it rather unlikely that this change in antibody serum half-life will have an effect (46, 58, 62). Indeed, in this early phase hardly any difference in the serum level of the www.annualreviews.org • Mechanism of IVIG Activity
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Figure 2 Proposed Fc fragment–dependent mechanisms of IVIG activity. (a) The neonatal Fc receptor (FcRn) binds to serum IgG at low pH after it has been endocytosed and transported into acidic vesicles. FcRn-bound IgG molecules are then recycled to the cell surface and released into the circulation at physiologic pH. (b) Three different models have been proposed to mediate the anti-inflammatory activity of the IVIG Fc fragment in vivo. First, the high dose of IgG molecules present in the IVIG preparation may compete with autoantibodies for FcRn binding and thus result in their enhanced clearance. Second, immune complexes present in the IVIG preparation may bind to activating FcγRs and thereby prevent binding of autoantibody immune complexes. In the third model, IVIG activity is crucially dependent on the presence of the inhibitory FcγRIIB. (Reproduced from the Journal of Experimental Medicine, 2007, 204:11–15. Copyright 2007 Rockefeller University Press.) 520
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autoantibody in the presence or absence of IVIG was observed. Moreover, the therapeutic dose of IVIG can be reduced from roughly 25 mg per mouse to 600–700 μg if a specific glycovariant of the IVIG Fc fragment is used (45). This dramatically lower dose, while maintaining its anti-inflammatory activity, has no effect on the half-life of serum or autoantibodies and thus argues against a role for FcRn in these fast models of autoantibody-mediated platelet depletion (12, 45). In addition to ITP, two other mouse model systems of autoantibody-mediated arthritis and autoantibody-induced skin blistering diseases demonstrated a role for IVIG in mediating its activity via FcRn (57, 60). In the serum transfer arthritis model, serum from arthritogenic mice is injected into wild-type animals, which develop a transient joint swelling over the next 20 days (63). Treatment of mice with IVIG is very efficient at blocking autoantibody-induced inflammation, which makes this model an attractive system to study the mechanism of IVIG activity. IVIG treatment resulted in a reduced serum half-life of the arthritogenic antibodies, and IVIG activity was reduced in mice deficient in FcRn and the inhibitory FcγRIIB (57). The central role of FcγRIIB for IVIG activity in vivo has been shown in many model systems and is discussed later in this review (43, 45, 46, 50). The major problem with using FcRn-deficient animals for these experiments is that the arthritogenic autoantibodies as well as IVIG have a dramatically reduced serum half-life. This necessitates very high doses of arthritogenic serum to obtain a level of inflammation that is still far below the response normally achieved in wildtype mice (57). In addition, the reduction in serum half-life of the autoantibodies was only investigated after administration of four consecutive 1 g/kg doses of IVIG, whereas one dose is normally sufficient to block arthritis in this model, making it difficult to evaluate whether the enhanced clearance rate induced by this high dose of IVIG is required for antiinflammatory activity.
Direct evidence against a role for FcRn in mediating IVIG activity in the serum transfer arthritis model comes from studies that analyzed the interaction of aglycosylated IgG with FcRn and the effect of the absence of this Fc fragment–attached sugar moiety on IVIG anti-inflammatory activity in vivo (45, 64). A mutation at position 297 that changes an arginine to an alanine (N297A) residue abrogated binding to classical FcγRs but kept its affinity for FcRn (64). Thus, aglycosylated IVIG should still be functional without this sugar moiety if FcRn saturation and enhanced autoantibody degradation are the mechanisms of action. This is not the case, however, as aglycosylated IVIG loses its anti-inflammatory activity (45). In a similar serum transfer approach, the capacity of IVIG to suppress antibodymediated skin blistering diseases was investigated (60). Diseases such as bullous pemphigoid, pemphigus foliaceus, and pemphigus vulgaris are characterized by subepidermal or intraepidermal blisters and by autoantibodies of the IgG isotype specific for hemidesmosomal or epidermal proteins, which are able to transfer the disease if injected into newborn mice (65). In this model, injection of IVIG leads to a reduction in the serum halflife of the autoantibodies and efficiently prevents the development of blisters. In contrast to other model systems, in this model IVIG activity is independent of the inhibitory FcγRIIB. Moreover, deletion of this negative regulator of antibody activity does not further exacerbate the autoimmune symptoms, which again is not consistent with most of the results obtained in adult mouse model systems to date (26, 27). Thus, FcγRIIB deletion results in a lower threshold for B cell and innate immune effector cell activation, leading to the generation of class switched autoantibodies, spontaneous dendritic cell maturation, higher levels of autoantibody-mediated tissue destruction, and the development of autoimmune diseases on otherwise resistant genetic backgrounds (66–74). Indeed, the expression
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and functionality of activating and inhibitory FcRs have not been studied in depth in newborn mice, making it hard to predict whether these findings can be generalized and are comparable with results obtained in adult mice and the adult immune system. Taken together, technical difficulties in designing an unequivocal experimental setting make it hard to predict whether IVIGmediated FcRn saturation is responsible for its activity in vivo. Nonetheless, reducing autoantibody half-life by modulating the antibody-FcRn interaction may be a promising therapeutic strategy.
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Activating Fc receptor blockade and cytokine modulation. The second major theory for how IVIG mediates its antiinflammatory activity is via blockade of activating FcγRs (Figure 2b). Indeed, because FcγRs are centrally important in antibodymediated effector functions, blocking of individual or all activating FcRs results in the abrogation of antibody activity in a variety of autoimmune and tumor models, such as ITP, NTN, arthritis, and several models of antibody-mediated tumor cell destruction (26, 50, 51, 62, 63, 75–81). Similarly, blocking human FcγRIIIA in a transgenic mouse model and in human ITP patients interferes with platelet depletion (46, 82– 84). In contrast, blocking or deleting the high-affinity FcγRI in vivo in human ITP patients or in mice was therapeutically ineffective, highlighting the importance of the lowaffinity FcγRs for antibody-mediated effector functions (62, 85). Thus, we focus on the low-affinity FcγRs in discussing the possible impact of IVIG-mediated interaction with activating FcγRs. Low- or medium-affinity receptors, such as mouse FcγRIIB, FcγRIII, and FcγRIV and even more so their human counterparts FcγRIIA/B/C and FcγRIIIA, cannot interact with monomeric IgG but can only bind to IgG in the form of an IC (27). Therefore, monomeric IgG, which constitutes more than 97% of the IVIG preparation, cannot 522
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be responsible for directly blocking activating FcγRs. As discussed above, however, different IVIG preparations may contain varying levels of dimeric or multimeric IgG molecules. Aged IVIG preparations with a higher content of IgG dimers have an enhanced antiinflammatory activity in a mouse model of ITP, although whether these dimeric molecules are able to block autoantibody binding to activating FcγRs has not been investigated (53). A more recent study reported that antibodies specific for soluble proteins in the presence of their antigen or antibodies specific for cell surface proteins on red blood cells, for example, can exhibit IVIG-like activity in ITP (52, 86). This finding is consistent with earlier data from human ITP patients treated with the so-called anti-D IgG, which is a pooled polyclonal IgG fraction that comes selectively from donors immunized to the rhesus D antigen [anti-Rh0(D)-positive]. Anti-D, which, compared with IVIG, is used at a 40,000-fold lower dose, also can prevent platelet consumption in human ITP, and this activity is lost in patients who do not express the rhesus D antigen (87–90). However, the use of a monoclonal anti-D antibody of the IgG1 subclass that can efficiently interact with human FcRs was not able to prevent platelet depletion in seven anti-Rh0(D)-positive patients, arguing against a simple IC-formation mechanism (91). Clearly, the use of anti-D or other hyperimmune sera in the presence of the respective antigen will create a high level of IC that may compete with the autoantibodyantigen complexes and inhibit their phagocytosis by a mechanism similar to directly blocking activating FcγRs with an FcγR-specific antibody. With respect to the many specificities present in the IVIG preparation, these complexes may form after administration into patients. Whether the level of IC formation is high enough to achieve a significant level of binding to activating FcγRs is unclear. More importantly, the use of ICs poses quite some danger to the patient as they will systemically
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trigger activating FcγRs and may even enhance inflammation by inducing release of proinflammatory cytokines from innate immune effector cells. Recently, two other mechanisms of IVIG activity involving FcγRIII were proposed. First, triggering activating FcγRs on dendritic cells in vitro and then adoptively transferring them into mice can have IVIG-like effects and can ameliorate murine ITP; thus, investigators concluded that IVIG can be replaced by antibodies specific for activating FcγRs (92). Although an intriguing finding, it remains to be seen whether this is the actual mechanism of IVIG activity, as IVIG preparations with enhanced activity have a reduced affinity for activating FcγRs in mice and humans (45, 93). Second, investigators suggested that IVIG mediates its anti-inflammatory activity by inhibiting the release of the proinflammatory cytokine IFN-γ from myeloid cells in an FcγRIII-dependent manner (94). Although many studies described cytokine-modulating effects by IVIG, the relevance of these findings for the therapeutic activity of IVIG in vivo remains unclear (95). Indeed, IVIG is fully functional in preventing platelet depletion in mouse strains deficient in a variety of proinflammatory cytokines and cytokine receptors, such as the IFN-γR, CCL3, IL12β, and TNF-α (96). More direct evidence against a central role for FcγRIII in IVIG activity comes from a recent study using a model of accelerated NTN. In this model, autoantibody-mediated kidney inflammation is mainly mediated by the activating FcγRIV, and IVIG is very potent in suppressing kidney destruction (49). Thus, we could investigate the role of activating FcγRIII in IVIG activity without simultaneously interfering with the interaction between the autoantibody and its activating FcγR. Importantly, deletion of FcγRIII had no influence on IVIG activity in vivo, whereas the absence of the inhibitory FcγRIIB abrogated the anti-inflammatory effect of IVIG. Taken together, the data suggest that IVIG-like effects can be achieved by blocking
the responsible activating FcγRs either with competing ICs or with FcγR-specific monoclonal antibodies that have the capacity to block binding of ICs to activating FcγRs. This highlights the importance of FcγRs in murine and human autoimmune diseases. At present, however, it seems unlikely that this is the actual mechanism of IVIG activity. Upregulation of the inhibitory FcγRIIB. As indicated briefly in the previous paragraphs, the other classical FcγR that has been associated repeatedly with the antiinflammatory activity of IVIG in vivo is the low-affinity inhibitory FcγRIIB (Figure 2b). Animals deficient in this protein are no longer protected by administration of IVIG in mouse models of ITP, rheumatoid arthritis, and NTN (43, 45, 46, 50, 57, 97). Moreover, IVIG therapy resulted in the upregulation of the inhibitory FcγRIIB on effector macrophages (43, 46, 50). In addition, a dramatic decrease in the expression of the triggering activating FcγRIV was observed in a model of NTN (50). This altered expression level of activating and inhibitory FcγRs will heighten the threshold for innate immune effector cell activation, which ultimately leads to a lower level of inflammation and platelet consumption. Consistent with the low affinity of FcγRIIB, a direct interaction with IVIG seems rather unlikely. In addition, the IVIGmediated upregulation of FcγRIIB on effector macrophages seems to be indirect as determined by the loss of IVIG activity and increased expression of FcγRIIB on effector macrophages in op/op mice (43). These mice lack the hematopoietic growth factor colonystimulating factor (CSF)-1, which results in the loss of select monocyte and macrophage subpopulations (98). Because IVIG activity is lost but antibody-mediated inflammation is maintained, investigators suggested that a CSF-1-dependent macrophage population has a regulatory function and is responsible for the upregulation of the inhibitory FcγR on effector macrophages (Figure 3) (12). Although this provides some information about www.annualreviews.org • Mechanism of IVIG Activity
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Figure 3 The role of the inhibitory FcγRIIB for IVIG activity. Binding of SA-rich immunoglobulins in the IVIG preparation to an as yet unknown receptor on CSF-1-dependent regulatory macrophages results in the upregulation of the inhibitory FcγRIIB on effector macrophages, which leads to an increased threshold for cell activation and ultimately reduces or blocks chronic inflammatory reactions. (Reproduced from the Journal of Experimental Medicine, 2007, 204:11–15. Copyright 2007 Rockefeller University Press.)
the cell types that are involved in IVIG activity, the fact of this regulatory function does not explain why such high doses are required to achieve it. Rather, it suggests that only a minor component in the IVIG preparation is the active component. This, at first sight, seems to be at odds with the limited heterogeneity within the IVIG preparation (which consists of only four different IgG subclasses) if one focuses on IgG Fc fragment–mediated effects. Differential antibody glycosylation. IgG antibodies are glycoproteins that contain a sugar moiety attached to each of the asparagine 297 (N297) residues in the two chains of the antibody Fc fragment (99). This glycan moiety is an integral structural component of the IgG molecule, forming part of the scaffold for FcγR binding 524
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(Figure 4). In addition, depending on the variable region sequences, roughly 20% of serum IgG antibodies have a Fab fragment– attached N-linked sugar side chain. These sugar moieties consist of a biantennary heptameric core sugar structure high in mannose and N-acetylglucosamine with variable amounts of branching and terminal sugar residues such as galactose, sialic acid (SA), N-acetylglucosamine, and fucose (Figure 4b) (100–102). Whereas Fab fragment–attached sugar moieties and the sugar domains of other serum proteins such as tranferrin or fetuin are usually fully processed (meaning that they contain all possible sugar residues), the Fc fragment–associated moiety is much more heterogeneous. In fact, more than 30 different antibody glycovariants have been detected in human serum, with about 25%–30% of
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FcγR
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b SA
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man GlcNAc
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Figure 4 The sugar domain of the antibody Fc fragment. (a) Shown is the crystal structure of the extracellular domain of human FcγRIIIA in complex with an immunoglobulin Fc fragment (CH2-CH3 domains). The Fc fragment–attached sugar moieties that protrude into the central cavity between the two antibody heavy chains are shown as a stick and ball model. (b) Cartoon of the antibody-attached sugar moiety. The heptameric core sugar structure consisting of mannose (man) and N-acetylglucosamine (GlcNAc) residues is shown in bold, and terminal or branching sugar residues are indicated. Most IgG glycoforms can be distinguished by the absence of terminal sialic acid (SA) or galactose (Gal) residues (IgG-G0 glycoform), the presence of one or two galactose residues (IgG-G1/2 glycoform), and the presence of one or two terminal SA residues (fully processed or native form).
them in the IgG-G0 glycoform (Figure 4b) without terminal SA or galactose residues (103). Thus, these 30 variants, multiplied by the four different IgG subclasses, result in more than 120 different glycoproteins in the IVIG preparation that could contain the active anti-inflammatory component. The im-
portance of this sugar moiety is highlighted by the loss of therapeutic activity of deglycosylated IVIG preparations (45). As discussed above, this excludes a simple FcRn competition model because the FcRn, unlike classical FcγRs, retains its affinity for deglycosylated Fc fragments. The loss of classical www.annualreviews.org • Mechanism of IVIG Activity
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FcγR binding could indicate that a direct interaction with these molecules is important. However, there is strong evidence against this scenario, as IVIG preparations as well as isolated Fc fragments enriched for terminal SA residues have a more than 10fold higher anti-inflammatory activity. These SA-rich IgG glycovariants have a decreased affinity for classical FcγRs in mice and humans, consistent with their strongly impaired activity in vivo (45, 93). This excludes the possibility that SA-rich IVIG preparations block access of autoantibody ICs to activating FcγRs and rather argues for a novel receptor on regulatory macrophages that can specifically recognize SA-rich IgG and promote an anti-inflammatory milieu. Data in favor of an important role of differential antibody glycosylation and especially sialylation in vivo come from human arthritis patients and mice with a variety of autoimmune diseases, such as systemic lupus erythematosus, arthritis, and NTN (45, 104–110). Especially during acute disease phases, a significant reduction in terminal SA residues in serum and antigen-specific antibodies can be observed, and the IgG-G0 glycovariant constitutes more than 50% of serum IgG (106). Thus, IVIG infusion would restore the level of SA-rich IgG that is necessary to regain an anti-inflammatory environment that suppresses the activity of autoantibodies by increasing inhibitory FcγRIIB expression.
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SUMMARY AND OUTLOOK Despite the widespread use of IVIG, we have only recently begun to shed some light on the mechanism of IVIG activity in vivo. Elucidating the molecular details of this activity is crucially important for gaining some general insights into the regulation of pro- and anti-inflammatory immune responses as well as for optimizing IVIG activity or even replacing it by a recombinant product in the future.
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Although probably none represent the actual mechanism of IVIG activity, several possibilities have already been described, such as enhancing autoantibody clearance by blocking the neonatal FcR or interfering with the interaction of autoimmune complexes with activating FcγRs. Although attractive strategies, both have drawbacks: Continuous blocking of FcRn will result in a more rapid clearance not only of autoantibodies but also of all other serum IgG molecules that have protective functions against microbial infections. Blocking activating FcγRs is, of course, the most direct strategy to interfere with innate effector cell activation, but it is far downstream in the inflammatory cascade and may also pose some significant dangers as the blocking antibodies or competing soluble IC might result in unspecific cell activation and the massive systemic release of proinflammatory cytokines, a so-called cytokine storm. Thus, potential FcγR-blocking antibodies or soluble ICs have to be carefully evaluated to prevent these severe side effects. In contrast, restoring a balanced immune response might be a very promising strategy in the longterm. Although we are just at the very beginning, the recent identification of antibody glycovariants with immunoregulatory activity might enable us to pursue more efficient and long-lasting therapeutic responses, especially in combination with therapies that aim at a specific depletion of autoantibody-producing B cells. Important topics to be addressed include determining whether genetic polymorphisms exist in the population that result in a differential antibody glycosylation pattern and which signals regulate antibody glycosylation in B cells during the steady state and during immune or autoimmune responses. A better understanding of the molecular details of differential antibody glycosylation might enable us to specifically modify these pathways during autoimmune responses and interfere with chronic inflammatory processes.
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SUMMARY POINTS 1. The two major clinical uses of IVIG are Ig replacement and anti-inflammatory therapy. 2. IVIG is produced from the pooled serum of thousands of donors enriched for the IgG fraction. 3. The anti-inflammatory activity of IVIG requires a high-dose treatment regimen. 4. IVIG contains autoreactive antibody species of varying specificity.
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5. A F(ab)2 -mediated mechanism may account for IVIG activity for select diseases. 6. Most in vivo evidence suggests that the Fc fragment contains the anti-inflammatory activity. 7. Blocking FcRn or activating FcγRs results in an IVIG-like activity by interfering with autoantibody half-life or binding to triggering activating FcγRs. 8. The inhibitory FcγRIIB is required for IVIG activity in vivo. 9. More than 30 different IgG glycovariants can be detected in human serum. 10. IgG antibodies from human arthritis patients and autoimmune mouse strains have a reduced level of terminal SA residues. 11. The SA-rich IgG fraction of IVIG has an enhanced anti-inflammatory activity.
FUTURE ISSUES 1. Why do autoimmune patients have aberrantly glycosylated antibodies? 2. Are there genetic factors that impact antibody glycosylation? 3. How is antibody glycosylation regulated? 4. Can recombinantly produced SA-rich IgG replace IVIG? 5. What is the cellular receptor that can recognize SA-rich IgG?
DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS This work was sponsored by grants from the NIH to J.V.R. and from the German Research Foundation (DFG) and the Bavarian Genome Research Network (BayGene) to F.N. We are especially grateful to Peter Sondermann (Roche) for providing the crystal structure shown in Figure 4. We apologize to all colleagues whose important work was not directly cited. These references can be found in the review articles cited in this paper.
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LITERATURE CITED
Annu. Rev. Immunol. 2008.26:513-533. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
1. Brandt D, Gershwin ME. 2006. Common variable immune deficiency and autoimmunity. Autoimmun. Rev. 5:465–70 2. LeBien TW. 2000. Fates of human B-cell precursors. Blood 96:9–23 3. Bayry J, Hermine O, Webster DA, Levy Y, Kaveri SV. 2005. Common variable immunodeficiency: the immune system in chaos. Trends Mol. Med. 11:370–76 4. Chapel H, Griffiths H, Brennan V, Bunch C, Lea J, Lee M. 1991. Hypogammaglobulinaemia in low grade B cell tumours; significance and therapy. Immunol. Invest. 20:187–91 5. Molica S, Musto P, Chiurazzi F, Specchia G, Brugiatelli M, et al. 1996. Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocytic leukemia. Results of a crossover study. Haematologica 81:121–26 6. Negi VS, Elluru S, Siberil S, Graff-Dubois S, Mouthon L, et al. 2007. Intravenous immunoglobulin: an update on the clinical use and mechanisms of action. J. Clin. Immunol. 27:233–45 7. Olopoenia L, Young M, White D, Barnes S, Rahbar F, Fomufod A. 1997. Intravenous immunoglobulin in symptomatic and asymptomatic children with perinatal HIV infection. J. Natl. Med. Assoc. 89:543–47 8. Prins C, Gelfand EW, French LE. 2007. Intravenous immunoglobulin: properties, mode of action and practical use in dermatology. Acta Derm. Venereol. 87:206–18 9. Sullivan KM, Kopecky KJ, Jocom J, Fisher L, Buckner CD, et al. 1990. Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation. N. Engl. J. Med. 323:705–12 10. Fehr J, Hofmann V, Kappeler U. 1982. Transient reversal of thrombocytopenia in idiopathic thrombocytopenic purpura by high-dose intravenous gamma globulin. N. Engl. J. Med. 306:1254–58 11. Imbach P, Barandun S, d’Apuzzo V, Baumgartner C, Hirt A, et al. 1981. High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1:1228–31 12. Nimmerjahn F, Ravetch JV. 2007. The antiinflammatory activity of IgG: the intravenous IgG paradox. J. Exp. Med. 204:11–15 13. Gelfand EW. 2006. Differences between IGIV products: impact on clinical outcome. Int. Immunopharmacol. 6:592–99 14. Bussel JB. 2002. Another interaction of the FcR system with IVIG. Thromb. Haemost. 88:890–91 15. Crow AR, Song S, Siragam V, Lazarus AH. 2006. Mechanisms of action of intravenous immunoglobulin in the treatment of immune thrombocytopenia. Pediatr. Blood Cancer 47:710–13 16. Durandy A, Wahn V, Petteway S, Gelfand EW. 2005. Immunoglobulin replacement therapy in primary antibody deficiency diseases—maximizing success. Int. Arch. Allergy Immunol. 136:217–29 17. Toubi E, Etzioni A. 2005. Intravenous immunoglobulin in immunodeficiency states: state of the art. Clin. Rev. Allergy Immunol. 29:167–72 18. Buchacher A, Iberer G. 2006. Purification of intravenous immunoglobulin G from human plasma—aspects of yield and virus safety. Biotechnol. J. 1:148–63 19. Hamrock DJ. 2006. Adverse events associated with intravenous immunoglobulin therapy. Int. Immunopharmacol. 6:535–42 20. Mimura Y, Ghirlando R, Sondermann P, Lund J, Jefferis R. 2001. The molecular specificity of IgG-Fc interactions with Fcγ receptors. Adv. Exp. Med. Biol. 495:49–53 528
Nimmerjahn
·
Ravetch
Annu. Rev. Immunol. 2008.26:513-533. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-17
ARI
16 February 2008
13:5
21. Woof JM, Burton DR. 2004. Human antibody-Fc receptor interactions illuminated by crystal structures. Nat. Rev. Immunol. 4:89–99 22. Vieira P, Rajewsky K. 1988. The half-lives of serum immunoglobulins in adult mice. Eur. J. Immunol. 18:313–16 23. Ghetie V, Ward ES. 2000. Multiple roles for the major histocompatibility complex class I-related receptor FcRn. Annu. Rev. Immunol. 18:739–66 24. Roopenian DC, Akilesh S. 2007. FcRn: the neonatal Fc receptor comes of age. Nat. Rev. Immunol. 7:715–25 25. Carroll MC. 2004. The complement system in regulation of adaptive immunity. Nat. Immunol. 5:981–86 26. Nimmerjahn F, Ravetch JV. 2006. Fcγ receptors: old friends and new family members. Immunity 24:19–28 27. Ravetch JV. 2003. Fc receptors. In Fundamental Immunology, ed. WE Paul, pp. 685–700. Philadelphia: Lippincott-Raven 28. Daeron M. 1997. Fc receptor biology. Annu. Rev. Immunol. 15:203–34 29. Hulett MD, Hogarth PM. 1994. Molecular basis of Fc receptor function. Adv. Immunol. 57:1–127 30. Ravetch JV, Clynes RA. 1998. Divergent roles for Fc receptors and complement in vivo. Annu. Rev. Immunol. 16:421–32 31. Basta M, Van Goor F, Luccioli S, Billings EM, Vortmeyer AO, et al. 2003. F(ab) 2 mediated neutralization of C3a and C5a anaphylatoxins: a novel effector function of immunoglobulins. Nat. Med. 9:431–38 32. Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, et al. 2006. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J. Allergy Clin. Immunol. 117:S525–53 33. Marchalonis JJ, Kaymaz H, Dedeoglu F, Schluter SF, Yocum DE, Edmundson AB. 1992. Human autoantibodies reactive with synthetic autoantigens from T-cell receptor beta chain. Proc. Natl. Acad. Sci. USA 89:3325–29 34. Prasad NK, Papoff G, Zeuner A, Bonnin E, Kazatchkine MD, et al. 1998. Therapeutic preparations of normal polyspecific IgG (IVIg) induce apoptosis in human lymphocytes and monocytes: a novel mechanism of action of IVIg involving the Fas apoptotic pathway. J. Immunol. 161:3781–90 35. Rossi F, Kazatchkine MD. 1989. Antiidiotypes against autoantibodies in pooled normal human polyspecific Ig. J. Immunol. 143:4104–9 36. Vassilev T, Gelin C, Kaveri SV, Zilber MT, Boumsell L, Kazatchkine MD. 1993. Antibodies to the CD5 molecule in normal human immunoglobulins for therapeutic use (intravenous immunoglobulins, IVIg). Clin. Exp. Immunol. 92:369–72 37. Vassilev TL, Kazatchkine MD, Van Huyen JP, Mekrache M, Bonnin E, et al. 1999. Inhibition of cell adhesion by antibodies to Arg-Gly-Asp (RGD) in normal immunoglobulin for therapeutic use (intravenous immunoglobulin, IVIg). Blood 93:3624–31 38. von Gunten S, Schaub A, Vogel M, Stadler BM, Miescher S, Simon HU. 2006. Immunologic and functional evidence for anti-Siglec-9 autoantibodies in intravenous immunoglobulin preparations. Blood 108:4255–59 39. Feasby T, Banwell B, Benstead T, Bril V, Brouwers M, et al. 2007. Guidelines on the use of intravenous immune globulin for neurologic conditions. Transfus. Med. Rev. 21:S57–107 40. French LE. 2006. Toxic epidermal necrolysis and Stevens Johnson syndrome: our current understanding. Allergol. Int. 55:9–16 www.annualreviews.org • Mechanism of IVIG Activity
529
ARI
16 February 2008
13:5
41. Viard I, Wehrli P, Bullani R, Schneider P, Holler N, et al. 1998. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282:490–93 42. Altznauer F, von Gunten S, Spath P, Simon HU. 2003. Concurrent presence of agonistic and antagonistic anti-CD95 autoantibodies in intravenous Ig preparations. J. Allergy Clin. Immunol. 112:1185–90 43. Bruhns P, Samuelsson A, Pollard JW, Ravetch JV. 2003. Colony-stimulating factor-1dependent macrophages are responsible for IVIG protection in antibody-induced autoimmune disease. Immunity 18:573–81 44. Debre M, Bonnet MC, Fridman WH, Carosella E, Philippe N, et al. 1993. Infusion of Fcγ fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet 342:945–49 45. Kaneko Y, Nimmerjahn F, Ravetch JV. 2006. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313:670–73 46. Samuelsson A, Towers TL, Ravetch JV. 2001. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291:484–86 47. Basta M, Dalakas MC. 1994. High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments. J. Clin. Invest. 94:1729–35 48. Basta M, Fries LF, Frank MM. 1991. High doses of intravenous Ig inhibit in vitro uptake of C4 fragments onto sensitized erythrocytes. Blood 77:376–80 49. Basta M, Langlois PF, Marques M, Frank MM, Fries LF. 1989. High-dose intravenous immunoglobulin modifies complement-mediated in vivo clearance. Blood 74:326–33 50. Kaneko Y, Nimmerjahn F, Madaio MP, Ravetch JV. 2006. Pathology and protection in nephrotoxic nephritis is determined by selective engagement of specific Fc receptors. J. Exp. Med. 203:789–97 51. Sylvestre DL, Ravetch JV. 1994. Fc receptors initiate the Arthus reaction: redefining the inflammatory cascade. Science 265:1095–98 52. Siragam V, Brinc D, Crow AR, Song S, Freedman J, Lazarus AH. 2005. Can antibodies with specificity for soluble antigens mimic the therapeutic effects of intravenous IgG in the treatment of autoimmune disease? J. Clin. Invest. 115:155–60 53. Teeling JL, Jansen-Hendriks T, Kuijpers TW, de Haas M, van de Winkel JG, et al. 2001. Therapeutic efficacy of intravenous immunoglobulin preparations depends on the immunoglobulin G dimers: studies in experimental immune thrombocytopenia. Blood 98:1095–99 54. Getman KE, Balthasar JP. 2005. Pharmacokinetic effects of 4C9, an anti-FcRn antibody, in rats: implications for the use of FcRn inhibitors for the treatment of humoral autoimmune and alloimmune conditions. J. Pharm. Sci. 94:718–29 55. Liu L, Garcia AM, Santoro H, Zhang Y, McDonnell K, et al. 2007. Amelioration of experimental autoimmune myasthenia gravis in rats by neonatal FcR blockade. J. Immunol. 178:5390–98 56. Vaccaro C, Zhou J, Ober RJ, Ward ES. 2005. Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat. Biotechnol. 23:1283–88 57. Akilesh S, Petkova S, Sproule TJ, Shaffer DJ, Christianson GJ, Roopenian D. 2004. The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease. J. Clin. Invest. 113:1328–33 58. Hansen RJ, Balthasar JP. 2002. Effects of intravenous immunoglobulin on platelet count and antiplatelet antibody disposition in a rat model of immune thrombocytopenia. Blood 100:2087–93
Annu. Rev. Immunol. 2008.26:513-533. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-17
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Nimmerjahn
·
Ravetch
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ANRV338-IY26-17
ARI
16 February 2008
13:5
59. Hansen RJ, Balthasar JP. 2002. Intravenous immunoglobulin mediates an increase in antiplatelet antibody clearance via the FcRn receptor. Thromb. Haemost. 88:898–99 60. Li N, Zhao M, Hilario-Vargas J, Prisayanh P, Warren S, et al. 2005. Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases. J. Clin. Invest. 115:3440–50 61. Masson PL. 1993. Elimination of infectious antigens and increase of IgG catabolism as possible modes of action of IVIg. J. Autoimmun. 6:683–89 62. Nimmerjahn F, Ravetch JV. 2005. Divergent immunoglobulin G subclass activity through selective Fc receptor binding. Science 310:1510–12 63. Ji H, Ohmura K, Mahmood U, Lee DM, Hofhuis FM, et al. 2002. Arthritis critically dependent on innate immune system players. Immunity 16:157–68 64. Shields RL, Namenuk AK, Hong K, Meng YG, Rae J, et al. 2001. High resolution mapping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FcγR. J. Biol. Chem. 276:6591–604 65. Stanley JR. 1999. Bullous pemphigoid. In Dermatology in General Medicine, ed. TB Fitzpatrick, AZ Eisen, K Wolff, IM Freedberg, S Katz, pp. 666–71. New York: McGraw-Hill 66. Boruchov AM, Heller G, Veri MC, Bonvini E, Ravetch JV, Young JW. 2005. Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions. J. Clin. Invest. 15:15 67. Clynes R, Maizes JS, Guinamard R, Ono M, Takai T, Ravetch JV. 1999. Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activation and inhibitory Fc receptors. J. Exp. Med. 189:179–85 68. Dhodapkar KM, Kaufman JL, Ehlers M, Banerjee DK, Bonvini E, et al. 2005. Selective blockade of inhibitory Fcγ receptor enables human dendritic cell maturation with IL12p70 production and immunity to antibody-coated tumor cells. Proc. Natl. Acad. Sci. USA 102:2910–15 69. Kalergis AM, Ravetch JV. 2002. Inducing tumor immunity through the selective engagement of activating Fcγ receptors on dendritic cells. J. Exp. Med. 195:1653–59 70. Nakamura A, Yuasa T, Ujike A, Ono M, Nukiwa T, et al. 2000. Fcγ receptor IIB-deficient mice develop Goodpasture’s syndrome upon immunization with type IV collagen: a novel murine model for autoimmune glomerular basement membrane disease. J. Exp. Med. 191:899–906 71. Regnault A, Lankar D, Lacabanne V, Rodriguez A, Thery C, et al. 1999. Fcγ receptormediated induction of dendritic cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune complex internalization. J. Exp. Med. 189:371–80 72. Wernersson S, Karlsson MC, Dahlstrom J, Mattsson R, Verbeek JS, Heyman B. 1999. IgG-mediated enhancement of antibody responses is low in Fc receptor γ chain-deficient mice and increased in FcγRII-deficient mice. J. Immunol. 163:618–22 73. Yuasa T, Kubo S, Yoshino T, Ujike A, Matsumura K, et al. 1999. Deletion of Fcγ receptor IIB renders H-2b mice susceptible to collagen-induced arthritis. J. Exp. Med. 189:187–94 74. Takai T, Ono M, Hikida M, Ohmori H, Ravetch JV. 1996. Augmented humoral and anaphylactic responses in FcγRII-deficient mice. Nature 379:346–49 75. Clynes R, Ravetch JV. 1995. Cytotoxic antibodies trigger inflammation through Fc receptors. Immunity 3:21–26 76. Park SY, Ueda S, Ohno H, Hamano Y, Tanaka M, et al. 1998. Resistance of Fc receptordeficient mice to fatal glomerulonephritis. J. Clin. Invest. 102:1229–38 77. Takai T, Li M, Sylvestre D, Clynes R, Ravetch JV. 1994. FcRγ chain deletion results in pleiotrophic effector cell defects. Cell 76:519–29 www.annualreviews.org • Mechanism of IVIG Activity
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ARI
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78. Zhang M, Zhang Z, Garmestani K, Goldman CK, Ravetch JV, et al. 2004. Activating Fc receptors are required for antitumor efficacy of the antibodies directed toward CD25 in a murine model of adult T-cell leukemia. Cancer Res. 64:5825–29 79. Fossati-Jimack L, Ioan-Facsinay A, Reininger L, Chicheportiche Y, Watanabe N, et al. 2000. Markedly different pathogenicity of four immunoglobulin G isotype-switch variants of an antierythrocyte autoantibody is based on their capacity to interact in vivo with the low-affinity Fcγ receptor III. J. Exp. Med. 191:1293–302 80. Nimmerjahn F, Bruhns P, Horiuchi K, Ravetch JV. 2005. FcγRIV: a novel FcR with distinct IgG subclass specificity. Immunity 23:41–51 81. Hamaguchi Y, Xiu Y, Komura K, Nimmerjahn F, Tedder TF. 2006. Antibody isotypespecific engagement of Fcγ receptors regulates B lymphocyte depletion during CD20 immunotherapy. J. Exp. Med. 203:743–53 82. Clarkson SB, Bussel JB, Kimberly RP, Valinsky JE, Nachman RL, Unkeless JC. 1986. Treatment of refractory immune thrombocytopenic purpura with an anti-Fcγ-receptor antibody. N. Engl. J. Med. 314:1236–39 83. Clarkson SB, Kimberly RP, Valinsky JE, Witmer MD, Bussel JB, et al. 1986. Blockade of clearance of immune complexes by an anti-Fcγ receptor monoclonal antibody. J. Exp. Med. 164:474–89 84. Binstadt BA, Geha RS, Bonilla FA. 2003. IgG Fc receptor polymorphisms in human disease: implications for intravenous immunoglobulin therapy. J. Allergy Clin. Immunol. 111:697–703 85. Ericson SG, Coleman KD, Wardwell K, Baker S, Fanger MW, et al. 1996. Monoclonal antibody 197 (anti-FcγRI) infusion in a patient with immune thrombocytopenia purpura (ITP) results in down-modulation of FcγRI on circulating monocytes. Br. J. Haematol. 92:718–24 86. Song S, Crow AR, Freedman J, Lazarus AH. 2003. Monoclonal IgG can ameliorate immune thrombocytopenia in a murine model of ITP: an alternative to IVIG. Blood 101:3708–13 87. Bussel JB, Graziano JN, Kimberly RP, Pahwa S, Aledort LM. 1991. Intravenous antiD treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect. Blood 77:1884–93 88. Oksenhendler E, Bierling P, Brossard Y, Schenmetzler C, Girard PM, et al. 1988. AntiRH immunoglobulin therapy for human immunodeficiency virus-related immune thrombocytopenic purpura. Blood 71:1499–502 89. Salama A, Kiefel V, Amberg R, Mueller-Eckhardt C. 1984. Treatment of autoimmune thrombocytopenic purpura with rhesus antibodies [anti-Rh0(D)]. Blut 49:29– 35 90. Salama A, Mueller-Eckhardt C, Kiefel V. 1983. Effect of intravenous immunoglobulin in immune thrombocytopenia. Lancet 2:193–95 91. Godeau B, Oksenhendler E, Brossard Y, Bartholeyns J, Leaute JB, et al. 1996. Treatment of chronic autoimmune thrombocytopenic purpura with monoclonal anti-D. Transfusion 36:328–30 92. Siragam V, Crow AR, Brinc D, Song S, Freedman J, Lazarus AH. 2006. Intravenous immunoglobulin ameliorates ITP via activating Fcγ receptors on dendritic cells. Nat. Med. 12:688–92 93. Scallon BJ, Tam SH, McCarthy SG, Cai AN, Raju TS. 2007. Higher levels of sialylated Fc glycans in immunoglobulin G molecules can adversely impact functionality. Mol. Immunol. 44:1524–34
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94. Park-Min KH, Serbina NV, Yang W, Ma X, Krystal G, et al. 2007. FcγRIII-dependent inhibition of interferon-γ responses mediates suppressive effects of intravenous immune globulin. Immunity 26:67–78 95. Zhou B, Zhao H, Yang RC, Han ZC. 2005. Multi-dysfunctional pathophysiology in ITP. Crit. Rev. Oncol. Hematol. 54:107–16 96. Crow AR, Song S, Semple JW, Freedman J, Lazarus AH. 2007. A role for IL-1 receptor antagonist or other cytokines in the acute therapeutic effects of IVIg? Blood 109:155–58 97. Crow AR, Song S, Freedman J, Helgason CD, Humphries RK, et al. 2003. IVIg-mediated amelioration of murine ITP via FcγRIIB is independent of SHIP1, SHP-1, and Btk activity. Blood 102:558–60 98. Stanley ER, Berg KL, Einstein DB, Lee PS, Yeung YG. 1994. The biology and action of colony stimulating factor-1. Stem. Cells 12(Suppl. 1):15–25 99. Arnold JN, Wormald MR, Sim RB, Rudd PM, Dwek RA. 2006. The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu. Rev. Immunol. 25:21–50 100. Butler M, Quelhas D, Critchley AJ, Carchon H, Hebestreit HF, et al. 2003. Detailed glycan analysis of serum glycoproteins of patients with congenital disorders of glycosylation indicates the specific defective glycan processing step and provides an insight into pathogenesis. Glycobiology 13:601–22 101. Jefferis R, Lund J, Mizutani H, Nakagawa H, Kawazoe Y, et al. 1990. A comparative study of the N-linked oligosaccharide structures of human IgG subclass proteins. Biochem. J. 268:529–37 102. Wormald MR, Rudd PM, Harvey DJ, Chang SC, Scragg IG, Dwek RA. 1997. Variations in oligosaccharide-protein interactions in immunoglobulin G determine the site-specific glycosylation profiles and modulate the dynamic motion of the Fc oligosaccharides. Biochemistry 36:1370–80 103. Arnold JN, Dwek RA, Rudd PM, Sim RB. 2006. Mannan binding lectin and its interaction with immunoglobulins in health and in disease. Immunol. Lett. 106:103–10 104. Nimmerjahn F, Anthony RM, Ravetch JV. 2007. Agalactosylated IgG antibodies depend on cellular Fc receptors for in vivo activity. Proc. Natl. Acad. Sci. USA 104:8433–37 105. Bond A, Cooke A, Hay FC. 1990. Glycosylation of IgG, immune complexes and IgG subclasses in the MRL-lpr/lpr mouse model of rheumatoid arthritis. Eur. J. Immunol. 20:2229–33 106. Malhotra R, Wormald MR, Rudd PM, Fischer PB, Dwek RA, Sim RB. 1995. Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein. Nat. Med. 1:237–43 107. Matsumoto A, Shikata K, Takeuchi F, Kojima N, Mizuochi T. 2000. Autoantibody activity of IgG rheumatoid factor increases with decreasing levels of galactosylation and sialylation. J. Biochem. 128:621–28 108. Mizuochi T, Hamako J, Nose M, Titani K. 1990. Structural changes in the oligosaccharide chains of IgG in autoimmune MRL/Mp-lpr/lpr mice. J. Immunol. 145:1794–98 109. Rademacher TW, Williams P, Dwek RA. 1994. Agalactosyl glycoforms of IgG autoantibodies are pathogenic. Proc. Natl. Acad. Sci. USA 91:6123–27 110. Rook GA, Steele J, Brealey R, Whyte A, Isenberg D, et al. 1991. Changes in IgG glycoform levels are associated with remission of arthritis during pregnancy. J. Autoimmun. 4:779–94
www.annualreviews.org • Mechanism of IVIG Activity
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Annual Review of Immunology
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:513-533. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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Contents
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The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan; email:
[email protected] Annu. Rev. Immunol. 2008. 26:535–84
Key Words
First published online as a Review in Advance on December 20, 2007
interferon regulatory factor, transcriptional regulation, innate immunity, immune cell development, oncogenesis
The Annual Review of Immunology is online at immunol.annualreviews.org This article’s doi: 10.1146/annurev.immunol.26.021607.090400 c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0535$20.00
Abstract The interferon regulatory factor (IRF) family, consisting of nine members in mammals, was identified in the late 1980s in the context of research into the type I interferon system. Subsequent studies over the past two decades have revealed the versatile and critical functions performed by this transcription factor family. Indeed, many IRF members play central roles in the cellular differentiation of hematopoietic cells and in the regulation of gene expression in response to pathogen-derived danger signals. In particular, the advances made in understanding the immunobiology of Toll-like and other pattern-recognition receptors have recently generated new momentum for the study of IRFs. Moreover, the role of several IRF family members in the regulation of the cell cycle and apoptosis has important implications for understanding susceptibility to and progression of several cancers.
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INTRODUCTION IRF: interferon regulatory factor
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Type I interferons: a family of cytokines that includes IFN-α (encoded by 13 functional genes in humans and 14 in mice) and IFN-β IFN-stimulated response element (ISRE): a common DNA motif found in the promoters of genes that are activated by type I IFNs Patternrecognition receptor (PRR): a receptor that recognizes pathogen-associated molecular patterns (PAMPs) to initiate innate immune responses
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Host defense serves two main functions: the generation of immune responses to invading pathogens and the suppression of tumor development. These are achieved by the efficient coordination of cellular responses by genetic regulatory networks in which a given transcription factor controls the expression of a diverse set of target genes, depending on the cell type and/or the nature of cellular stimuli. We review the current literature on how interferon (IFN) regulatory factors (IRFs) orchestrate and control homeostatic mechanisms of host defense. Although IRFs were first and best characterized as transcriptional regulators of type I IFNs and IFN-inducible genes, this family is now recognized as playing a pivotal part in the regulation of many facets of innate and adaptive immune responses. In addition to its contributions to immunity, the role of IRFs in the regulation of oncogenesis is also discussed herein. The IRF family of transcription factors, the first member of which, IRF1, was discovered in 1988, consists of nine members in humans and mice: IRF1, IRF2, IRF3, IRF4 (also known as PIP, LSIRF, or ICSAT), IRF5, IRF6, IRF7, IRF8 (also known as ICSBP), and IRF9 (also known as ISGF3γ) (Table 1) (1, 2). In addition, IRF10 was identified in chickens, although it is absent in humans and mice (3). Each IRF contains a well-conserved N-terminal DNA-binding domain (DBD) of ∼120 amino acids that possesses five conserved tryptophan repeats and bears a resemblance to the DBD of Myb transcription factors (2, 4). The IRF DBD forms a helix-turn-helix domain and recognizes a DNA sequence corresponding to the IFN-stimulated response element (ISRE, A /G NGAAANNGAAACT) (5). An analysis of the crystal structure of the DBD of IRF1 bound to the PRDI of the IFN-β enhancer revealed that 5 -GAAA-3 is the core recognition sequence of the helix-turn-helix motif (6). A subsequent analysis of the crystal structure of the IRF2 DBD in complex with a tandem
Tamura et al.
repeat of GAAA shows that 5 -AANNGAAA3 is the consensus IRF recognition sequence (7). The C-terminal regions of IRFs, except IRF1 and IRF2, carry an IRF association domain (IAD) that is responsible for homo- and heteromeric interactions with other family members or other transcription factors such as PU.1 and signal transducer and activator of transcription (STAT) (1, 2). The IADs share structural similarities with the Madhomology 2 (MH2) domains of the Smad family of transcription factors, which also mediate protein-protein interactions (8, 9). Interaction of IRFs with other transcription factors can further define the nucleotide sequences adjacent to the core IRF-binding motif to which the protein complex binds, as exemplified by the binding of the PU.1-IRF4 or the PU.1-IRF8 complex. Gene-targeting studies performed on all nine IRFs had been carried out by 2006 and have revealed the markedly diverse roles played by this family. Since our 2001 review in the Annual Review of Immunology (2), the crucial involvement of many IRFs (IRF1, IRF3, IRF4, IRF5, IRF7, and IRF8) in innate immune responses elicited by patternrecognition receptors (PRRs) has been clarified in greater detail. Major progress has also been made in understanding the role of IRFs (IRF1, IRF2, IRF4, and IRF8) in the development of various immune cells. Moreover, evidence has accumulated on the critical role of several IRFs (IRF1, IRF3, IRF5, and IRF8) in the control of cell growth, cell survival, and oncogenesis. We refer the reader to related review articles on IRFs published elsewhere (10–13).
REGULATION OF INNATE IMMUNE RESPONSES Recognition of invading pathogens is central to the host immune system. The innate immune system depends on a limited number of germline-encoded receptors called PRRs
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to recognize pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and viral nucleic acids (14). Depending on the nature of the pathogen and cell type involved, signal transduction pathways are activated by PAMP-engaged PRRs so as to elicit antimicrobial responses by inducing various target genes that include those encoding type I IFNs, proinflammatory cytokines, and chemokines. One of the major and best characterized of the players that transmit PRR signals to the nucleus is nuclear factor κB (NF-κB), activated by virtually all PRRs. In the past few years, however, extensive studies have revealed that IRFs are also widely involved in most PRR signaling events, thereby conferring a more diverse immune activation capability on the platform that links innate and adaptive immunities. IRF3 and IRF7 are primarily responsible for the activation of type I IFN genes downstream of PRR activation, although IRF1, IRF5, and IRF8 can also contribute to it. IRF1, IRF3, IRF5, and IRF8 also induce the expression of proinflammatory cytokines and other genes in response to PRR activation. Two classes of PRRs, cytosolic PRRs and membrane-bound Toll-like receptors (TLRs), have been identified (14, 15). In this section, we summarize the recent progress made in understanding the role of IRFs in the various PRR signaling pathways.
IRFs and Cytosolic PRR Signaling The cytosolic PRRs include the retinoic acid inducible gene I (RIG-I) family, IFNinducible double-stranded RNA (dsRNA)dependent protein kinase (PKR), DNAdependent activator of IRFs (DAI), and nucleotide-binding oligomerization domain (NOD) proteins (14–16). PKR is the first sensor found to detect intracellular dsRNA and is produced during replication of certain RNA viruses. However, gene-targeting studies in mice show that although PKR contributes to type I IFN production in response to polyriboinosinic polyribocytidylic
acid (poly(rI:rC)), a synthetic dsRNA (17), it only plays a minor role in type I IFN gene induction in response to viral infection (18). The RIG-I family of proteins, however, recognizes cytoplasmic viral RNA and is vital to the activation of IRFs. Several NOD family members recognize cytoplasmic bacterial PAMPs and are implicated in the activation of NF-κB and caspases, but an involvement of IRF members downstream of the NOD pathways has not been identified. DAI is a newly identified sensor for cytoplasmic DNA whose signaling pathway is still being elucidated. In this section, we describe the activation mechanisms and biological functions—with an emphasis on type I IFN gene induction— of IRF7, IRF3, and IRF5 in the cytosolic PRR signaling mediated by the RIG-I family and by DAI (Figure 1).
TLR: Toll-like receptor
Activation of IRFs by the RIG-I/MDA5 signaling pathway. Two RNA helicase enzymes, RIG-I (also called DDX58) and MDA5 (also called Helicard), have been identified as essential cytosolic receptors for intracellular viral RNA to induce type I IFN genes in various cell types, except plasmacytoid dendritic cells (pDCs) (19–22). This functional distinction is important because in vivo experiments show that cells other than pDCs also act as essential IFN-producing cells in response to many viruses (17, 23). RIG-I and MDA5 contain a C-terminal DExD/H box RNA helicase domain as well as two N-terminal caspase recruitment domains (CARDs) (24). The helicase domain is responsible for the detection of viral RNA, whereas the CARDs activate downstream signaling pathways. The in vivo relevance of RIG-I and MDA5 was demonstrated by studies using mice deficient in RIG-I or MDA5 (20, 21, 25). On the one hand, RIG-I mounts antiviral responses against a set of negative-strand single-stranded (ss)RNA viruses such as Newcastle disease virus (NDV), vesicular stomatitis virus (VSV), Sendai virus, and influenza virus, as well as some positive-strand ssRNA viruses such as Japanese encephalitis virus. www.annualreviews.org • The IRF Family Transcription Factors
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538 • Stimulates expression of IFN-inducible genes (GBP, iNOS, Caspase-1, Cox-2, CIITA, TAP1, and LMP2) • Binds to MyD88 and enhances TLR-dependent gene induction in IFN-γ-treated cells (IFN-β, iNOS, IL-12p35, and IL-12p40) • Attenuates type I IFN responses by antagonizing IRF1 and IRF9 • In some cases cooperates with IRF1 to activate transcription (IL-12p40 and Cox-2)
• Induces type I IFNs (IFN-α4 and IFN-β) and chemokines (CXCL10) upon virus infection, TLR stimulation, and DNA stimulation
• Binds to MyD88 and negatively regulates TLR-dependent induction of proinflammatory cytokine genes
Expression
• Constitutive and IFN-inducible in various cell types • Inducible by DNA damage at transcriptional and posttranslational levels • Mainly in the nucleus and partially in the cytoplasm • Modified by TLR signaling to efficiently translocate to the nucleus
• Constitutive and IFN-inducible in various cell types
• Constitutive in various cell types • Mainly in the cytoplasm • Phosphorylated upon virus infection, TRIF-dependent signaling, cytosolic PRR signaling, and DNA damage, and then translocates to the nucleus
• Constitutive in B cells, Ms, and CD11b+ DCs and inducible by antigen stimulation in T cells and by TLR signaling in Ms • Mainly in the nucleus and partially in the cytoplasm
IRF
IRF1
IRF2
IRF3
IRF4
Role in immune cell function (target genes)
A summary of IRF family member functions
Tamura et al. • Required for differentiation of CD4+ DCs • Supports B cell development (Ig light chains) • Required for plasma cell differentiation (Blimp-1 and AID) and GC formation • Required for Th2 differentiation (IL-4)
Unknown
Role in cell growth
• May possess oncogenic potential
• Stimulates apoptosis in Ms upon bacterial infection • May promote DNA damage–induced apoptosis
• Suppresses oncogene-induced transformation (Lysyl oxidase) • Required for DNA damage–induced growth arrest (p21/WAF1/CIP1) • Required for DNA damage–induced apoptosis
References
133, 135, 137, 138, 238, 240, 244, 246, 253, 261, 262, 266
36, 39, 51, 54, 56, 59, 61, 99, 105, 350
48, 53, 179, 180, 220, 224, 228, 234, 252, 260, 271, 336
2, 53, 134, 220–222, 231–233, 249, 250, 256, 260, 271, 272, 278, 280, 294, 295, 349
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• Required for differentiation of CD4+ DCs • Required for NK cell development • Suppresses basophil expansion • Promotes Th1 differentiation (IL-12 in Ms) • Suppresses Th2 differentiation (represses IL-4)
• Required for NK cell development (IL-15 in bone marrow stromal cells) • Required for differentiation of CD8+ T cells • Promotes Th1 differentiation through NK cells (IL-15), Ms/DCs (IL-12), and a T cell–intrinsic mechanism • Suppresses Th2 differentiation (represses IL-4)
Role in development of immune cells and other cells
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Table 1
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• Binds to MyD88 and positively regulates TLR-dependent induction of proinflammatory cytokine genes (IL-12p40, IL-6, and TNF-α) • Induces type I IFNs and proinflammatory cytokines upon virus infection (type I IFNs, IL-6, and TNF-α) Unknown • Binds to MyD88 and positively regulates TLR-dependent induction of type I IFNs (IFN-α/β)
• Binds to TRAF6 and is required for TLR9 signaling in DCs and Ms • Promotes type I IFN production in DCs (IFN-α/β) • Stimulates IFN-γ- and PAMP-inducible genes (IL-12p40, iNOS, FcγRI, PML, and others)
• Binds to STAT1 and STAT2 to form ISGF3 and stimulates type I IFN–inducible genes (OAS, PKR, IRF7, and many others)
• Constitutive in B cells and DCs, and inducible by type I IFNs and TLR signaling • Mainly in the cytoplasm • Phosphorylated upon virus infection, TLR-dependent signaling, and DNA damage, and then translocates to the nucleus
• Constitutive in skin
• Constitutive in B cells, pDCs, and monocytes and inducible by type I IFNs in various cell types • Mainly in the cytoplasm • Phosphorylated upon virus infection and TLR-dependent signaling, and then translocates to the nucleus
• Constitutive in B cells, Ms, and CD11b− DCs and further inducible by IFN-γ in Ms and by antigen stimulation in T cells • Mainly in the nucleus and partially in the cytoplasm
• Constitutive and inducible by IFN-γ in various cell types • Mainly in the nucleus
IRF5
IRF6
IRF7
IRF8
IRF9
Unknown
• Required for differentiation of CD8α+ DCs and pDCs • Stimulates M differentiation (Blimp-1, METS, and lysosomal/endosomal enzyme-related genes; represses disabled-2) • Supports B cell development (Ig light chains) • Stimulates the GC program (BCL6 and AID) • Promotes Th1 differentiation through Ms/DCs (IL-12)
• Mediates type I IFN induction of p53 (p53)
• Inhibits myeloid cell growth (Blimp-1, METS, and p15/INK4B) • Promotes apoptosis in myeloid cells • Its absence leads to CML-like disease
Unknown
4, 331, 353, 354
52, 140, 142, 173, 175, 187, 189, 190, 193, 199, 202, 214, 215, 238, 243, 352
44, 45, 49, 50, 64, 115, 123, 124, 128, 351
267, 268
46, 65, 130, 314, 315
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Unknown
Unknown
• Suppresses oncogene-induced transformation • Required for DNA damage–induced apoptosis
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• Required for keratinocyte differentiation
Unknown
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www.annualreviews.org • The IRF Family Transcription Factors
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On the other hand, MDA5 senses the presence of positive-strand ssRNA picornaviruses such as encephalomyocarditis virus (EMCV), Theiler’s virus, and Mengo virus. The molecular basis for the differential viral recognition by these two RNA helicases was recently reported. RIG-I senses the uncapped
5 -triphosphate end of RNA, a molecular signature that is absent in the cytosolic RNA of eukaryotic cells and in viruses detected by MDA5 (26, 27). MDA5, in contrast, recognizes dsRNA including poly(rI:rC) (21, 25). In addition, evidence has been provided that RIG-I and MDA5 mediate the induction of
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RNA virus
DNA virus
Intracellular bacterium
V protein Phagosome
RIG-I or MDA5 Helicase dsRNA or 5'P-RNA NS3/4A
CARDs
PPP
dsDNA L. monocytogenes
VISA
DAI and others
TRAF3 IKKγ
Mitochondrion RIP1 IKKγ IKKα IKKβ
IRF3
FADD
IKKγ
TBK1 or IKKε
TBK1
TRAF6
IRF7 IKKα IKKβ
IRF7 IRF3 I B
I B
NF- B p50
p65
IRF7
IRF5 IRF8
Pro-inflammatory cytokines 540
Tamura et al.
IRF3
P
Type I IFNs
P
IRF7 IRF3
P
P
Pro-inflammatory cytokines
p50
p65
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IFN responses by small self-RNAs generated by RNaseL (28). The adaptor molecule that links the sensing of viral RNA by RIG-I or MDA5 to downstream signaling was identified by multiple groups and variously named virus-induced signaling adaptor (VISA) (29), mitochondrial antiviral signaling protein (MAVS) (30), IFNβ-promoter stimulator 1 (IPS-1) (31), and CARD adaptor inducing IFN (Cardif ) (32); we refer to it as IPS-1 throughout this review for convenience. IPS-1 contains an Nterminal CARD that shares homology with and mediates CARD-CARD interactions between the CARDs of RIG-I and MDA5 to transmit downstream signaling. IPS-1 also contains a transmembrane region that targets itself to the mitochondrial outer membrane. This localization is essential for triggering downstream signaling and indicates a link between mitochondria and antiviral immunity. Importantly, mice deficient in IPS-1 are defective in RIG-I- and MDA5-, but not TLR-, B-DNA-, or DNA virus–mediated activation of IRFs and NF-κB; these mice are also susceptible to RNA virus infection (33, 34). How IPS-1 relays the signals from RIG-I and MDA5 to IRFs and NF-κB is still incom-
pletely understood; however, a recent study suggests that NEMO/IKKγ acts downstream of IPS-1 and upstream of IRF and NF-κB activation (35). NEMO/IKKγ, through TANK, interacts with the kinases that phosphorylate IRF3, IRF7, and IRF5, namely TANKbinding kinase 1 (TBK1, also known as T2K and NAK) and IKKε (IKKi) to activate IRFs (36–39). At the same time, NEMO/IKKγ presumably forms a complex with canonical IKKs (IKKα and IKKβ) to activate the NF-κB pathway. How IPS-1 transmits signals to NEMO/IKKγ remains unknown, but it interacts with several signaling proteins such as TRAF3 and TRAF6, the adaptor FADD, and the kinase RIP-1 (29, 31). Among them, TRAF3 (40, 41) interacts with both IPS-1 and TBK1, raising the possibility that TRAF3 links IPS-1 to a complex containing NEMO/IKKγ, TANK, and TBK1/IKKε. Although both TBK1 and IKKε can phosphorylate serine residues in the C-terminal (regulatory) region of IRF3 and IRF7 in vitro, gene-targeting studies show that TBK1 is the main contributor to type I IFN gene induction in virus-infected mouse embryonic fibroblasts (MEFs) (42, 43). As discussed in more detail below, TBK1 also functions downstream of
MEF: mouse embryonic fibroblast
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Figure 1 Activation of IRFs by cytosolic PRRs. The presence of RNA or dsDNA in the cytosol triggers host responses via a specific cytoplasmic pattern-recognition system. The binding of uncapped 5 -triphosphate RNA or dsRNA to the helicase domain of RIG-I/MDA5 induces the interaction between the CARD of RIG-I or MDA5 and the CARD-like domain of the adaptor protein IPS-1, which is located on the mitochondrial membrane. This receptor-adaptor interaction results in the activation of TBK1 and IKKε. Activated TBK1 induces the phosphorylation of the specific serine residues of IRF3 and IRF7. These IRFs then translocate into the nucleus and activate the type I IFN genes. In some cases, IRF5 or IRF8 participate in this IFN gene induction pathway. TRAF3, IKKγ/NEMO, and TANK positively regulate TBK1-mediated IRF activation. FADD, RIP-1, and TRAF6 interact with IPS-1 and are implicated in the NF-κB activation pathway, resulting in the induction of proinflammatory cytokine genes. dsDNA such as B-DNA is recognized by DAI. IRF3 and TBK1 interact with DAI, resulting in the induction of type I IFN genes. IRF7 is also involved in this pathway. Recognition of dsDNA by DAI activates NF-κB as well, which results in the induction of proinflammatory cytokine genes. The HCV NS3/4A protein and V proteins of paramyxovirus inhibit this pathway by cleaving IPS-1 and by binding to MDA5, respectively. (Abbreviations: IFN, interferon; IRF, IFN regulatory factor; RIG-I, retinoic acid inducible gene I; MDA5, melanoma differentiation-associated gene 5; CARD, caspase recruitment domain; IPS-1, IFN-β-promoter stimulator 1; TRAF, tumor necrosis factor receptor–associated factor; TANK, TRAF family member–associated NF-κB activator; TBK1, TANK-binding kinase 1; IKK, IκB kinase; NEMO, NF-κB essential modulator; FADD, FAS-associated via death domain; RIP-1, receptor interacting protein-1; DAI, DNA-dependent activator of IFN regulatory factors; HCV, hepatitis C virus.) www.annualreviews.org • The IRF Family Transcription Factors
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TLR3 and TLR4 to activate IRF3, whereas IRF7 is activated by other protein kinases during TLR7 and TLR9 signaling (37, 38, 44, 45).
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Contributions of IRFs to RIG-I/MDA5 signaling. Five IRFs (IRF1, IRF3, IRF5, IRF7, and IRF8) have been implicated as positive regulators of type I IFN gene induction (2, 46–52). Although IRF1 was the first family member discovered capable of activating type I IFN genes in vitro, NDVinduced type I IFN levels were normal in Irf1−/− MEFs, indicating that IRF1 is not essential for the induction of type I IFN genes by the virus-activated cytosolic pathway (53). The two IRF family members that have the greatest structural homology, IRF7 and IRF3, have been subsequently shown to be essential for the RIG-I/MDA5-mediated type I IFN gene induction pathway. Both reside in the cytosol in a latent form in unstimulated cells. Upon viral infection, specific serine residues in the C-terminal (regulatory) regions are phosphorylated, which causes the IRFs to undergo nuclear translocation. A two-step phosphorylation model by TBK1 is suggested for IRF3. First, phosphorylation at Ser396 to Ser405 in site 2 alleviates auto-inhibition to allow interaction with the coactivator cyclic-AMP-responsive-elementbinding protein (CREB)-binding protein (CBP). CBP facilitates the phosphorylation of Ser385 or Ser386 at site 1, which then allows for IRF dimerization (54, 55). Thus, the holocomplex containing dimerized IRF3 and IRF7 (either as a homodimer or a heterodimer) and coactivators such as CBP or p300 is formed in the nucleus (51, 56–59) and then binds to target ISRE DNA sequences within the promoters of type I IFN genes and certain chemokine genes. The histone acetyltransferase activities of the coactivators presumably lead to alterations in the local chromatin, resulting in the recruitment of basal transcription factors. In the case of the IFN-β gene promoter, other transcription factors such as NF-κB and activator protein 1 (AP1) are also recruited to 542
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form an enhanceosome to initiate efficient transcription (1, 2, 60). The initial hypothesis for the mode of IRF3/IRF7 induction of type I IFN genes was the positive-feedback model, in which IRF3 is primarily responsible for the induction of IFN-β in the early phase of a response, whereas IRF7, whose mRNA expression is induced by IFN-β, functions in the later phase of a response to induce IFN-α expression (61, 62). Indeed, IFN-α gene induction is reduced in Ifnb−/− MEFs (63), and type I IFN mRNA induction is impaired in Irf3−/− MEFs upon NDV infection (61). However, a subsequent study performed on Irf 7−/− MEFs revealed that both the early and later phases of type I IFN gene induction upon infection by ssRNA viruses (VSV and EMCV) are abolished in the absence of IRF7 (64). Thus, although IRF7 is initially expressed at a low level, the formation of a heterodimer between IRF7 and IRF3, rather than an IRF3 homodimer, is presumed to be more crucial for the production of IFN-α and IFN-β. Positive-feedback regulation of IRF7 then comes into effect to achieve the full induction of type I IFN genes during the later phases of the response. Recently, IRF5 has been shown to be involved in the RIG-I signaling pathway (65). Irf5−/− mice are highly vulnerable to VSV infection, accompanied by a decrease in type I IFN induction in the sera. The requirement of IRF5 is cell type selective; Irf5−/− macrophages (Ms) are defective in the production of type I IFNs by these viruses, whereas Irf5−/− MEFs are not, possibly because IRF5 is more highly expressed in hematopoietic cells. In addition, Irf5−/− mice show reduced levels of proinflammatory cytokines, such as IL-6, in the sera and in M cultures upon infection with these viruses, suggesting that IRF5 is also involved in the induction of proinflammatory cytokine genes. Although IRF5, like IRF3 and IRF7, can be phosphorylated by TBK1 (66), the detailed activation mechanism of IRF5 in the RIG-I signaling pathway, as well as how IRF5 participates in the transcriptional regulation
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of type I IFNs and proinflammatory cytokine genes, are still incompletely understood (also see below). Recently, it was reported that IRF8 is required for type I IFN induction in virus-stimulated DCs (52). IRF8 binds to the promoters of type I IFN genes and may participate in the subsequent IRF7-mediated amplifying phase of IFN transcription. Cytosolic DNA sensors. In addition to the cytosolic RNA-sensing mechanisms, recent attention has been focused on characterizing cytosolic DNA-sensing systems, as they also evoke protective and pathological immune responses. Indeed, the induction of type I IFN genes by DNA was reported more than four decades ago (67, 68). More recently, this issue was revisited in relation to TLR signaling, in particular TLR9 because it is activated by hypomethylated DNA (14, 15). However, a TLR9-independent mechanism(s) of type I IFN gene expression has also been described in which herpes simplex virus 1 (HSV-1) DNA virus can induce type I IFNs in cells deficient in TLR9 signaling (69). Furthermore, IFNβ induced via the TBK1-IRF3 pathway (70) by the obligate cytoplasmic bacteria Listeria monocytogenes is mainly mediated by DNA and is also independent of TLR signaling (71). Finally, cytosolic delivery of synthetic dsDNA into cells results in the expression of type I IFNs, and this induction also occurs independently of TLR signaling (72). These observations in toto indicate the presence of a cytosolic DNA sensor(s) that can initiate innate immune responses, including the induction of type I IFN genes, independent of TLR signaling. Recently, a candidate DNA sensor called DAI was identified (73). This protein, first identified as DLM-1 in tumor stromal tissue (74), possesses two DBDs for left-handed Zform DNA (Z-DNA) and, hence, is also referred to as Z-DNA-binding protein (ZBP1) (75, 76). With the discovery of its biological function as a DNA sensor, the name DAI has been proposed (73). A synthetic dsDNA, poly(dA-dT) poly (dT-dA), termed B-DNA because it likely
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takes on a right-handed B-form configuration, can strongly evoke innate immune responses (72). On the one hand, when DAI is artificially expressed in a murine fibroblast cell line, B-DNA induction of genes encoding type I IFNs, IL-6, and CXCL10 is significantly augmented. On the other hand, knockdown of DAI expression by RNA interference inhibits the activation of these genes upon BDNA, but not upon poly(rI:rC), treatment, indicating that DAI selectively controls this DNA-mediated signaling pathway. Such an effect of DAI has also been observed for other pathogen-derived DNAs such as bacterial and viral DNAs, suggesting the involvement of DAI in the host defense against pathogens. Can DAI directly recognize DNA and, if so, how does it transmit signals? Investigators have shown that DAI, which mainly resides in the cytosol, directly interacts with B-DNA in the cell and that this DNA-DAI interaction requires the N-terminal half of the protein that contains two known DBDs (75, 76) and a newly identified DBD (73). The in vitro interaction of recombinant DAI with B-DNA has recently been observed (T. Taniguchi, unpublished observation). Furthermore, DAI interaction with IRF3 and TBK1 through its C-terminal region is enhanced when cells are stimulated with B-DNA. Indeed, DAI requires both the N-terminal DNA-binding region and C-terminal TBK1/IRF-binding region for the B-DNA-mediated induction of type I IFN genes, supporting the notion that DNA is not only critical to initiate but also to sustain the active signaling complex (73). The requirement of IRF3 was demonstrated when B-DNA induction of IFN-β was abolished in Irf3−/− MEFs, but was normal in Irf 7−/− or Irf5−/− MEFs (71–73). The full induction of IFN-α, however, requires both IRF3 and IRF7 because both Irf3−/− and Irf 7−/− MEFs show impairment in its induction. DAI is likely to function redundantly with other DNA-sensing molecules. The DNAmediated induction of type I IFNs and other genes is not completely abolished in www.annualreviews.org • The IRF Family Transcription Factors
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DAI-knockdown cells (73; T. Taniguchi, unpublished observation), and activation of target genes by IFN-stimulatory DNA (ISD) is cell type dependent (71, 73).
IRFs and TLR Signaling To date, 13 functional TLRs (10 in human and 12 in mice) have been identified and found to recognize a variety of PAMPs derived from bacteria, viruses, fungi, and/or protozoa to trigger immune responses, including the induction of proinflammatory and type I IFN genes (77–79). All TLRs contain an intracellular Toll/IL-1 receptor (TIR) domain that transmits downstream signals by recruiting one or more TIR-containing adaptor proteins (14, 15, 80). These adaptors include MyD88 (myeloid differentiation primary-response protein 88), TIRAP (TIR domain–containing adaptor protein; also called MAL), TRIF (TIR domain– containing adaptor inducing IFN-β; also called TICAM1), and TRAM (TRIF-related adaptor molecule; also called TICAM2) (15, 80–87). Signaling through TLRs can be broadly categorized into two pathways: the MyD88-dependent pathway and the TRIFdependent pathway (or MyD88-independent pathway) (88, 89). All TLRs except TLR3 activate the MyD88-dependent pathway. By contrast, TLR3 and TLR4 activate the TRIFdependent pathway. Although most TLRs directly associate with either MyD88 or TRIF upon PAMP stimuli, TLR4 requires the additional adaptors TIRAP (81) and TRAM (82, 90) for the recruitment of MyD88 and TRIF, respectively. Both the MyD88-dependent and TRIFdependent pathways lead to the activation of at least three major downstream molecules: NF-κB, mitogen-activated protein kinases (MAPKs), and IRFs (11, 15, 77, 80, 91, 92). In the MyD88-dependent pathway, MyD88 first recruits IL-1 receptor-associated kinases 1/4 (IRAK1/4) and then TRAF6 and transforming growth factor (TGF)-β-activated kinase 1 (TAK1) (15, 83, 86, 92–94). TAK1 activates Tamura et al.
NF-κB and MAPKs through the phosphorylation of IKKβ and MAPK kinase 6 (MKK6), respectively (95). In addition, multiple IRFs are also recruited to the multimolecular complex containing MyD88 and TRAF6. In the following sections, we discuss the role of IRFs in the TRIF-dependent pathway and then summarize the contribution of each IRF to the MyD88-dependent pathway (Figure 2). IRF3 and IRF7 in the TRIF-dependent pathway. Both TLR4 and TLR3 utilize the TRIF-dependent pathway; TLR4 recruits TRAM-TRIF to activate IRF3 to induce IFN-β (TLR4 also activates the MyD88dependent signaling pathway), and TLR3 directly recruits TRIF to activate IRF3 and IRF7 to induce both IFN-α and IFN-β (11, 15). TLR4 is a cell surface receptor that recognizes non-nucleic acid ligands such as LPS from Gram-negative bacteria, and F (fusion) protein of the respiratory syncytial virus (RSV) and Moloney murine leukemia virus (96–98). TLR4 signaling results in the induction of the gene encoding IFN-β, but not the genes encoding IFN-α except IFN-α4 (99, 100, 101). The induction of the Ifnb gene by TLR4 is mostly MyD88-independent and TRAM-TRIF-dependent, whereas the induction of genes encoding proinflammatory cytokine genes or chemokines, such as IL-6, TNF-α, CCL5/RANTES, CXCL10, or CCL2, depends on MyD88 and TRAM-TRIF (102, 103). TRAM-TRIF recruits TRAF3, NAP1, and then the IRF kinase TBK1 (37, 38, 40, 104). The induction of IFN-β in response to LPS is abolished in Irf3−/− DCs, whereas this induction is almost normal in Irf 7−/− cells (64, 99, 105). Consistent with this role, Irf3−/− mice exhibit resistance to LPS-induced endotoxin shock (99) for which IFN-β induction is critical (106). Thus, IFN-β induction by TLR4 is mainly mediated by IRF3 rather than IRF7 via its phosphorylation by TBK1, a mechanism similar to that of the RIG-I pathway. It is not clear why TLR4-mediated activation of TBK1 via the TRAM-TRIF
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Figure 2 TLR-mediated IRF activation pathways. (a) TLR4 signals through at least four adaptors, MyD88, TIRAP, TRIF, and TRAM. Among them, TRAM and TRIF mediate the activation of IRF3. TRIF associates with TBK1 through NAP1 and TRAF3, which mediates the phosphorylation (P) of IRF3 (and IRF7, if present). Phosphorylated IRF3 forms homodimers and induces expression of genes encoding IFN-β and CXCL10. (b) IRF7 directly binds to MyD88 in the endosomal compartment and regulates the type I IFN gene induction program. Upon TLR9 stimulation, IRF7 interacts with MyD88 and is activated/phosphorylated by IRAK1 and IKKα. TRAF3 and TRAF6 interact with MyD88 and IRAK1 and are also involved in IRF7 activation. (c) IRF5 interacts with and is activated by MyD88 and TRAF6 by a still unknown mechanism. Activated IRF5 translocates to the nucleus to activate proinflammatory cytokine gene transcription, presumably in cooperation with NF-κB. IRF8 is also involved in TLR9-mediated signaling by directly activating proinflammatory cytokine genes and/or by the activation of NF-κB. IRF4 binds to MyD88 in a region overlapping with that of IRF5 and inhibits the further binding of IRF5 to MyD88, thereby attenuating the induction of proinflammatory cytokine genes. (d ) IFN-γ stimulation induces the expression of IRF1 via the formation of homodimers of phosphorylated STAT1. Induced IRF1 interacts with and is activated by MyD88 by an unknown mechanism and translocates to the nucleus to induce genes encoding IFN-β, iNOS, and IL-12p35. Note that the pathways depicted here operate in a cell type–specific manner. (Abbreviations: MyD88, myeloid differentiation primary-response protein 88; NAP1, nucleosome assembly protein 1; TIR, Toll/IL-1 receptor; TIRAP, TIR domain–containing adaptor protein; TRIF, TIR domain–containing adaptor inducing IFN-β; TRAM, TRIF-related adaptor molecule; IRAK, IL-1 receptor–associated kinase; TRAF, TNF receptor–associated factor; STAT1, signal transducer and activator of transcription 1; iNOS, inducible nitric oxide synthase.)
pathway is linked to the activation of IRF3 and not IRF7. Interestingly, however, when IRF7 is upregulated by pretreatment with recombinant IFN-β, LPS induction of IFNβ mRNA can be observed in Irf3−/− DCs (99). Therefore, under certain conditions
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TLR3 is expressed within the membrane of endosomes and phagosomes or at the cell surface, in the case of endothelial and natural killer (NK) cells. TLR3 recognizes the synthetic dsRNA analog poly(rI:rC) and probably recognizes viral dsRNA derived from either dsRNA viruses, such as reovirus, or as replication intermediates from ssRNA viruses, such as West Nile virus and RSV (107–109). In addition, TLR3 is involved in the defense against infection by HSV and murine cytomegalovirus (dsDNA viruses) as well as the parasites Leishmania donovani and Schistosoma mansoni (110–113), indicating that ligands other than dsRNA might also activate TLR3. Similar to TLR4, the activation of TLR3 can induce type I IFN gene expression via a MyD88-independent, TRIF- and TBK1-dependent signaling pathway (84, 87, 102, 103, 107). Indeed, the induction of type I IFN genes by poly(rI:rC) stimulation is severely impaired in Trif−/− or Tbk1−/− cells (102, 103). Although IRF3 plays an essential role in this induction, the poly(rI:rC)mediated induction of type I IFN mRNAs is still observed in Irf3−/− DCs. This residual induction is completely abolished in IRF3 and IRF7 doubly deficient DCs (H. Yanai & T. Taniguchi, unpublished observation). Therefore, in contrast to TLR4 signaling, IRF3 and IRF7 are both required for the maximal, TRIF-mediated induction of type I IFN genes. Although kinases TBK1 and IKKε can both phosphorylate IRF3 and IRF7 (36, 39), a gene-targeting study has revealed that TBK1 is most critical to the activation of IRF3 and IRF7 (37).
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Activation of IRF7 by the MyD88dependent signaling pathway. Recently, much attention has focused on the highlevel induction of type I IFN genes by pDCs (114–116). In contrast to conventional DCs (cDCs) and MEFs, pDCs express high levels of TLR7 and TLR9 in endosomes and produce large amounts of type I IFNs in response to corresponding TLR ligands. TLR7 recognizes ssRNA derived from genomic RNA 546
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of viruses such as influenza virus and VSV, whereas TLR9 recognizes hypomethylated CpG DNA motifs in bacteria or DNA viruses such as HSV (113, 117–121). In contrast to TLR3- or TLR4-mediated, TRIF-dependent IFN gene induction, TLR9 and TLR7 exclusively utilize MyD88 as its signaling adaptor (15). Indeed, type I IFN expression is abolished when MyD88-deficient pDCs are stimulated with ligands to these TLRs (114–119, 122). Because the induction of type I IFNs is crucially dependent on the activation of IRFs, this raises the question of how these TLRs can activate IRFs through the MyD88 adaptor protein. Investigators have shown that IRF7, but not IRF3, directly interacts with the death domain of MyD88 (123, 124). Splenic pDCs derived from Irf 7−/− mice exhibited a profound defect in type I IFN gene induction either upon infection by viruses (HSV and VSV) or treatment with synthetic TLR ligands (CpG-A and ssRNA), whereas the induction was normal in Irf3−/− pDCs (64). Therefore, in contrast to the IRF3-dependent type I IFN gene induction by the TRIF pathway, robust MyD88-dependent IFN gene induction in pDCs depends on IRF7. IRF7 also interacts with TRAF6 such that the overexpression of TRAF6-induced type I IFN genes occurs through the activation of IRF7 (123). The IRAK family of serine/threonine kinases, which are signal transducers between MyD88 and TRAF6, are also involved where IRAK1 and IRAK4 (like IRF7) bind to the death domain of MyD88, and pDCs derived from Irak4−/− or Irak1−/− mice have a defect in IFN-α production upon stimulation of TLR9 or TLR7 (45, 123). A more recent study has shown that IKKα is essential for the phosphorylation of IRF7 (44). Therefore, the IRAK4-IRAK1-IKKα kinase cascade, known to be operational in the NFκB activation pathway, likely also leads to IRF7 activation. In addition, TRAF3 and osteopontin are also involved in this pathway, but their exact functions are unknown (40, 125).
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Spatiotemporal regulation of the MyD88IRF7 pathway in pDCs. Although the essential role of IRF7 in MyD88-dependent IFN gene induction is clear, another interesting issue is why pDCs, but not other cell types such as cDCs, produce large amounts of type I IFNs in response to the same TLR9 ligands. Though posited as a potential explanation, the higher constitutive expression level of IRF7 in pDCs compared with other cell types (126) does not fully account for the robust production of type I IFNs by pDCs. Instead, the spatiotemporal regulation of TLR9 (and probably TLR7) signaling appears to be critical for this specific feature of pDCs. In pDCs, the IFN-inducing TLR9 ligand CpG-A preferentially colocalizes to the MyD88-IRF7-containing endosomal compartment (127, 128). In contrast, the same ligand mainly localizes to lysosomes in cDCs and Ms. Further underscoring the importance of this selective localization, targeting CpG-A to the endosome resulted in the robust production of type I IFNs in cDCs and Ms (128, 129). Thus, pDCs have a unique mechanism for retaining CpG-A in the endosome where MyD88 and IRF7 are localized; the prolonged signaling of TLR by CpG-A stimulation in endosomal compartments results in the robust production of type I IFNs through a sustained positive-feedback loop, likely involving the accumulation and activation of IFN-induced, de novo synthesized IRF7. Consistent with these data, pDCs from mice deficient in type I IFN receptor signaling (Ifnar1−/− ) are defective in robust type I IFN gene induction by CpG-A (64). Because CpG-B, which more strongly induces proinflammatory cytokines than does CpG-A, undergoes rapid lysosomal trafficking, the lysosomal TLR9 signaling may be crucial for effectively evoking this response. TLR signaling and IRF5. Similar to IRF7, IRF5 also interacts with MyD88 and TRAF6 (130). However, unlike IRF7, which binds to the death domain of MyD88, IRF5 interacts with the central region (the intermediary
domain and part of the TIR domain) of MyD88. Following TLR9 activation, IRF5 translocates to the nucleus and binds to the promoter of target genes, such as Il12b, that contain an ISRE. Indeed, the induction of proinflammatory cytokines, such as IL-12, TNF-α, and IL-6, is impaired in Irf5−/− Ms after stimulation with poly(rI:rC), LPS, flagellin, ssRNA, and CpG-B. Other genes such as those encoding IκBζ and CXCL2 are also regulated by IRF5 following TLR9 activation (130, 131), although whether IRF5 regulates these genes directly or indirectly is not clear. In accordance with the above observation, Irf5−/− mice show resistance to lethal endotoxin shock induced by CpG-B or LPS. However, recent studies have indicated a cell type dependency for the role of IRF5 in cytokine gene induction (132, 133). Irf5−/− bone marrow–derived Ms and DCs show normal production of proinflammatory cytokines in response to LPS or peptide glycan (PGN) (132), whereas DCs but not Ms display an impairment when stimulated with poly(rI:rC) (133). In addition, type I IFN gene induction in Irf5−/− splenic pDCs by CpG-A stimulation is almost normal (130) but is diminished in bone marrow–derived Irf5−/− pDCs (132). The activation mechanism of IRF5, a more detailed mode of IRF5 action in the nucleus, and the relationship between IRF5 and other mediators such as NF-κB and IRF7 are important issues to be clarified in the future. MyD88 signaling pathway for IRF1 activation. In addition to IRF7 and IRF5, IRF1 also directly interacts with MyD88 (134). Although IRF1 is strongly induced by type II IFN (IFN-γ), IFN-γ signaling itself cannot fully activate IRF1. Instead, TLR9 engagement causes MyD88-associated IRF1 to undergo posttranslational modifications and migrate into the nucleus more efficiently than does non-MyD88-associated IRF1. The critical role of MyD88-dependent “IRF1 licensing” is underscored by the observation that the induction of a specific gene subset downstream of the TLR-MyD88 pathway—such www.annualreviews.org • The IRF Family Transcription Factors
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as those genes encoding IFN-β, inducible nitric oxide synthase (iNOS), and IL-12p35— is impaired in Irf1−/− cDCs and Ms stimulated with IFN-γ plus CpG (134). Thus, IRF1 is critical for the IFN-γ enhancement of the TLR-dependent gene induction program.
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IRF4 and IRF8 in TLR signaling. Further studies on other IRF family members revealed that IRF4 also forms a complex with MyD88 (133). Although IRF4 resides mostly in the nucleus, a significant fraction is also present in the cytoplasm, where it colocalizes with MyD88. Unlike the MyD88-interacting IRFs described above, IRF4 negatively regulates TLR signaling, as TLR-induced proinflammatory cytokines are enhanced in Irf4−/− cells (133, 135). Furthermore, Irf4−/− mice are highly sensitive to endotoxin shock induced by CpG-B, a potent inducer of proinflammatory cytokines (122, 136). Importantly, Irf4 mRNA is induced upon TLR activation; because IRF4 and IRF5 bind to the same region of MyD88, TLR-induced IRF4 can compete with and inhibit the sustained binding of IRF5 to MyD88. This suggests a role for IRF4 in the negative-feedback regulation of TLR signaling. As the expression of IRF4 is restricted to immune cells, particularly B cells, T cells, Ms, and DCs (12, 137, 138), IRF4 may selectively control MyD88-dependent gene regulation in a cell type–specific manner. IRF8 is another immune cell–specific IRF family member and has homology with IRF4. Recent studies have shown that IRF8 participates in the TLR9-MyD88-dependent signaling pathway. For example, Irf8−/− DCs fail to produce proinflammatory cytokines such as TNF-α and IL-6 upon stimulation with CpG, whereas normal levels of these cytokines are produced in response to LPS. This defect coincides with the inability of Irf8−/− DCs to activate NF-κB and MAPKs in response to TLR9 stimulation (139), suggesting that IRF8 can act upstream of NF-κB. Although IRF8 does not bind to MyD88 (133), IRF8 does interact with TRAF6 (140), indicating that IRF8 may function in the cytosol. In the nucleus, 548
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IRF8 is required for the expression of the gene encoding IL-12p40 upon various PAMP stimuli in Ms and DCs (141–145) and for the induction of type I IFN genes by viruses and TLR ligands in DCs (52) (also see below). Although the precise mode of IRF8 action is still incompletely understood (for example, it is unknown if IRF8 translocates from the cytoplasm to the nucleus upon PAMP stimulation), IRF8’s participation in the MyD88dependent signaling pathway may add to the diversity of the signaling cascade downstream of TLRs and enable the cell type– and ligandspecific activation of target genes.
Viral Factors Affecting IRF Activation Pathways Many viruses have evolved mechanisms to dispose of the host immune response. Given the diverse and potent effects of IRFs on the immune system, it is not surprising that these transcription factors and their activation pathways are the target of viral immune disturbance. For example, the V proteins of paramyxoviruses associate with MDA5 and inhibit dsRNA-induced activation of the IFNβ promoter (19). Vaccinia virus produces N1L to antagonize TLR signaling at the level of IKKs and TBK1 (146). Hepatitis C virus (HCV) encodes nonstructural proteins 3 and 4A (NS3/4A) protease that cleave IPS-1 and TRIF, thereby inhibiting the activation of IRF3 and/or IRF7 during HCV infection (147, 148). Infected cell protein 0 (ICP0) from HSV-1 inhibits IRF3 activation (149). Rotavirus nonstructural protein 1 (NSP1) mediates the degradation of IRF3, IRF5, and IRF7 (150, 151). Kaposi’s sarcoma–associated herpesvirus/human herpes virus 8 encodes replication and transcription activator, a ubiquitin E3 ligase that promotes IRF7 ubiquitination and proteasome-mediated degradation (152). Furthermore, Kaposi’s sarcoma–associated herpesvirus encodes a cluster of three viral IRFs, vIRF1, vIRF2, and vIRF3/latencyassociated nuclear antigen 2 (LANA2)
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(153–155). Although vIRF1 displays a high sequence similarity to IRF8 (156), all three vIRFs show homology in their N-terminal regions to the DBD of IRFs. However, these factors lack several of the tryptophan residues that are essential for DNA binding and thus, in contrast to IRFs, are presumed to be unable to bind directly to DNA. Although its precise mechanism has not been elucidated, vIRF1 functions as a repressor of virus-mediated induction of type I IFN genes in a transient transfection assay (157–159). Additionally, vIRF2 and vIRF3/LANA2 also inhibit the activation of promoters of type I IFN genes, which may involve interference with host IRFs. Indeed, vIRF3/LANA2 binds to and inhibits the DNA-binding activity of IRF7 (160, 161). The fact that viruses have exploited derivatives of IRFs to compromise antiviral immunity underscores the importance of the IRF systems in immunity against viral infections and highlights the coevolution of vertebrates and viruses.
Implications for Autoimmune Diseases The accurate discrimination between self and nonself molecules is critical for host defense. Besides the beneficial aspects of the host defense system against nonself pathogenderived molecules via PRRs, ample evidence suggests that the aberrant activation of immune systems, evoked by the recognition of self molecules such as self-DNA or -RNA, contributes to the development of autoimmune diseases. Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by the loss of tolerance to diverse self nucleic acid–containing macromolecules, such as U1 small nuclear RNA with proteins (snRNPs) and DNA and histones (162–166). SLE patients make high-titer auto-antibodies to chromatin, leading to the formation of immune complexes that can bind to Fc receptors and stimulate PRRs, in particular TLR7, TLR8, or TLR9 (162–164, 166). Therefore, the aberrant activation of TLR7/8/9-
mediated IRFs by immunogenic self-RNA or self-DNA might contribute to the pathogenesis of SLE. Supporting this notion, two recent studies reported an allelic association between the IRF5/rs2004640 T allele and SLE (167, 168), although further studies are needed to address fully how IRF5 contributes to SLE. A better understanding of the IRF activation pathways may provide a platform for developing specific therapeutics for autoimmune diseases such as SLE.
REGULATION OF IMMUNE CELL DEVELOPMENT In addition to the functions assigned to IRFs in differentiated immune cells, multiple IRFs (IRF1, IRF2, IRF4, and IRF8) have pivotal roles in the development of immune cells, such as dendritic, myeloid, NK, B, and T cells, as recent studies have revealed. These findings have added to our understanding of the molecular mechanism for how the immune system is assembled from numerous and highly specialized cell types.
Systemic lupus erythematosus (SLE): an autoimmune disease characterized by the loss of tolerance to a diverse set of self-antigens and the consequent production of autoantibodies Antigen-presenting cell (APC): a cell that displays antigens to T cells via the major histocompatibility complex (MHC) Th: T helper or effector T cells; express CD4 and include Th1, Th2, Th17, and follicular B helper T
DC Subset Development Governed by IRF8, IRF4, IRF2, and IRF1 DCs are professional antigen-presenting cells (APCs) that are crucial in initiating innate and adaptive immune responses (169). These cells sense invading pathogens through PRRs, as described above, and respond by secreting various cytokines and by upregulating the expression of major histocompatibility complex (MHC) II and costimulatory molecules on their cell surface. DCs also capture and process antigens and present antigenic peptides on MHC molecules to T cells, thereby eliciting Th1 and Th2 responses or inducing tolerance. Importantly, DCs are a heterogeneous population of multiple subtypes with diverse functions (170, 171). For instance, mouse splenic DCs can be classified into at least four subsets: CD4+ DCs, CD8α+ DCs, CD4− CD8α− (double negative, DN) DCs, and pDCs. These subsets express different www.annualreviews.org • The IRF Family Transcription Factors
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sets of genes and manifest distinct functions (172). Generation of DC subsets regulated by IRF8 and IRF4. The expression of two structurally related IRFs, IRF8 and IRF4, is subset-selective (138, 173, 174). CD8α+ DCs and pDCs express high levels of IRF8, but no and low levels of IRF4, respectively. Conversely, IRF4 expression is high in DN DCs and CD4+ DCs, but IRF8 expression is low and absent, respectively. Analysis of Irf8−/− , Irf4−/− , and Irf8−/− Irf4−/− mice reveals that the above pattern of IRF8/IRF4 expression correlates with their requirement for DC subtype development (Figure 3). Thus, CD8α+ DCs and pDCs are largely missing in Irf8−/− mice, whereas the number of CD4+ DCs is severely reduced in Irf4−/− mice (138, 142, 173–175). Irf8−/− Irf4−/− mice have only a few DN DCs and totally lack other DC subtypes in the spleen (173). The few residual CD11c+ DC-like cells arising in Irf8−/− Irf4−/− mice are devoid of CIITA and MHC II expression at the mRNA levels and are unable to stimuDC progenitors IRF4
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Figure 3 Regulation of DC development by IRF family members. IRF8 is required for the development of CD8α+ DCs and pDCs (142, 175). IRF4 is critical for the development of CD4+ DCs (138, 173). The differentiation of DN DCs requires IRF8 or IRF4 (173). pDC development is also partially regulated by IRF4. The requirement of IRF8 and IRF4 for DC subset development correlates with their subset-selective expression. IRF8 is also important for functional differentiation of Langerhans cells (LCs) (176). IRF2 is required for the development of splenic CD4+ DCs as well as CD4+ LCs through negatively regulating type I IFN signaling (179, 180). IRF1 positively regulates CD8α+ DC differentiation, whereas it negatively regulates pDC differentiation (182). 550
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late T cell proliferative responses (173). Granulocyte macrophage colony-stimulating factor (GM-CSF)-mediated DC differentiation depends on IRF4, whereas Fms-like tyrosine kinase 3 (Flt3) ligand-mediated differentiation depends largely on IRF8 (138, 173). Furthermore, the full differentiation and function of epidermal Langerhans cells (LCs) and dermal DCs require IRF8 (176). Gene transfer experiments into Irf8−/− Irf4−/− bone marrow progenitor cells in vitro demonstrated that both IRFs have an overlapping activity to drive common processes of DC development, such as the induction of Ciita (encoding CIITA), while also possessing distinct activities in order to stimulate subset-specific gene expression, leading to the generation of functionally divergent DCs (173). It is tempting to speculate that DN DCs might represent a “prototype” DC subset generated via a default developmental pathway and that the emergence of IRFs permitted the acquisition of more diverse DC subtypes and functions. DC function regulated by IRF8. The above studies also indicate the specific role of IRF8 in DC function, i.e., DCs’ response to immune stimuli. Irf8−/− DCs, but not Irf4−/− DCs, fail to produce IL-12p40 or IFN-α in response to various PAMPs or NDV (142, 143, 173, 174). Moreover, the introduction of IRF8, but not IRF4, can confer upon Irf8−/− Irf4−/− DCs the ability to produce these cytokines in response to several PAMPs (173). The capability of IRF8 to support the production of type I IFNs and IL12 is achieved not only by the regulation of DC development but also by a direct involvement of IRF8 in the transcriptional regulation of the genes encoding these cytokines. It has been repeatedly documented that IRF8 serves as a transcriptional activator of IL-12p40 and IL-12p35 genes (141, 144, 145, 177). A recent study demonstrates the active participation of IRF8 in transcription of type I IFN genes (52). In addition, the knockdown of Irf8 expression shows that IRF8 is required for the positive
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regulation of Indo (encoding indoleamine 2,3 dioxygenase; IDO) and the negative regulation of Tyrobp (encoding DAP12) in tolerogenic DCs (IFN-γ-treated mouse CD8α+ DCs and LPS-matured, IFN-γ-treated human monocyte-derived DCs) (178). DC development regulated by IRF2 and IRF1. IRF2 and IRF1 also regulate DC subset development. Irf2−/− mice exhibit a selective loss of splenic and epidermal CD4+ CD8α− DCs. This defect is due to abnormally augmented type I IFN signaling; the deficiency was rescued by the introduction into Irf2−/− mice of a null mutation for the IFN receptor complex (thus, Irf2−/− Ifnar1−/− ) (179, 180). Interestingly, although type I IFNs can promote the latestage differentiation or maturation of DCs (181), these cytokines attenuate differentiation if added during the early stages of DC development (18, 179). Irf1−/− mice, in contrast, exhibit a modest but constant increase in pDC and decrease in CD8α+ DC numbers (182). Irf1−/− DCs express much higher levels of IL-10, TGFβ, and the tolerogenic enzyme IDO, while being defective in IL-12p40 production. As a consequence, Irf1−/− DCs fail to mature fully, are unable to stimulate the proliferation of allogeneic T cells, and induce an IL10-mediated suppressive activity in allogeneic CD4+ CD25+ regulatory T cells, suggesting a novel role of IRF1 in regulating the tolerogenic features of DCs (182). Altogether, multiple IRFs are critically involved in the regulation of DC development and function. Through their specific and common activities, IRFs appear to equip DCs with the diversity required for directing optimal immune responses. The role of IRFs in human DC subtypes is less clear than it is in mouse DCs at present. However, transcripts from the genes encoding IRFs are expressed in human DCs (126, 183–185). Future studies for identifying IRF target genes, interacting proteins, and the relationship with other transcription factors known to regulate DC
development such as PU.1 and Spi-B, both of which may be common partners for IRF8 and IRF4, as well as RelB, STAT3, Gfi1, Ikaros, Runx3, and Id2 (186), would further clarify the molecular programs required for the development and function of DC subtypes.
Myeloid Cells: MΦ and Granulocyte Differentiation Regulated by IRF8 and Other IRFs Role of IRF8 in myeloid cell development. An unexpected role of IRF8 in myeloid cell development was first suggested by the observation that Irf8−/− mice exhibit a systemic expansion of neutrophils followed by a fatal blast crisis, resembling human chronic myelogenous leukemia (CML) (187). In addition, a mutation in the Irf8 gene causes a CML-like syndrome in BXH-2 mice (188). Subsequent studies have revealed that there is a cell-intrinsic function of IRF8 in the differentiation, growth, and apoptosis of myeloid cells. Irf8−/− mice harbor increased numbers of progenitor cells that are hyperresponsive to both GM-CSF and granulocyte colonystimulating factor (G-CSF) (189). Cell transfer studies show an intrinsic leukemogenic potential and long-term reconstitution capability of Irf8−/− progenitors. In contrast, their response to macrophage colony-stimulating factor (M-CSF) was strongly reduced, and, surprisingly, most of the Irf8−/− progenitor cells differentiated into granulocytes even in the presence of M-CSF. Consistent with these observations, there are significantly fewer cells of the M lineage in Irf8−/− bone marrow than in wild-type counterparts (189). Myeloid progenitor cells give rise to granulocytes and Ms. Studies with Irf8−/− myeloid progenitor cell lines and freshly isolated bone marrow progenitor cells from Irf8−/− mice have indicated IRF8’s role in the lineage selection of myeloid progenitors; IRF8 drives their differentiation toward Ms and inhibits granulocytic (neutrophilic) differentiation (190, 191) (Figure 4). Moreover, in both cases IRF8 strongly inhibits cell www.annualreviews.org • The IRF Family Transcription Factors
CML: chronic myelogenous leukemia Apoptosis: also called programmed cell death, a highly regulated mechanism of altruistic suicide of a cell that occurs during development and host defense in multicellular organisms
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The role of IRFs in myeloid cell development. IRF8 controls the fate of myeloid progenitor cells by directing M differentiation and inhibiting neutrophilic differentiation (189–191). In addition, IRF8 negatively regulates proliferation and promotes apoptosis in myeloid cells. As a result, Irf8−/− mice develop a CML-like syndrome (187). Importantly, IRF8 expression is severely diminished in human CML patients (197). IRF1 is required for the full maturation of neutrophils and Ms (219). IRF2 negatively regulates the expansion of basophils (224).
growth. Consistent with these observations, IRF8 expression is detected in mouse and human hematopoietic progenitor cell populations and persists in Ms, whereas it declines in granulocytes (191, 192). Also, IRF8 positively regulates apoptosis in myeloid cells (193). Irf8−/− Ms terminate M-CSF signaling more rapidly than do wild-type cells owing to accumulation of c-Cbl, a ubiquitin ligase that targets an activated M-CSF receptor for degradation (194). These results demonstrate IRF8’s critical role in the development of myeloid cells and illustrate why the loss of IRF8 leads to a CML-like syndrome. Given that IRF8 transcript levels are severely reduced in cells from human CML patients (195–197), CML cells may have a previously unrecognized defect in the IRF8regulated myeloid differentiation program, i.e., a disproportional differentiation toward granulocytes.
IRF8 target genes and MΦ differentiation. IRF8 acts either as an activator or a repressor depending on its interacting factors and 552
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target DNA elements (198, 199). On the one hand, IRF8 associates with IRF1, IRF2, and IRF4 and the Ets repressor TEL on ISREs that have a tandem repeat of the core IRFbinding motif GAAA (200). In this case, the overexpression of IRF8 generally represses ISRE-driven transcription, although only a limited number of genes such as Isg15 are known to be affected by endogenous IRF8. On the other hand, IRF8 also interacts with an Ets transcription factor PU.1, the master regulator of B cell and M differentiation. Here, IRF8 activates transcription of genes that carry the Ets-IRF composite element (EICE, GGAANNGAAA), the Ets/IRF response element (EIRE, GGAAANNGAAA, a subset of the ISREs), or the IRF-Ets composite sequence (IECS, GAAANN(N)GGAA). The EICE is especially critical in the B cell lineage, whereas during M differentiation the IECS is responsible for multiple IRF8 target genes such as those encoding Cathepsin C and Cystatin C (201). The EICE and EIRE are also active in cells stimulated by IFN-γ, which strongly induces IRF8 gene expression. Other DNA elements that do not fall into the above consensus sequences, for instance those found in Cdkn2b and Nf1 genes, are also targeted by IRF8 during M differentiation (202, 203). Overall, studies of IRF8 target genes show that IRF8 controls several key genes that repress cell growth and apoptosis in myeloid cells, while it also induces many genes important for M function. During growth control, IRF8 directly induces Prdm1 and Etv3, genes that encode for Blimp-1 and METS, respectively (204). Both genes are transcriptional repressors of Myc and are capable of inhibiting cell growth. In addition, IRF8 directly activates the transcription of Cdkn2b, which encodes an inhibitor for cyclin-dependent kinase p15Ink4b (202). Furthermore, IRF8 represses antiapoptotic genes Bcl2l1 (encoding Bcl-XL ) and BCL2 and thereby controls apoptosis (193, 205). Interestingly, the Nf1 gene, which encodes the Ras-GAP neurofibromatosis 1 (NF1) protein, is a direct target gene for IRF8 (203, 206). NF1 inactivates
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Ras in hematopoietic cells, and Nf1−/− hematopoietic cells cause myeloproliferative symptoms because of hypersensitivity to GMCSF. These authors show that IRF8 induces Nf1 to suppress Ras signaling and cell proliferation of myeloid cells in response to GM-CSF or M-CSF. Another recent finding describes IRF8 as indispensable for the expression of the Pml gene and the formation of nuclear bodies in myeloid cells (207). Given that the promyelocytic leukemia protein (PML) is important for a variety of cell functions such as cell cycle regulation, apoptosis, DNA repair, and tumor suppression, PML may be responsible for some of the leukemia suppressor activity of IRF8. Although the mechanism of IRF8 stimulation of M differentiation and function has been clarified to the degree described above, the mechanism of how IRF8 represses granulocytic differentiation is still poorly defined.
IRF8 target genes for MΦ function. IRF8 also directly induces several endosomal/lysosomal enzyme-related genes such as those encoding cathepsin C, lysozyme, cystatin C, and prosaposin (201) and represses the Dab2 gene encoding disabled-2 that stimulates M adhesion and spreading (208), enabling Ms to establish their proper functionality. Moreover, IRF8 contributes to the induction of numerous genes in IFN-γtreated cells. In addition to the target DNA elements described above, IRF8 can stimulate transcription of genes carrying a subset of the IFN-γ activation site (GAS) via indirect DNA binding (209). IRF8 target genes in cells treated with IFN-γ and PAMP are regulated by multiprotein complexes containing IRF8 and other transcription factors, especially PU.1 and in some cases IRF1; these genes include those encoding IL-12p40, IL-12p35, gp91phox , p67phox , TLR4, TLR9, iNOS, Fcγ receptor I (FcγRI), IRF8 itself, IL-18, CCL5/RANTES, and Nramp1 (198, 210–212).
Owing to the defects in the development and function of DCs and Ms described above, Irf8−/− mice are highly susceptible to various pathogens such as Listeria monocytogenes (213), vaccinia virus (187), lymphocytic choriomeningitis virus (LCMV) (187), Toxoplasma gondii (214), Leishmania major (215), Yersinia enterocolitica (216), and Brucella abortus (217). Regulation of myeloid differentiation by IRF1 and IRF2. Irf1 expression is upregulated during myeloid differentiation (218). Irf1−/− bone marrow cells exhibit an increased number of immature granulocytic precursors while their colony-forming ability in response to both G-CSF and M-CSF is decreased, suggesting a defective maturation process (219) (Figure 4). As an IFN-inducible transcriptional activator for the ISRE-containing genes, IRF1 transcriptionally targets many genes, including those encoding GBP, iNOS, Caspase-1, Cox-2, CIITA, and gp91phox in IFN-stimulated Ms (2, 220–223). In IFNγ-primed PAMP-stimulated cells, IRF1 is further activated by the TLR-MyD88 pathway, as already discussed, and induces a subset of genes such as those encoding IL-12p40, IL-12p35, iNOS, IL-18, and IFN-β (2, 134, 223). Irf2−/− mice display an expansion of basophils, resulting in an increase in IL-4 production (224) (Figure 4). The same study shows that these abnormalities are responsible for the excess Th2 polarization observed in naive Irf2−/− mice. An in vitro ectopic expression study shows that IRF2 is inhibitory to granulocytic differentiation and stimulates megakaryotic differentiation (225). In Irf2−/− Ms, the expression of the gene encoding Caspase-1 is enhanced, suggesting that IRF2 counteracts IRF1 (226). This augmented Caspase-1 expression may be responsible for the accelerated apoptosis observed in Irf2−/− Ms treated with a fungal metabolite gliotoxin or IFN-γ plus LPS (226, 227). Unexpectedly, the induction of genes encoding IL-12p40 and Cox-2 has been found to be www.annualreviews.org • The IRF Family Transcription Factors
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Germinal center (GC): a site within secondary lymphoid organs where B cells perform somatic hypermutation and class switch recombination following antigen and T cell stimulation
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diminished in Irf2−/− Ms treated with IFN-γ and/or LPS, suggesting that IRF2 cooperates with, rather than antagonizes, IRF1 to induce these genes (220, 228, 229).
The Development of Natural Killer Cells Regulated by IRF1 and IRF2 by Distinct Mechanisms Several studies have shown that the numbers of NK (NK1.1+ TCRα/β− ) cells are dramatically reduced, and NK cell activities such as cytotoxicity and IL-12-dependent IFN-γ production are absent in Irf1−/− mice (230– 233). The lack of IRF1 selectively affects the bone marrow stromal cells that constitute the microenvironment for NK cell development, but not NK progenitors, per se (Figure 5). Indeed, IRF1 in stromal cells is required for transcription of the gene encoding IL-15, a cytokine essential for NK cell development (231). This defect of Irf1−/− mice in IL-15 production also causes impaired development
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Bone marrow stroma cells Figure 5 Regulation of NK cell development by IRF1 and IRF2. IRF1 is indispensable for NK cell development by regulating the expression of IL-15, a cytokine that supports NK cell development in bone marrow stromal cells (231). Although not shown in this figure, IRF1 is also essential for the development of NKT cells and intestinal intraepithelial T cells (232), because these cells also require IL-15 for their development. IRF2, on the other hand, supports NK cell development in an NK cell–intrinsic manner (234). 554
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of NKT (NK1.1+ TCRα/β+ ) cells and intestinal intraepithelial T cells (232). Irf2−/− mice also carry an impairment in NK cell development and function (234) (Figure 5). Unlike the case of IRF1, however, IRF2 affects NK cell development in an NK cell–intrinsic manner. Irf2−/− mice selectively lack mature CD11bhigh Dx5high NK cells, likely because of accelerated apoptosis (235).
B and Plasma Cells: Multiple Developmental Steps Involving IRF4 and IRF8 Pre-B to B cell transition regulated by IRF4 and IRF8. The cooperative regulation of immune cell development by IRF4 and IRF8 also operates in B cell differentiation. Both IRFs are expressed in immature states of B cells, including pre-B cells in the bone marrow (236, 237). A redundant role of IRF4 and IRF8 in promoting pre-B to IgM+ B cell transition was revealed by the observation that B cells in Irf4−/− Irf8−/− but not in Irf4−/− or Irf8−/− mice are arrested at the cycling preB stage (238) (Figure 6). These IRFs activate conventional immunoglobulin (Ig) light chain (i.e., κ and λ) gene transcription and rearrangement, while they downregulate the preantigen receptor complex by suppressing the expression of surrogate light chain VpreB and λ5 genes (238, 239). Indeed, it is well documented that IRF4 and IRF8 interact with Ets transcription factors PU.1 or SpiB on the EICEs found in the Ig κ 3 and λ enhancers to activate transcription (240, 241). Supporting evidence for the overlapping function of the two IRFs was shown when introduction of either IRF4 or IRF8 rescued the maturation arrest of Irf4−/− Irf8−/− B cells in vitro (239). The role of IRF8 in the germinal center program. Upon T cell–dependent antigen challenge, peripheral IgM+ B cells enter the GC of secondary lymphoid tissues, where they undergo affinity maturation and
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isotype switching. Interestingly, IRF8 expression increases and IRF4 expression is suppressed in centroblasts within the dark zone (236, 242). IRF8 directly regulates the induction of two critical genes, AICDA and BCL6, during the GC reaction in both human and mouse (243). The AICDA gene encodes activation-induced cytidine deaminase (AID), which is required for both somatic hypermutation and class switch recombination, and the BCL6 gene encodes B cell lymphoma ¨ 6 (BCL6) protein, a Kruppel-type zinc finger transcriptional repressor that functions as a master regulator of the GC program. Although GCs can still form in Irf8−/− mice, Irf8−/− GC B cells show less organized morphology and reduced levels of Aicda and Bcl6 gene expression (243) (Figure 6). Regulation of germinal center reaction and plasma cell differentiation by IRF4. When centrocytes in the GC light zone differentiate into high-affinity antibody-producing plasma cells, the expression of IRF8 declines, whereas the expression of IRF4 gradually increases (236, 244, 245). An earlier study has reported that Irf4−/− mice display a profound reduction in serum Ig, fail to produce antigenspecific antibodies, and do not generate GCs (137). A more detailed role for IRF4 in isotype switching and plasma cell differentiation was recently discovered by two groups (244, 246) (Figure 6). Using mice with conditional or conventional deletion of Irf4 alleles, these studies showed that class switch recombination and plasma cell differentiation from centrocytes or memory B cells require IRF4. Both studies also showed that IRF4 is indispensable for Aicda gene induction, illustrating the molecular basis for the failure of isotype switching in Irf4−/− B cells. Furthermore, one of the studies identified the Prdm1 gene as a direct target of IRF4 (244), although the other group found no regulation of Prdm1 by IRF4 (246). The Prdm1 gene encodes the zinc-finger transcriptional repressor Blimp-1, which is a master regulator
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Figure 6 Regulation of B cell and plasma cell differentiation by IRF4 and IRF8. Differentiation from pre-B to IgM+ B cell requires IRF4 or IRF8 (238). IRF8 positively regulates the germinal center (GC) program (243). IRF4 is essential for class switch recombination in the late stage of GC reaction and for plasma cell differentiation from centrocytes or memory B cells (244, 246).
of plasma cell differentiation (247). Although AID and Blimp-1 are key components of antagonistic developmental states (GC reaction and plasma cell differentiation, respectively), graded expression of IRF4 sequentially activates the two genes; during the final stage of GC reaction, a relatively low level of IRF4 stimulates the expression of the Aicda gene to achieve class switch recombination, and then a higher concentration of IRF4 induces the Prdm1 gene that in turn represses the expression of Bcl6 and Aicda, thereby terminating the GC reaction and inducing plasma cell differentiation (244). The induction of Prdm1 by IRF4 is reminiscent of that by IRF8 in myeloid progenitor cells. However, the reason IRF8 does not induce Prdm1 in GC B cells may be because of the potent repression by Bcl6 in order to maintain the GC reaction program. Interestingly, IRF4 can interact with STAT6 and promote the expression of IL-4-inducible genes in B cells treated with CD40 and IL-4 (248). In addition to the above developmental defects, elder (10 to 15 weeks) Irf4−/− mice display a generalized lymphadenopathy because of an expansion of B and T cells in lymph nodes and spleen (but not thymus), suggesting that IRF4 is also important for the homeostasis of mature lymphocytes (137). www.annualreviews.org • The IRF Family Transcription Factors
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T Cells: Thymocyte Development and Th1/Th2 Differentiation Regulated by Multiple IRFs
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Development and/or function of CD8 + T cells regulated by IRF1, IRF2, and other IRFs. Irf1−/− mice display a profound reduction of mature CD4− CD8+ T cells in the thymus and peripheral lymphoid organs, suggesting a lineage-specific defect in thymocyte development (53) (Figure 7). Although Irf1−/− thymic stromal cells express decreased IRF2
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Figure 7 T cell differentiation regulated by IRF family members. In the thymus, IRF1 plays an essential role in CD8+ T cell development (53). Cytotoxic T lymphocyte (CTL) activation is positively regulated by IRF1, IRF4, and IRF8 (53, 137, 187). IRF2 is required for preventing hyperresponsiveness of CD8+ T cells to antigen stimulation, which is mediated by IRF2’s negative regulation of type I IFN signaling (252). Th1 differentiation requires IRF1, IRF2, and IRF8 (214, 215, 228, 233, 256). IRF1 is indispensable for CD4+ T cells to respond to the Th1 cytokine IL-12 (233) and is also required for the induction of genes encoding IL-12 in Ms and DCs (134, 233, 256). In addition, IRF1 is essential for the development of NK cells that produce IFN-γ, a M-stimulating cytokine (231, 232). IRF8 is critical for differentiation of Ms and several DC subsets and also for the induction of IL-12p40 in these cells (142, 175, 190, 214, 215). IRF2 is required for NK cell development and the induction of the gene encoding IL-12p40 (228, 234). In addition, IRF2 negatively regulates Th2 polarization in naive mice by limiting the number of basophils that secrete the Th2 cytokine, IL-4 (224). IRF4 is required for CD4+ T cells to differentiate into Th2 cells (261). 556
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levels of LMP2, TAP1, and MHC I (53, 249), the defect in CD8+ T cell development in Irf1−/− mice does not reside in the thymic environment and is instead due to thymocyteintrinsic defects in differentiation from immature T cells (TCRαβ− CD4+ CD8+ ) to mature CD8+ T cells (250). Further studies using MHC I–restricted TCR transgenic mice (H-Y and P14) reveal that IRF1 controls both the positive and negative selection of CD8+ thymocytes (250). Moreover, Irf1−/− thymocytes are defective in TCR-mediated signal transduction, and the induction of negative selection in TCR transgenic thymocytes from Irf1−/− mice require a 1000-fold higher level of the selecting peptide than that for wild-type mice. Thus, IRF1 may regulate the expression of gene(s) required for lineage commitment and selection of CD8+ T cells in developing thymocytes (250). The introduction of a Bcl2 transgene driven by the Eμ or lck promoter in Irf1−/− mice restores the development of CD8+ T cells (but not NK, NKT, or TCRγδ+ intestinal intraepithelial lymphocytes), suggesting that IRF1 may be required for survival signals involving Bcl2 to support CD8+ T cell development (251). Consistent with the impairment of CD8+ T cell in Irf1−/− mice, the cytotoxic T lymphocyte (CTL) response to LCMV-infected target cells is significantly reduced in these mice. In contrast, Irf2−/− mice show normal CTL activity against LCMV-infected target cells, and some nonspecific cytotoxicity was detected (53). Upon LCMV infection, Irf4−/− mice show no CTL activity against target cells, whereas in Irf8−/− mice CTL responses after VSV and vaccinia virus infection revealed a three- to tenfold reduction of CTL activity (137, 187). Therefore, IRF1, IRF2, IRF4, and IRF8 all contribute to the regulation of CTL activity (Figure 7). The CD8+ T cell abnormality in naive Irf2−/− mice causes a spontaneous inflammatory skin disease resembling psoriasis (53, 252). Irf2−/− CD8+ T cells exhibited a hyperresponsiveness to antigen stimulation in vitro, accompanied by a notable upregulation
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of type I IFN–inducible gene expression. Furthermore, disease development and CD8+ T cell abnormality are suppressed by the introduction of nullizygosity to the genes that positively regulate the type I IFN signaling pathway (252). Thus, IRF2 represents a unique negative regulator that attenuates type I IFNinduced gene transcription and is necessary for balancing the beneficial and harmful effects of type I IFN signaling in the immune system. IRF4 is expressed in mature T cells and is further induced by concanavalin A or CD3 cross-linking in mature T cells (253). In Irf4−/− mice, thymocyte development appears to take place normally, but T cell functions such as cytokine production, cytotoxic activity, and proliferation are abrogated. In addition, adult Irf4−/− mice display progressive lymphadenopathy (137). Two conflicting results have been reported with regard to IRF4 regulation of apoptosis in T cells. One study shows that ectopic expression of IRF4 in the Jurkat human T cell line results in a significant enhancement of Fas-mediated apoptosis and that primary CD4+ T cells from Irf4−/− are defective in activation-induced cell death and in Fas receptor polarization (254). However, another study demonstrated that Irf4−/− CD4+ T cells are highly sensitive to apoptosis by TCR or Fas triggering (255). The latter study further shows that upon Leishmania major infection in Irf4−/− mice, the lesiondraining lymph nodes initially develop typical lymphadenopathy, but that this hyperplasia is followed by enhanced apoptosis and almost total loss of cellularity. Regulation of Th1/Th2 differentiation by IRF1, IRF2, IRF4, and IRF8. IRF1 is indispensable for the development of Th1-type immune responses, and its absence leads to the induction of Th2-type immune responses (233, 256). In fact, Irf1−/− mice are vulnerable to Listeria monocytogenes and Leishmania major, but resistant to Nippostrongylus brasiliensis (233, 256). The compromised Th1 differentiation of CD4+ T cells in Irf1−/− mice is due
to defects in multiple cell types (Figure 7). First, as described above, Irf1−/− Ms and DCs are defective in the induction of IL-12, a cytokine essential for Th1 differentiation, because of the impaired expression of genes encoding IL-12p40 and IL-12p35. Second, Irf1 is a target gene of IL-12 (257, 258), and IRF1 activates the Il12rb1 promoter, rendering Irf1−/− CD4+ T cells hyporesponsive to IL-12 (233, 259). Third, Irf1−/− mice lack NK cells, which produce IFN-γ to stimulate Ms to secrete IL-12 (see above). Unexpectedly, IL-12 production is also suppressed in Irf2−/− Ms (228, 234), and Irf2−/− mice are susceptible to Leishmania major infection owing to a defect in Th1 cell differentiation (234) (Figure 7). IRF2 apparently contributes to IL-12p40 gene expression in cooperation with IRF1 and other factors, rather than functioning as a transcriptional repressor. The defective NK cell differentiation present in Irf2−/− mice likely contributes to the impaired Th1 response (see above). In addition, excessive Th2 polarization in naive Irf2−/− mice is attributed to the expansion of basophils (see above) that produce the Th2 cytokine IL-4. Interestingly, IFN-γ represses the expression of IL-4 via IRF1 and IRF2 to promote Th1 and attenuate Th2 responses (260). IRF8 and IRF4 oppositely regulate Th1/Th2 differentiation (Figure 7). Irf8−/− mice are impaired in developing Th1 responses (214, 215), whereas Irf4−/− mice are defective in mounting Th2 responses (261–263). Although activated T cells express IRF8, Irf8−/− T cells show a capacity for normal Th1/Th2 differentiation when transplanted into Rag2−/− mice (213); thus, the defective Th1 response in Irf8−/− mice is attributed to the defects in Ms and DCs. IRF8 is required for the expression of genes encoding IL-12, as already discussed. In addition, CD8α+ DCs, whose development depends on IRF8, are a major producer of the Th1-promoting cytokine IL-12 and preferentially drive Th1 responses (264, 265). www.annualreviews.org • The IRF Family Transcription Factors
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Irf4−/− T cells, in contrast, are unable to differentiate into Th2 cells. IRF4 stimulates the expression of the Th2-inducing cytokine IL-4 via physical interaction with NFATc2 and/or NFATc1 (262, 266). Naive T helper cells from Irf4−/− mice are defective in the production of IL-4 and other Th2 cytokines. Upon IL-4 treatment in vitro, Irf4−/− CD4+ T cells proliferate poorly and fail to express GATA3, a transcription factor critical for Th2 development, suggesting that IRF4 has a T cell–intrinsic role (261, 263). IRF4 is also required for the development of CD4+ DCs, which may contribute to the defective Th2 responses seen in Irf4−/− mice because they are thought to stimulate Th2 responses (264, 265). Indeed, IRF8 and IRF4 inversely affect the Th1/Th2 balance by regulating DCs (173). Consistent with its role in promoting humoral immune responses, IRF4 is required for the somatic hypermutation and formation of antibody-secreting plasma cells, as described above. Thus, IRF8 and IRF4 participate in and are critical for the induction of cellular and humoral immune responses, respectively.
Regulation of Keratinocyte Development by IRF6 In humans, mutations in the IRF6 gene cause two related disorders, Van der Woude syndrome and popliteal pterygium syndrome. Recently, two groups have shown that mice with null or missense mutations in the Irf6 gene have abnormal skin, limb, and craniofacial development (267, 268). Furthermore, both studies reveal a critical role for IRF6 in keratinocyte development; Irf6 mutant keratinocytes are hyperproliferative and fail to terminally differentiate. Interestingly, mice deficient for IKKα, a kinase involved in the phosphorylation of IRF7 via TLR-MyD88 signaling, display a similar skeletal phenotype as a secondary effect of abnormal keratinocyte differentiation (269), suggesting that IRF6 and IKKα may converge on the same pathway(s). The role of IRF6 in immune responses 558
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is unknown, but given that keratinocytes express functional TLRs and MyD88 and are able to kill pathogenic fungi and bacteria by producing antimicrobial substances (270), the participation of IRF6 in the innate immune function of keratinocytes is an interesting possibility.
REGULATION OF ONCOGENESIS Another critical facet of IRFs’ function in host defense is the regulation of oncogenesis. Indeed, as outlined below, many IRFs, such as IRF1, IRF3, IRF5, and IRF8, possess tumor suppressor gene activities.
IRF1 in Tumor Suppression Regulation of cell cycle and apoptosis by IRF1. The notion that IRFs participate in the regulation of oncogenesis first arose from studies performed on IRF1. The expression of IRF1 is regulated throughout the cell cycle; Irf1 mRNA expression is markedly elevated in NIH3T3 cells subjected to serum starvation but rapidly declines upon seruminduced cell cycle progression (271). Irf1−/− MEFs are deficient in their ability to undergo DNA damage–induced cell cycle arrest, a phenotype similar to that observed in MEFs lacking the tumor suppressor p53 (272). Importantly, transcriptional induction of the gene encoding the CDK inhibitor p21WAF1/CIP1 by gamma irradiation depends on both IRF1 and p53. In such DNA-damaged cells, IRF1 protein level was elevated via an ATM-dependent increase in both mRNA expression and protein half-life, so as to act on the p21 promoter region containing the IRF1- and p53-binding sites (272, 273). Thus, these two transcription factors cooperate in the DNA damage– induced cell cycle arrest by activating a common target gene. Other reports have also demonstrated the involvement of IRF1 in cell growth arrest (274–277). Apoptosis is one mechanism by which precancerous cells can be eliminated from the
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host. IRF1 is required for apoptosis induced by DNA damage or other stimuli. Wild-type MEFs, if introduced with an activated oncogene such as c-Ha-Ras, undergo apoptosis instead of arresting the cell cycle when treated with anticancer drugs or ionizing radiation. This apoptosis is a hallmark of tumor suppression and is dependent on both IRF1 and p53 (278). DNA damage–induced apoptosis in mitogenically activated mature T lymphocytes is dependent on IRF1 but independent of p53 (279, 280), whereas in thymocytes it is dependent on p53 but not on IRF1. Thus, IRF1 and p53 regulate DNA damage–induced apoptosis cooperatively and independently, depending on the type and differentiation stage of the cell. Interestingly, GAAP-1, a transcriptional activator of both IRF1 and p53, has a proapoptotic activity (281). In addition, numerous studies have shown that IRF1 is also essential for apoptosis induced by other stimuli. For example, IRF1 is required for IFN-γ-induced apoptosis in primary cultured hepatocytes (274) and ovarian cancer cells (282) and for IFN-γ-mediated enhancement of Fas/CD95-induced apoptosis (283). The target genes of IRF1 responsible for apoptotic responses have not been firmly identified but may include genes encoding Caspase 1 (280, 282, 284), Caspase 7 (283, 285), Caspase 8 (286), and TRAIL (TNFrelated apoptosis-inducing ligand) (287). Tumor suppressive activity of IRF1. Consistent with the observations described above, a tumor suppressor–like activity for IRF1 has been demonstrated in oncogenic transformation assays using Irf1−/− MEFs. The malignant transformation of normal MEFs, as assessed by formation of colonies in a soft agar and of tumors in nude mice, requires the activities of at least two oncogenes (288). However, the loss of IRF1 and the introduction of activated c-Ha-Ras is sufficient to transform Irf1−/− MEFs (278). Moreover, conditions under which activated Ras inhibits cell growth of myeloid cells involve IRF1 and the induction of p21WAF1/CIP1 (289). Multiple
studies also show that ectopic expression of IRF1 can suppress the malignant properties of cancer cell lines and oncogene-transformed cell lines in vitro and in vivo (290–293). In the mouse, the loss of IRF1 alleles alone rarely induces tumor development (294). However, IRF1 deficiency dramatically exacerbates tumor predispositions caused by the expression of a c-Ha-Ras transgene or by nullizygosity of the p53-encoding gene, Trp53 (294). This accelerated tumor development may not be due to the abovementioned immunological disorders that resulted in the absence of IRF1 because in chimeric mice consisting of Irf1−/− Trp53−/− cells and Trp53−/− cells, generated by the aggregation of their respective embryos, most tumors originate from Irf1−/− Trp53−/− cells (294). In addition to an increased incidence, notable alterations in the relative proportion of the types of tumors observed in Irf1−/− Trp53−/− mice suggest that IRF1 is not hypostatic with respect to p53. Furthermore, Irf1−/− Trp53−/− MEFs are more sensitive to drug-induced mutagenesis and exhibit hyperactive proliferation compared with single-null cells. Thus, Irf1 is a tumor susceptibility gene the loss of which, in combination with other genetic alterations, significantly increases the incidence of tumors. In attempting to clarify the mechanism underlying accelerated tumor susceptibility in the absence of IRF1, the lysyl oxidase (Lox) gene was identified as a target of IRF1 (295). Lox plays a critical role in the biogenesis of connective tissue matrices and is identical to the independently discovered Ras recision gene (rrg) implicated in the reversion of Ras-transformed NIH3T3 cells by preventing activation of NF-κB (296, 297). Ectopic expression of Lox partially suppresses the transformed phenotype of c-Ha-Ras-expressing Irf1−/− MEFs, suggesting that Lox may be one of the IRF1 target genes involved in mediating IRF1’s tumor suppressive activity (295). IRF1 and human cancers. In addition to the functional analyses described above, a number www.annualreviews.org • The IRF Family Transcription Factors
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of clinical studies have indicated that the loss of IRF1 may promote the development of some forms of human cancer, especially leukemia. The IRF1 gene maps to the chromosomal region 5q31.1 (298, 299), a region that frequently shows cytogenetic abnormalities in leukemia and preleukemic myelodysplastic syndrome (MDS) (300). It has been reported that among 13 patients with leukemia or MDS who exhibited cytogenetic abnormalities in this region, IRF1 was the only gene found to be consistently deleted or rearranged in either or both alleles (299). Moreover, 12 of 14 patients with MDS/AML associated with 5q abnormalities also had a loss of one allele of IRF1 (301). In addition to IRF1’s association with hematopoietic malignancies, the loss of one IRF1 allele is correlated with esophageal and gastric cancers (302, 303), and, in one out of four cases of gastric cancers examined, the deletion is accompanied by an inactivating point mutation in the other allele (304). In addition to the genetic alterations at the IRF1 gene per se, several mechanisms lead to the loss-of-function of IRF1. Nucleophosmin, a putative ribosome assembly factor often overexpressed in leukemic cells, binds to IRF1 and inhibits its function (305). Other studies have suggested that splicing aberrations in the IRF1 gene also account for the loss of IRF1 expression (306, 307). A mechanism for inactivation of IRF1 by human papilloma virus (HPV) 16-encoded E7 oncoprotein has also been reported (308). In addition, numerous reports indicate a decreased expression of IRF1 mRNA in several types of cancers, such as CML, breast cancer, endometrial cancer, and hepatocellular carcinoma (307, 309–312).
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Tumor Suppressive Function of IRF5 IRF5 has emerged as another IRF family member that possesses a tumor suppressor ability. Using Irf5−/− mice, a recent study demonstrated that IRF5 is required for DNA damage–induced apoptosis; c-HaRas-expressing Irf5−/− MEFs fail to undergo apoptosis efficiently in response to X-ray ir560
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radiation or anticancer drug treatment (65), and Irf5−/− MEFs undergo malignant transformation upon c-Ha-Ras expression as measured by formation of colonies in a soft agar and by the establishment of tumors in nude mice. However, IRF5 is not necessary for DNA damage–induced cell cycle arrest because Irf5−/− MEFs (without c-Ha-Ras) do stop cell growth in response to the same stimuli as efficiently as do wild-type MEFs. In addition, Irf5−/− MEFs are resistant to VSVinduced apoptosis, resulting in enhanced viral propagation despite the fact that the cells can produce normal levels of type I IFNs and IL-6 (65). Using Ifnar1−/− and Trp53−/− MEFs, it has been shown that Irf5 mRNA is induced upon viral infection through type I IFN signaling and upon DNA damage by p53 (65), the latter of which is consistent with a previous report indicating that the IRF5 gene is a direct target of p53 (313). IRF5 is then activated by an unknown mechanism(s) and translocates to the nucleus where it may regulate apoptosis-related gene(s) (65, 314). Because several p53 targets, such as the genes encoding Puma and Noxa, are induced normally in Irf5−/− MEFs, it is likely that IRF5 acts on an apoptotic pathway distinct from that for p53 (65). Indeed, overexpression of IRF5 inhibits in vitro and in vivo B cell lymphoma tumor growth in the absence of wild type p53 (315), and ectopic expression of IRF5 sensitizes p53-proficient and p53-deficient colon cancer cells to DNA damage–induced apoptosis (314). Interestingly, IRF5 mRNA expression may be suppressed in human leukemia cells (315). Further studies are required to clarify the transcriptional pathway by which IRF5 stimulates apoptosis.
IRF8 and IRF4 in the Regulation of Leukemia Several lines of evidence have indicated an antagonizing relationship between IRF8 and myeloid leukemias, especially CML. Human CML is caused by Bcr/Abl, the
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t(9; 22)-derived fusion oncoprotein with an aberrant kinase activity. As already discussed, Irf8−/− mice develop a CML-like syndrome (187). Consistent with this, IRF8 transcripts are absent in CML and AML patients, and several IRF8 target genes such as Bcl2 and Pml are downregulated in CML cells (205, 207). Moreover, therapeutic IFN-α for human CML induces IRF8 expression in vivo (197), and IRF8 expression correlates positively with pretreatment risk features and cytogenetic response to IFN-α in CML (196). In the laboratory, ectopic expression of IRF8 is able to override the mitogenic activity of Bcr/Abl by activating several genes that interfere with the c-Myc pathway, a downstream target of Bcr/Abl (204) and, in fact, ameliorate Bcr/Abl-mediated murine myeloid leukemia in vivo (316). These data indicate that the loss of IRF8 expression may be a major event leading to the development of human CML and that the restoration of IRF8 expression can antagonize the oncogenic activity of Bcr/Abl. IRF8 appears to exert its antileukemic activity not only by the direct control of cell growth, differentiation, and apoptosis (see above), but also by modulating antitumor immunity. Coexpression of IRF8 in a Bcr/Abltransformed pro-B cell line causes a CD8+ cytotoxic T cell response that prevents the establishment of leukemia in vivo (317). Indeed, it is well established that human CML cells are sensitive to T cell–mediated immunity. Because T cells are stimulated by APCs, IRF8’s ability to support the differentiation and function of Ms and DCs may also be relevant to antitumor immunity. In addition, given that IFN-α therapy is effective in human CML, it is interesting to note that IRF8 is required for the development of pDCs that produce high levels of type I IFNs and that IRF8 is a transcriptional activator of type I IFN genes (52). Interestingly, IRF4 transcript levels are also significantly low in CML patients (318, 319), suggesting that the decreased expression of both IRF8 and IRF4, the two IRFs that cooperatively regulate DC and B cell develop-
ment, may be involved in the pathogenesis of CML. Investigators have suggested that IRF8 manifests antitumor activity even in nonhematopoietic tumors. For instance, IFN-γinduced IRF8 sensitizes human colon carcinoma cells to Fas-mediated apoptosis (320), and IRF8 expression is repressed by DNA methylation in human metastatic colon carcinoma cell lines and murine mammary carcinoma with lung metastasis in vivo (321).
Regulation of Apoptosis by IRF3 One host defense mechanism to prevent viral propagation is apoptosis of virus-infected cells. Virus-induced apoptosis may be mediated by activated IRF3 because, on the one hand, expression of a constitutively active mutant of IRF3 triggered apoptosis, while on the other hand dominant-negative mutants of IRF3 strongly inhibited Sendai virus– and NDV-induced apoptosis (322, 323). Interestingly, data suggest that IRF3-mediated apoptosis is independent of p53 and IFN (323). Instead, the gene encoding TRAIL, which is implicated to be involved in virus-induced apoptosis, has been identified as a potential mediator of IRF3-induced apoptosis because it was transcriptionally activated by ectopic expression of IRF3 (324). IRF3 does not appear to mediate virus-induced apoptosis against all viruses, as VSV-infected Irf3−/− MEFs efficiently undergo apoptosis as efficiently as infected wild-type cells do (65). Interestingly, Irf5−/− MEFs show a defect in VSV-induced apoptosis, suggesting that IRF5 functions in this viral response (65). IRF3 also participates in bacteriuminduced apoptosis. Certain bacteria induce M apoptosis by producing virulence factors that inhibit cell survival pathways such as the p38 or NF-κB pathways, suggesting the existence of a hidden proapoptotic pathway downstream of TLR signaling. A requirement for IRF3 has been shown when Irf3−/− Ms failed to undergo apoptosis induced by LPS in the presence of a p38 inhibitor www.annualreviews.org • The IRF Family Transcription Factors
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or upon Salmonella typhimurium infection (325). Finally, IRF3 may play a role in DNA damage–induced apoptosis. Upon being phosphorylated in response to DNA damaging agents, IRF3 translocates from the cytoplasm to the nucleus and activates transcription (323, 326). One study has provided evidence that DNA-dependent protein kinase (DNA-PK) may be responsible for the phosphorylation of IRF3 in response to DNA damage (327). Consistent with its role in DNA damage–induced apoptosis, IRF3 can inhibit the growth of cancer cell lines in vitro and in vivo, as shown by several overexpression studies (328, 329). It is also interesting that HPV 16’s E6 oncoprotein binds to and inhibits IRF3 transcriptional activity (330). Although further studies are required, these data suggest that IRF3 may function as an additional tumor suppressive IRF.
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IRF9 and Oncogenesis A critical link between type I IFNs and the p53 pathway was recently discovered when type I IFNs transcriptionally activated the tumor suppressor p53 gene through ISGF3; thus, Irf9−/− MEFs fail to upregulate p53 upon IFN-β stimulation (331). This p53 induction is functionally significant because IFN-β suppressed oncogene-induced malignant cell transformation and enhanced DNA damage– induced apoptosis of cancer cells. Further, p53 is required for virus-induced apoptosis. These results indicate a link between type I IFNs and p53 in tumor suppression and antiviral immunity (331). Hence, as a component of ISGF3, IRF9 boosts the p53 pathway when cells are exposed to endogenously induced or exogenously administered type I IFNs. In addition, the Irf9 gene is directly activated by c-Myc, and a cell line lacking IRF9 expression has been shown to be more susceptible to the cytocidal action of anticancer drugs (332). These findings suggest an additional role of IRF9 in cell cycle regulation, 562
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although further work is required to clarify this point.
Oncogenic Potential of IRF2 and IRF4 In addition to its role as an IFN attenuator, the overexpression of IRF2 in NIH3T3 cells causes oncogenic transformation (271). Furthermore, a retroviral library genetic screen has identified IRF2 as an inhibitor of activated N-Ras-induced growth suppression in leukemic cells (333). Although the exact mechanism is unknown, IRF2 may exert its oncogenic function by interfering with IRF1 and/or other IRF family members that bind to the same ISREs (334). Indeed, the concomitant expression of IRF1 in NIH3T3 cells made to overexpress IRF2 revert these cells to a nontransformed phenotype (271). However, IRF2 can also activate gene transcription under certain conditions (335) and, in fact, stimulates the expression of genes involved in oncogenesis such as histone H4 (336, 337). The activity of IRF2 is regulated in a cell growth–dependent manner where IRF2 is acetylated and binds to the H4 promoter in proliferating cells only (338). Several experiments have suggested a connection between IRF4 expression and cancers. In human T cells, the expression of IRF4 mRNA is induced by human T cell leukemia virus-1 (HTLV-1) infection (339). Moreover, overexpression of the HTLV-1 oncoprotein Tax induces IRF4 mRNA expression in Jurkat T cells, and constitutive expression of IRF4 in these T cells results in reduced expression of the G2-M checkpoint gene encoding Cyclin B1 and DNA repair genes encoding Rad51, XRCC1, Yng1, RPA, and PCNA. Such transcriptional changes are strikingly similar to those that occur in HTLV-infected T cells (340, 341), suggesting a possible involvement of IRF4 in HTLV-1-induced leukemogenesis. Interestingly, in some patients with multiple myeloma and cell lines derived from this tumor, a chromosomal translocation t(6;14)(p25;q32) juxtaposes the Ig heavy chain
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locus to IRF4/MUM1 (multiple myeloma 1), resulting in the overexpression of IRF4 (342). IRF4 indeed possesses a transforming activity in vitro; exogenous expression of IRF4 in Rat-1 cells causes anchorage-independent growth (342). However, overexpression of IRF4 alone is not sufficient for leukemogenesis in transgenic mice in lymphocytes (343), suggesting that additional factors are required for the oncogenic activity of IRF4 in vivo.
IMPLICATIONS AND PERSPECTIVES A prompt and controlled cellular response is central to host defense against pathogens and tumors. In this article, we reviewed how the IRF family of transcription factors directly impacts a number of aspects of host defense, from the development and function of a multitude of myeloid and lymphoid tissues to immune activation downstream of PRRs and danger signals. We also discussed how IRF family members exert control over the cell cycle and apoptosis and, thus, are involved in the oncogenesis of several cancers. Clearly, IRF family members do not function in these processes alone and are known to directly and indirectly cooperate and antagonize members of their own family, as well as members of other classes of transcription factors (for details, see Reference 10). Although beyond the main scope of this review and, hence, not touched upon here in more detail, the nature of intermolecular contact between IRFs and other transcription factors is an interesting area for future study. Indeed, it has already been shown that these interactions vary between essentially weak association caused by their independent binding to adjacent target DNA elements, as is known to occur between IRFs and NF-κB (60), to more direct interaction, such as is the case when IRF3 binds to the p65 subunit of NF-κB (also known as REL-A) to transactivate a set of NF-κB-dependent genes without binding to an ISRE (344).
The relationship between IRFs and NFκB is of particular interest because both are activated by a remarkably common set of stimuli, such as PAMPs and DNA damage. Both transcription factors play an essential role in immune cell development and function and, indeed, cooperatively regulate the expression of many cytokine genes. However, IRFs and NF-κB appear to exert opposite effects on cell growth and survival. In contrast to the tumor suppressive effects of IRFs, NF-κB acts as a potent prosurvival transcription factor and contributes to the development of tumors, including inflammation-linked cancers (345, 346). Precisely how these two transcription factor families cooperate and antagonize one another is an important question to be addressed. One evolutionary perspective on IRFs is important to mention. Because type I IFN and IRF genes are present in vertebrates, but not invertebrates, we surmise that they evolved after the divergence of these two branches. Recent studies have suggested that viral infection in invertebrates triggers an RNA-silencingbased antiviral response (also known as RNA interference or RNAi). However, presumably such a response was insufficient to eradicate viruses in proto-vertebrates, thereby creating selective pressure under which the IRF-IFN system evolved. Interestingly, the presence of genes with some sequence similarities to vertebrate IRF and type I IFN receptor genes was reported by the recent genome-wide sequence analyses in the urochordate Ciona intestinalis, an organism that shares a common ancestor with vertebrates (347, 348). This is consistent with the idea that the IRF-IFN system arose at the boundary of early vertebrate evolution. Given that the IRF family is critical for two aspects of host defense—immunity against pathogens and tumor suppression—a more detailed understanding of how the IRF system’s signaling pathways are turned on and off could make the IRF family an attractive target not only for therapy for infectious diseases and immune disorders, but also in the multidisciplinary therapy of cancers. www.annualreviews.org • The IRF Family Transcription Factors
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DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
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We thank Drs. A. Takaoka and K. Honda for valuable discussions and advice. This work was supported by Kakenhi (Grant-in-Aid for Scientific Research) on Priority Areas “Integrative Research Toward the Conquest of Cancer” from the Ministry of Education, Culture, Sports, Science and Technology of Japan. D.S. is a Japan Society for the Promotion of Science postdoctoral fellow.
LITERATURE CITED 1. Mamane Y, Heylbroeck C, Genin P, Algarte M, Servant MJ, et al. 1999. Interferon regulatory factors: the next generation. Gene 237:1–14 2. Taniguchi T, Ogasawara K, Takaoka A, Tanaka N. 2001. IRF family of transcription factors as regulators of host defense. Annu. Rev. Immunol. 19:623–55 3. Nehyba J, Hrdlickova R, Burnside J, Bose HR Jr. 2002. A novel interferon regulatory factor (IRF), IRF-10, has a unique role in immune defense and is induced by the v-Rel oncoprotein. Mol. Cell. Biol. 22:3942–57 4. Veals SA, Schindler C, Leonard D, Fu XY, Aebersold R, et al. 1992. Subunit of an αinterferon-responsive transcription factor is related to interferon regulatory factor and Myb families of DNA-binding proteins. Mol. Cell. Biol. 12:3315–24 5. Darnell JE Jr, Kerr IM, Stark GR. 1994. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415–21 6. Escalante CR, Yie J, Thanos D, Aggarwal AK. 1998. Structure of IRF-1 with bound DNA reveals determinants of interferon regulation. Nature 391:103–6 7. Fujii Y, Shimizu T, Kusumoto M, Kyogoku Y, Taniguchi T, Hakoshima T. 1999. Crystal structure of an IRF-DNA complex reveals novel DNA recognition and cooperative binding to a tandem repeat of core sequences. EMBO J. 18:5028–41 8. Qin BY, Liu C, Srinath H, Lam SS, Correia JJ, et al. 2005. Crystal structure of IRF-3 in complex with CBP. Structure 13:1269–77 9. Takahasi K, Suzuki NN, Horiuchi M, Mori M, Suhara W, et al. 2003. X-ray crystal structure of IRF-3 and its functional implications. Nat. Struct. Biol. 10:922–27 10. Honda K, Takaoka A, Taniguchi T. 2006. Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity 25:349–60 11. Honda K, Taniguchi T. 2006. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat. Rev. Immunol. 6:644–58 12. Lohoff M, Mak TW. 2005. Roles of interferon-regulatory factors in T-helper-cell differentiation. Nat. Rev. Immunol. 5:125–35 13. Ozato K, Tsujimura H, Tamura T. 2002. Toll-like receptor signaling and regulation of cytokine gene expression in the immune system. Biotechniques Suppl.:66–68, 70, 72 14. Janeway CA Jr, Medzhitov R. 2002. Innate immune recognition. Annu. Rev. Immunol. 20:197–216 15. Akira S, Uematsu S, Takeuchi O. 2006. Pathogen recognition and innate immunity. Cell 124:783–801 564
Tamura et al.
Annu. Rev. Immunol. 2008.26:535-584. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-18
ARI
26 February 2008
20:26
16. Fritz JH, Ferrero RL, Philpott DJ, Girardin SE. 2006. Nod-like proteins in immunity, inflammation and disease. Nat. Immunol. 7:1250–57 17. Diebold SS, Montoya M, Unger H, Alexopoulou L, Roy P, et al. 2003. Viral infection switches nonplasmacytoid dendritic cells into high interferon producers. Nature 424:324– 28 18. Honda K, Sakaguchi S, Nakajima C, Watanabe A, Yanai H, et al. 2003. Selective contribution of IFN-α/β signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection. Proc. Natl. Acad. Sci. USA 100:10872–77 19. Andrejeva J, Childs KS, Young DF, Carlos TS, Stock N, et al. 2004. The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-β promoter. Proc. Natl. Acad. Sci. USA 101:17264–69 20. Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, et al. 2005. Cell type-specific involvement of RIG-I in antiviral response. Immunity 23:19–28 21. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, et al. 2006. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–5 22. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, et al. 2004. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5:730–37 23. Dalod M, Salazar-Mather TP, Malmgaard L, Lewis C, Asselin-Paturel C, et al. 2002. Interferon α/β and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo. J. Exp. Med. 195:517–28 24. Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, et al. 2005. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J. Immunol. 175:2851–58 25. Gitlin L, Barchet W, Gilfillan S, Cella M, Beutler B, et al. 2006. Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc. Natl. Acad. Sci. USA 103:8459–64 26. Hornung V, Ellegast J, Kim S, Brzozka K, Jung A, et al. 2006. 5 -Triphosphate RNA is the ligand for RIG-I. Science 314:994–97 27. Pichlmair A, Schulz O, Tan CP, Naslund TI, Liljestrom P, et al. 2006. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5 -phosphates. Science 314:997–1001 28. Malathi K, Dong B, Gale M Jr, Silverman RH. 2007. Small self-RNA generated by RNase L amplifies antiviral innate immunity. Nature 448:816–19 29. Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB. 2005. VISA is an adapter protein required for virus-triggered IFN-β signaling. Mol. Cell 19:727–40 30. Seth RB, Sun L, Ea CK, Chen ZJ. 2005. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF 3. Cell 122:669–82 31. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, et al. 2005. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat. Immunol. 6:981–88 32. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, et al. 2005. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167–72 33. Kumar H, Kawai T, Kato H, Sato S, Takahashi K, et al. 2006. Essential role of IPS-1 in innate immune responses against RNA viruses. J. Exp. Med. 203:1795–803 34. Sun Q, Sun L, Liu HH, Chen X, Seth RB, et al. 2006. The specific and essential role of MAVS in antiviral innate immune responses. Immunity 24:633–42 35. Zhao T, Yang L, Sun Q, Arguello M, Ballard DW, et al. 2007. The NEMO adaptor bridges the nuclear factor-κB and interferon regulatory factor signaling pathways. Nat. Immunol. 8:592–600 www.annualreviews.org • The IRF Family Transcription Factors
565
ARI
26 February 2008
20:26
36. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, et al. 2003. IKKε and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol. 4:491–96 37. Hemmi H, Takeuchi O, Sato S, Yamamoto M, Kaisho T, et al. 2004. The roles of two IκB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J. Exp. Med. 199:1641–50 38. Perry AK, Chow EK, Goodnough JB, Yeh WC, Cheng G. 2004. Differential requirement for TANK-binding kinase-1 in type I interferon responses to Toll-like receptor activation and viral infection. J. Exp. Med. 199:1651–58 39. Sharma S, tenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J. 2003. Triggering the interferon antiviral response through an IKK-related pathway. Science 300:1148–51 40. Oganesyan G, Saha SK, Guo B, He JQ, Shahangian A, et al. 2006. Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 439:208– 11 41. Saha SK, Pietras EM, He JQ, Kang JR, Liu SY, et al. 2006. Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif. EMBO J. 25:3257–63 42. Matsui K, Kumagai Y, Kato H, Sato S, Kawagoe T, et al. 2006. Cutting edge: role of TANK-binding kinase 1 and inducible IκB kinase in IFN responses against viruses in innate immune cells. J. Immunol. 177:5785–89 43. McWhirter SM, Fitzgerald KA, Rosains J, Rowe DC, Golenbock DT, Maniatis T. 2004. IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts. Proc. Natl. Acad. Sci. USA 101:233–38 44. Hoshino K, Sugiyama T, Matsumoto M, Tanaka T, Saito M, et al. 2006. IκB kinase-α is critical for interferon-α production induced by Toll-like receptors 7 and 9. Nature 440:949–53 45. Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, et al. 2005. Interleukin-1 receptorassociated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9mediated interferon-α induction. J. Exp. Med. 201:915–23 46. Barnes BJ, Moore PA, Pitha PM. 2001. Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon α genes. J. Biol. Chem. 276:23382–90 47. Fujita T, Kimura Y, Miyamoto M, Barsoumian EL, Taniguchi T. 1989. Induction of endogenous IFN-α and IFN-β genes by a regulatory transcription factor, IRF-1. Nature 337:270–72 48. Harada H, Fujita T, Miyamoto M, Kimura Y, Maruyama M, et al. 1989. Structurally similar but functionally distinct factors, IRF-1 and IRF-2, bind to the same regulatory elements of IFN and IFN-inducible genes. Cell 58:729–39 49. Marie I, Durbin JE, Levy DE. 1998. Differential viral induction of distinct interferon-α genes by positive feedback through interferon regulatory factor-7. EMBO J. 17:6660–69 50. Sato M, Hata N, Asagiri M, Nakaya T, Taniguchi T, Tanaka N. 1998. Positive feedback regulation of type I IFN genes by the IFN-inducible transcription factor IRF-7. FEBS Lett. 441:106–10 51. Sato M, Tanaka N, Hata N, Oda E, Taniguchi T. 1998. Involvement of the IRF family transcription factor IRF-3 in virus-induced activation of the IFN-β gene. FEBS Lett. 425:112–16 52. Tailor P, Tamura T, Kong HJ, Kubota T, Kubota M, et al. 2007. Type I interferon induction in dendritic cells requires IRF-8 that effects the feedback phase of transcription. Immunity 27:228–39
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ANRV338-IY26-18
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53. Matsuyama T, Kimura T, Kitagawa M, Pfeffer K, Kawakami T, et al. 1993. Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development. Cell 75:83–97 54. Mori M, Yoneyama M, Ito T, Takahashi K, Inagaki F, Fujita T. 2004. Identification of Ser-386 of interferon regulatory factor 3 as critical target for inducible phosphorylation that determines activation. J. Biol. Chem. 279:9698–702 55. Panne D, McWhirter SM, Maniatis T, Harrison SC. 2007. Interferon response factor 3 is regulated by a dual phosphorylation dependent switch. J. Biol. Chem. 282:22816–22 56. Lin R, Heylbroeck C, Pitha PM, Hiscott J. 1998. Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation. Mol. Cell. Biol. 18:2986–96 57. Suhara W, Yoneyama M, Iwamura T, Yoshimura S, Tamura K, et al. 2000. Analyses of virus-induced homomeric and heteromeric protein associations between IRF-3 and coactivator CBP/p300. J. Biochem. 128:301–7 58. Weaver BK, Kumar KP, Reich NC. 1998. Interferon regulatory factor 3 and CREBbinding protein/p300 are subunits of double-stranded RNA-activated transcription factor DRAF1. Mol. Cell. Biol. 18:1359–68 59. Yoneyama M, Suhara W, Fukuhara Y, Fukuda M, Nishida E, Fujita T. 1998. Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300. EMBO J. 17:1087–95 60. Wathelet MG, Lin CH, Parekh BS, Ronco LV, Howley PM, Maniatis T. 1998. Virus infection induces the assembly of coordinately activated transcription factors on the IFNβ enhancer in vivo. Mol. Cell 1:507–18 61. Sato M, Suemori H, Hata N, Asagiri M, Ogasawara K, et al. 2000. Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-α/β gene induction. Immunity 13:539–48 62. Taniguchi T, Takaoka A. 2002. The interferon-α/β system in antiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors. Curr. Opin. Immunol. 14:111–16 63. Erlandsson L, Blumenthal R, Eloranta ML, Engel H, Alm G, et al. 1998. Interferon-β is required for interferon-α production in mouse fibroblasts. Curr. Biol. 8:223–26 64. Honda K, Yanai H, Negishi H, Asagiri M, Sato M, et al. 2005. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434:772–77 65. Yanai H, Chen HM, Inuzuka T, Kondo S, Mak TW, et al. 2007. Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression. Proc. Natl. Acad. Sci. USA 104:3402–7 66. Lin R, Yang L, Arguello M, Penafuerte C, Hiscott J. 2005. A CRM1-dependent nuclear export pathway is involved in the regulation of IRF-5 subcellular localization. J. Biol. Chem. 280:3088–95 67. Jensen KE, Neal AL, Owens RE, Warren J. 1963. Interferon responses of chick embryo fibroblasts to nucleic acids and related compounds. Nature 200:433–34 68. Rotem Z, Cox RA, Isaacs A. 1963. Inhibition of virus multiplication by foreign nucleic acid. Nature 197:564–66 69. Hochrein H, Schlatter B, O’Keeffe M, Wagner C, Schmitz F, et al. 2004. Herpes simplex virus type-1 induces IFN-α production via Toll-like receptor 9-dependent and -independent pathways. Proc. Natl. Acad. Sci. USA 101:11416–21 70. Stockinger S, Reutterer B, Schaljo B, Schellack C, Brunner S, et al. 2004. IFN regulatory factor 3-dependent induction of type I IFNs by intracellular bacteria is mediated by a TLR- and Nod2-independent mechanism. J. Immunol. 173:7416–25 www.annualreviews.org • The IRF Family Transcription Factors
53. Reports the first gene-targeting study of IRFs.
61. Provides evidence for the involvement of IRF3 in type I IFN gene induction upon virus infection.
64. Provides definitive evidence that IRF7 is the main regulator of type I IFN gene induction.
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71. Stetson DB, Medzhitov R. 2006. Recognition of cytosolic DNA activates an IRF3dependent innate immune response. Immunity 24:93–103 72. Ishii KJ, Coban C, Kato H, Takahashi K, Torii Y, et al. 2006. A Toll-like receptorindependent antiviral response induced by double-stranded B-form DNA. Nat. Immunol. 7:40–48 73. Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H, et al. 2007. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448:501–5 74. Fu Y, Comella N, Tognazzi K, Brown LF, Dvorak HF, Kocher O. 1999. Cloning of DLM1, a novel gene that is up-regulated in activated macrophages, using RNA differential display. Gene 240:157–63 75. Ha SC, Van Quyen D, Hwang HY, Oh DB, Brown BA 2nd, et al. 2006. Biochemical characterization and preliminary X-ray crystallographic study of the domains of human ZBP1 bound to left-handed Z-DNA. Biochim. Biophys. Acta 1764:320–23 76. Schwartz T, Behlke J, Lowenhaupt K, Heinemann U, Rich A. 2001. Structure of the DLM-1-Z-DNA complex reveals a conserved family of Z-DNA-binding proteins. Nat. Struct. Biol. 8:761–65 77. Kawai T, Akira S. 2006. TLR signaling. Cell Death Differ. 13:816–25 78. Medzhitov R. 2001. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1:135–45 79. Takeda K, Akira S. 2005. Toll-like receptors in innate immunity. Int. Immunol. 17:1–14 80. O’Neill LA, Bowie AG. 2007. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat. Rev. Immunol. 7:353–64 81. Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, et al. 2001. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413:78–83 82. Fitzgerald KA, Rowe DC, Barnes BJ, Caffrey DR, Visintin A, et al. 2003. LPS-TLR4 signaling to IRF-3/7 and NF-κB involves the Toll adapters TRAM and TRIF. J. Exp. Med. 198:1043–55 83. Medzhitov R, Preston-Hurlburt P, Kopp E, Stadlen A, Chen C, et al. 1998. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol. Cell 2:253–58 84. Oshiumi H, Matsumoto M, Funami K, Akazawa T, Seya T. 2003. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-β induction. Nat. Immunol. 4:161–67 85. Oshiumi H, Sasai M, Shida K, Fujita T, Matsumoto M, Seya T. 2003. TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to Toll-like receptor 4 TICAM-1 that induces interferon-β. J. Biol. Chem. 278:49751–62 86. Wesche H, Henzel WJ, Shillinglaw W, Li S, Cao Z. 1997. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7:837–47 87. Yamamoto M, Sato S, Mori K, Hoshino K, Takeuchi O, et al. 2002. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-β promoter in the Toll-like receptor signaling. J. Immunol. 169:6668–72 88. Moynagh PN. 2005. TLR signalling and activation of IRFs: revisiting old friends from the NF-κB pathway. Trends Immunol. 26:469–76 89. Takeda K, Akira S. 2004. TLR signaling pathways. Semin. Immunol. 16:3–9 90. Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, et al. 2003. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat. Immunol. 4:1144–50 91. Colonna M. 2007. TLR pathways and IFN-regulatory factors: to each its own. Eur. J. Immunol. 37:306–9
Annu. Rev. Immunol. 2008.26:535-584. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-18
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Tamura et al.
Annu. Rev. Immunol. 2008.26:535-584. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-18
ARI
26 February 2008
20:26
92. Meylan E, Tschopp J. 2006. Toll-like receptors and RNA helicases: two parallel ways to trigger antiviral responses. Mol. Cell 22:561–69 93. H¨acker H, Vabulas RM, Takeuchi O, Hoshino K, Akira S, Wagner H. 2000. Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6. J. Exp. Med. 192:595–600 94. O’Neill LA. 2006. How Toll-like receptors signal: what we know and what we don’t know. Curr. Opin. Immunol. 18:3–9 95. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. 2001. TAK1 is a ubiquitindependent kinase of MKK and IKK. Nature 412:346–51 96. Haynes LM, Moore DD, Kurt-Jones EA, Finberg RW, Anderson LJ, Tripp RA. 2001. Involvement of Toll-like receptor 4 in innate immunity to respiratory syncytial virus. J. Virol. 75:10730–37 97. Kurt-Jones EA, Popova L, Kwinn L, Haynes LM, Jones LP, et al. 2000. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat. Immunol. 1:398–401 98. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, et al. 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–88 99. Sakaguchi S, Negishi H, Asagiri M, Nakajima C, Mizutani T, et al. 2003. Essential role of IRF-3 in lipopolysaccharide-induced interferon-β gene expression and endotoxin shock. Biochem. Biophys. Res. Commun. 306:860–66 100. Hoshino K, Kaisho T, Iwabe T, Takeuchi O, Akira S. 2002. Differential involvement of IFN-β in Toll-like receptor-stimulated dendritic cell activation. Int. Immunol. 14:1225–31 101. Kawai T, Takeuchi O, Fujita T, Inoue J, Muhlradt PF, et al. 2001. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J. Immunol. 167:5887–94 102. Hoebe K, Du X, Georgel P, Janssen E, Tabeta K, et al. 2003. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424:743–48 103. Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, et al. 2003. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301:640–43 104. H¨acker H, Karin M. 2006. Regulation and function of IKK and IKK-related kinases. Science STKE 2006:re13 105. Werner SL, Barken D, Hoffmann A. 2005. Stimulus specificity of gene expression programs determined by temporal control of IKK activity. Science 309:1857–61 106. Karaghiosoff M, Steinborn R, Kovarik P, Kriegshauser G, Baccarini M, et al. 2003. Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock. Nat. Immunol. 4:471–77 107. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. 2001. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413:732–38 108. Rudd BD, Smit JJ, Flavell RA, Alexopoulou L, Schaller MA, et al. 2006. Deletion of TLR3 alters the pulmonary immune environment and mucus production during respiratory syncytial virus infection. J. Immunol. 176:1937–42 109. Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA. 2004. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat. Med. 10:1366–73 110. Aksoy E, Zouain CS, Vanhoutte F, Fontaine J, Pavelka N, et al. 2005. Double-stranded RNAs from the helminth parasite Schistosoma activate TLR3 in dendritic cells. J. Biol. Chem. 280:277–83 www.annualreviews.org • The IRF Family Transcription Factors
569
ARI
26 February 2008
20:26
111. Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, et al. 2007. TLR3 deficiency in patients with herpes simplex encephalitis. Science 317:1522–27 112. Flandin JF, Chano F, Descoteaux A. 2006. RNA interference reveals a role for TLR2 and TLR3 in the recognition of Leishmania donovani promastigotes by interferon-γ-primed macrophages. Eur. J. Immunol. 36:411–20 113. Tabeta K, Georgel P, Janssen E, Du X, Hoebe K, et al. 2004. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc. Natl. Acad. Sci. USA 101:3516–21 114. Asselin-Paturel C, Boonstra A, Dalod M, Durand I, Yessaad N, et al. 2001. Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat. Immunol. 2:1144–50 115. Colonna M, Trinchieri G, Liu YJ. 2004. Plasmacytoid dendritic cells in immunity. Nat. Immunol. 5:1219–26 116. Nakano H, Yanagita M, Gunn MD. 2001. CD11c+ B220+ Gr-1+ cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells. J. Exp. Med. 194:1171–78 117. Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A. 2003. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J. Exp. Med. 198:513–20 118. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. 2004. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–31 119. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, et al. 2004. Speciesspecific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303:1526–29 120. Krug A, Luker GD, Barchet W, Leib DA, Akira S, Colonna M. 2004. Herpes simplex virus type 1 activates murine natural interferon-producing cells through Toll-like receptor 9. Blood 103:1433–37 121. Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW, Iwasaki A, Flavell RA. 2004. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl. Acad. Sci. USA 101:5598–603 122. Hemmi H, Kaisho T, Takeda K, Akira S. 2003. The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J. Immunol. 170:3059–64 123. Honda K, Yanai H, Mizutani T, Negishi H, Shimada N, et al. 2004. Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Tolllike receptor signaling. Proc. Natl. Acad. Sci. USA 101:15416–21 124. Kawai T, Sato S, Ishii KJ, Coban C, Hemmi H, et al. 2004. Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat. Immunol. 5:1061–68 125. Shinohara ML, Lu L, Bu J, Werneck MB, Kobayashi KS, et al. 2006. Osteopontin expression is essential for interferon-α production by plasmacytoid dendritic cells. Nat. Immunol. 7:498–506 126. Izaguirre A, Barnes BJ, Amrute S, Yeow WS, Megjugorac N, et al. 2003. Comparative analysis of IRF and IFN-α expression in human plasmacytoid and monocyte-derived dendritic cells. J. Leukoc. Biol. 74:1125–38 127. Guiducci C, Ott G, Chan JH, Damon E, Calacsan C, et al. 2006. Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation. J. Exp. Med. 203:1999–2008
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128. Honda K, Ohba Y, Yanai H, Negishi H, Mizutani T, et al. 2005. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434:1035–40 129. Yasuda K, Rutz M, Schlatter B, Metzger J, Luppa PB, et al. 2006. CpG motif-independent activation of TLR9 upon endosomal translocation of “natural” phosphodiester DNA. Eur. J. Immunol. 36:431–36 130. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, et al. 2005. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434:243–49 131. Ouyang X, Negishi H, Takeda R, Fujita Y, Taniguchi T, Honda K. 2007. Cooperation between MyD88 and TRIF pathways in TLR synergy via IRF5 activation. Biochem. Biophys. Res. Commun. 354:1045–51 132. Yasuda K, Richez C, Maciaszek JW, Agrawal N, Akira S, et al. 2007. Murine dendritic cell type I IFN production induced by human IgG-RNA immune complexes is IFN regulatory factor (IRF)5 and IRF7 dependent and is required for IL-6 production. J. Immunol. 178:6876–85 133. Negishi H, Ohba Y, Yanai H, Takaoka A, Honma K, et al. 2005. Negative regulation of Toll-like-receptor signaling by IRF-4. Proc. Natl. Acad. Sci. USA 102:15989–94 134. Negishi H, Fujita Y, Yanai H, Sakaguchi S, Ouyang X, et al. 2006. Evidence for licensing of IFN-γ-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program. Proc. Natl. Acad. Sci. USA 103:15136–41 135. Honma K, Udono H, Kohno T, Yamamoto K, Ogawa A, et al. 2005. Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macrophages in response to LPS. Proc. Natl. Acad. Sci. USA 102:16001–6 136. Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, et al. 1995. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–49 137. Mittrucker HW, Matsuyama T, Grossman A, Kundig TM, Potter J, et al. 1997. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 275:540–43 138. Suzuki S, Honma K, Matsuyama T, Suzuki K, Toriyama K, et al. 2004. Critical roles of interferon regulatory factor 4 in CD11bhigh CD8α− dendritic cell development. Proc. Natl. Acad. Sci. USA 101:8981–86 139. Tsujimura H, Tamura T, Kong HJ, Nishiyama A, Ishii KJ, et al. 2004. Toll-like receptor 9 signaling activates NF-κB through IFN regulatory factor-8/IFN consensus sequence binding protein in dendritic cells. J. Immunol. 172:6820–27 140. Zhao J, Kong HJ, Li H, Huang B, Yang M, et al. 2006. IRF-8/interferon (IFN) consensus sequence-binding protein is involved in Toll-like receptor (TLR) signaling and contributes to the cross-talk between TLR and IFN-γ signaling pathways. J. Biol. Chem. 281:10073–80 141. Masumi A, Tamaoki S, Wang IM, Ozato K, Komuro K. 2002. IRF-8/ICSBP and IRF1 cooperatively stimulate mouse IL-12 promoter activity in macrophages. FEBS Lett. 531:348–53 142. Schiavoni G, Mattei F, Sestili P, Borghi P, Venditti M, et al. 2002. ICSBP is essential for the development of mouse type I interferon-producing cells and for the generation and activation of CD8α+ dendritic cells. J. Exp. Med. 196:1415–25 143. Tsujimura H, Tamura T, Gongora C, Aliberti J, Reis e Sousa C, et al. 2003. ICSBP/IRF-8 retrovirus transduction rescues dendritic cell development in vitro. Blood 101:961–69 144. Wang IM, Contursi C, Masumi A, Ma X, Trinchieri G, Ozato K. 2000. An IFN-γinducible transcription factor, IFN consensus sequence binding protein (ICSBP), stimulates IL-12 p40 expression in macrophages. J. Immunol. 165:271–79 www.annualreviews.org • The IRF Family Transcription Factors
130. Shows that IRF5 is essential for TLR-mediated induction of proinflammatory cytokines.
137. Describes the phenotype of mice deficient in Irf4, indicating its role in lymphocyte development and function.
571
ARI
26 February 2008
20:26
145. Zhu C, Rao K, Xiong H, Gagnidze K, Li F, et al. 2003. Activation of the murine interleukin-12 p40 promoter by functional interactions between NFAT and ICSBP. J. Biol. Chem. 278:39372–82 146. DiPerna G, Stack J, Bowie AG, Boyd A, Kotwal G, et al. 2004. Poxvirus protein N1L targets the I-κB kinase complex, inhibits signaling to NF-κB by the tumor necrosis factor superfamily of receptors, and inhibits NF-κB and IRF3 signaling by Toll-like receptors. J. Biol. Chem. 279:36570–78 147. Li K, Foy E, Ferreon JC, Nakamura M, Ferreon AC, et al. 2005. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc. Natl. Acad. Sci. USA 102:2992–97 148. Seth RB, Sun L, Chen ZJ. 2006. Antiviral innate immunity pathways. Cell Res. 16:141–47 149. Lin R, Noyce RS, Collins SE, Everett RD, Mossman KL. 2004. The herpes simplex virus ICP0 RING finger domain inhibits IRF3- and IRF7-mediated activation of interferonstimulated genes. J. Virol. 78:1675–84 150. Barro M, Patton JT. 2007. Rotavirus NSP1 inhibits expression of type I interferon by antagonizing the function of interferon regulatory factors IRF3, IRF5, and IRF7. J. Virol. 81:4473–81 151. Graff JW, Mitzel DN, Weisend CM, Flenniken ML, Hardy ME. 2002. Interferon regulatory factor 3 is a cellular partner of rotavirus NSP1. J. Virol. 76:9545–50 152. Yu Y, Wang SE, Hayward GS. 2005. The KSHV immediate-early transcription factor RTA encodes ubiquitin E3 ligase activity that targets IRF7 for proteosome-mediated degradation. Immunity 22:59–70 153. Gao SJ, Boshoff C, Jayachandra S, Weiss RA, Chang Y, Moore PS. 1997. KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway. Oncogene 15:1979– 85 154. Offermann MK. 2007. Kaposi sarcoma herpesvirus-encoded interferon regulator factors. Curr. Top. Microbiol. Immunol. 312:185–209 155. Paun A, Pitha PM. 2007. The IRF family, revisited. Biochimie 89:744–53 156. Russo JJ, Bohenzky RA, Chien MC, Chen J, Yan M, et al. 1996. Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8). Proc. Natl. Acad. Sci. USA 93:14862– 67 157. Burysek L, Yeow WS, Lubyova B, Kellum M, Schafer SL, et al. 1999. Functional analysis of human herpesvirus 8-encoded viral interferon regulatory factor 1 and its association with cellular interferon regulatory factors and p300. J. Virol. 73:7334–42 158. Li M, Damania B, Alvarez X, Ogryzko V, Ozato K, Jung JU. 2000. Inhibition of p300 histone acetyltransferase by viral interferon regulatory factor. Mol. Cell. Biol. 20:8254–63 159. Lin R, Genin P, Mamane Y, Sgarbanti M, Battistini A, et al. 2001. HHV-8 encoded vIRF-1 represses the interferon antiviral response by blocking IRF-3 recruitment of the CBP/p300 coactivators. Oncogene 20:800–11 160. Burysek L, Yeow WS, Pitha PM. 1999. Unique properties of a second human herpesvirus 8-encoded interferon regulatory factor (vIRF-2). J. Hum. Virol. 2:19–32 161. Joo CH, Shin YC, Gack M, Wu L, Levy D, Jung JU. 2007. Inhibition of interferon regulatory factor 7 (IRF7)-mediated interferon signal transduction by the Kaposi’s sarcomaassociated herpesvirus viral IRF homolog vIRF3. J. Virol. 81:8282–92 162. Boule MW, Broughton C, Mackay F, Akira S, Marshak-Rothstein A, Rifkin IR. 2004. Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatinimmunoglobulin G complexes. J. Exp. Med. 199:1631–40
Annu. Rev. Immunol. 2008.26:535-584. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-18
572
Tamura et al.
Annu. Rev. Immunol. 2008.26:535-584. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-18
ARI
26 February 2008
20:26
163. Lau CM, Broughton C, Tabor AS, Akira S, Flavell RA, et al. 2005. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202:1171–77 164. Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, MarshakRothstein A. 2002. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:603–7 165. Ronnblom L, Alm GV. 2003. Systemic lupus erythematosus and the type I interferon system. Arthritis Res. Ther. 5:68–75 166. Vollmer J, Tluk S, Schmitz C, Hamm S, Jurk M, et al. 2005. Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8. J. Exp. Med. 202:1575–85 167. Graham RR, Kozyrev SV, Baechler EC, Reddy MV, Plenge RM, et al. 2006. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat. Genet. 38:550–55 168. Sigurdsson S, Nordmark G, Goring HH, Lindroos K, Wiman AC, et al. 2005. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am. J. Hum. Genet. 76:528–37 169. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, et al. 2000. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18:767–811 170. Ardavin C. 2003. Origin, precursors and differentiation of mouse dendritic cells. Nat. Rev. Immunol. 3:582–90 171. Shortman K, Liu YJ. 2002. Mouse and human dendritic cell subtypes. Nat. Rev. Immunol. 2:151–61 172. Edwards AD, Chaussabel D, Tomlinson S, Schulz O, Sher A, Reis e Sousa C. 2003. Relationships among murine CD11chigh dendritic cell subsets as revealed by baseline gene expression patterns. J. Immunol. 171:47–60 173. Tamura T, Tailor P, Yamaoka K, Kong HJ, Tsujimura H, et al. 2005. IFN regulatory factor-4 and -8 govern dendritic cell subset development and their functional diversity. J. Immunol. 174:2573–81 174. Tsujimura H, Tamura T, Ozato K. 2003. Cutting edge: IFN consensus sequence binding protein/IFN regulatory factor 8 drives the development of type I IFN-producing plasmacytoid dendritic cells. J. Immunol. 170:1131–35 175. Aliberti J, Schulz O, Pennington DJ, Tsujimura H, Reis e Sousa C, et al. 2003. Essential role for ICSBP in the in vivo development of murine CD8α+ dendritic cells. Blood 101:305–10 176. Schiavoni G, Mattei F, Borghi P, Sestili P, Venditti M, et al. 2004. ICSBP is critically involved in the normal development and trafficking of Langerhans cells and dermal dendritic cells. Blood 103:2221–28 177. Liu J, Guan X, Tamura T, Ozato K, Ma X. 2004. Synergistic activation of interleukin12 p35 gene transcription by interferon regulatory factor-1 and interferon consensus sequence-binding protein. J. Biol. Chem. 279:55609–17 178. Orabona C, Puccetti P, Vacca C, Bicciato S, Luchini A, et al. 2006. Toward the identification of a tolerogenic signature in IDO-competent dendritic cells. Blood 107:2846–54 179. Honda K, Mizutani T, Taniguchi T. 2004. Negative regulation of IFN-α/β signaling by IFN regulatory factor 2 for homeostatic development of dendritic cells. Proc. Natl. Acad. Sci. USA 101:2416–21 180. Ichikawa E, Hida S, Omatsu Y, Shimoyama S, Takahara K, et al. 2004. Defective development of splenic and epidermal CD4+ dendritic cells in mice deficient for IFN regulatory factor-2. Proc. Natl. Acad. Sci. USA 101:3909–14 www.annualreviews.org • The IRF Family Transcription Factors
573
Annu. Rev. Immunol. 2008.26:535-584. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-18
ARI
26 February 2008
187. Describes the phenotype of Irf8/Icsbp−/− mice, revealing an unexpected role of IRF8 in hematopoietic cell growth, differentiation, and function.
574
20:26
181. Santini SM, Lapenta C, Logozzi M, Parlato S, Spada M, et al. 2000. Type I interferon as a powerful adjuvant for monocyte-derived dendritic cell development and activity in vitro and in Hu-PBL-SCID mice. J. Exp. Med. 191:1777–88 182. Gabriele L, Fragale A, Borghi P, Sestili P, Stellacci E, et al. 2006. IRF-1 deficiency skews the differentiation of dendritic cells toward plasmacytoid and tolerogenic features. J. Leukoc. Biol. 80:1500–11 183. Ahn JH, Lee Y, Jeon C, Lee SJ, Lee BH, et al. 2002. Identification of the genes differentially expressed in human dendritic cell subsets by cDNA subtraction and microarray analysis. Blood 100:1742–54 184. Ju XS, Ruau D, Jantti P, Sere K, Becker C, et al. 2007. Transforming growth factor β1 up-regulates interferon regulatory factor 8 during dendritic cell development. Eur. J. Immunol. 37:1174–83 185. Lehtonen A, Veckman V, Nikula T, Lahesmaa R, Kinnunen L, et al. 2005. Differential expression of IFN regulatory factor 4 gene in human monocyte-derived dendritic cells and macrophages. J. Immunol. 175:6570–79 186. Zenke M, Hieronymus T. 2006. Towards an understanding of the transcription factor network of dendritic cell development. Trends Immunol. 27:140–45 187. Holtschke T, Lohler J, Kanno Y, Fehr T, Giese N, et al. 1996. Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell 87:307–17 188. Turcotte K, Gauthier S, Tuite A, Mullick A, Malo D, Gros P. 2005. A mutation in the Icsbp1 gene causes susceptibility to infection and a chronic myeloid leukemia-like syndrome in BXH-2 mice. J. Exp. Med. 201:881–90 189. Scheller M, Foerster J, Heyworth CM, Waring JF, Lohler J, et al. 1999. Altered development and cytokine responses of myeloid progenitors in the absence of transcription factor, interferon consensus sequence binding protein. Blood 94:3764–71 190. Tamura T, Nagamura-Inoue T, Shmeltzer Z, Kuwata T, Ozato K. 2000. ICSBP directs bipotential myeloid progenitor cells to differentiate into mature macrophages. Immunity 13:155–65 191. Tsujimura H, Nagamura-Inoue T, Tamura T, Ozato K. 2002. IFN consensus sequence binding protein/IFN regulatory factor-8 guides bone marrow progenitor cells toward the macrophage lineage. J. Immunol. 169:1261–69 192. Qian Z, Fernald AA, Godley LA, Larson RA, Le Beau MM. 2002. Expression profiling of CD34+ hematopoietic stem/progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia. Proc. Natl. Acad. Sci. USA 99:14925–30 193. Gabriele L, Phung J, Fukumoto J, Segal D, Wang IM, et al. 1999. Regulation of apoptosis in myeloid cells by interferon consensus sequence-binding protein. J. Exp. Med. 190:411– 21 194. Kallies A, Rosenbauer F, Scheller M, Knobeloch KP, Horak I. 2002. Accumulation of cCbl and rapid termination of colony-stimulating factor 1 receptor signaling in interferon consensus sequence binding protein-deficient bone marrow-derived macrophages. Blood 99:3213–19 195. Diaz-Blanco E, Bruns I, Neumann F, Fischer JC, Graef T, et al. 2007. Molecular signature of CD34+ hematopoietic stem and progenitor cells of patients with CML in chronic phase. Leukemia 21:494–504 196. Schmidt M, Hochhaus A, Nitsche A, Hehlmann R, Neubauer A. 2001. Expression of nuclear transcription factor interferon consensus sequence binding protein in chronic myeloid leukemia correlates with pretreatment risk features and cytogenetic response to interferon-α. Blood 97:3648–50 Tamura et al.
Annu. Rev. Immunol. 2008.26:535-584. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-18
ARI
26 February 2008
20:26
197. Schmidt M, Nagel S, Proba J, Thiede C, Ritter M, et al. 1998. Lack of interferon consensus sequence binding protein (ICSBP) transcripts in human myeloid leukemias. Blood 91:22– 29 198. Kanno Y, Levi BZ, Tamura T, Ozato K. 2005. Immune cell-specific amplification of interferon signaling by the IRF-4/8-PU.1 complex. J. Interferon Cytokine Res. 25:770–79 199. Tamura T, Ozato K. 2002. ICSBP/IRF-8: its regulatory roles in the development of myeloid cells. J. Interferon Cytokine Res. 22:145–52 200. Kuwata T, Gongora C, Kanno Y, Sakaguchi K, Tamura T, et al. 2002. Gamma interferon triggers interaction between ICSBP (IRF-8) and TEL, recruiting the histone deacetylase HDAC3 to the interferon-responsive element. Mol. Cell. Biol. 22:7439–48 201. Tamura T, Thotakura P, Tanaka TS, Ko MS, Ozato K. 2005. Identification of target genes and a unique cis element regulated by IRF-8 in developing macrophages. Blood 106:1938–47 202. Schmidt M, Bies J, Tamura T, Ozato K, Wolff L. 2004. The interferon regulatory factor ICSBP/IRF-8 in combination with PU.1 up-regulates expression of tumor suppressor p15(Ink4b) in murine myeloid cells. Blood 103:4142–49 203. Zhu C, Saberwal G, Lu Y, Platanias LC, Eklund EA. 2004. The interferon consensus sequence-binding protein activates transcription of the gene encoding neurofibromin 1. J. Biol. Chem. 279:50874–85 204. Tamura T, Kong HJ, Tunyaplin C, Tsujimura H, Calame K, Ozato K. 2003. ICSBP/IRF8 inhibits mitogenic activity of p210 Bcr/Abl in differentiating myeloid progenitor cells. Blood 102:4547–54 205. Burchert A, Cai D, Hofbauer LC, Samuelsson MK, Slater EP, et al. 2004. Interferon consensus sequence binding protein (ICSBP; IRF-8) antagonizes BCR/ABL and downregulates bcl-2. Blood 103:3480–89 206. Huang W, Saberwal G, Horvath E, Zhu C, Lindsey S, Eklund EA. 2006. Leukemiaassociated, constitutively active mutants of SHP2 protein tyrosine phosphatase inhibit NF1 transcriptional activation by the interferon consensus sequence binding protein. Mol. Cell. Biol. 26:6311–32 207. Dror N, Rave-Harel N, Burchert A, Azriel A, Tamura T, et al. 2007. Interferon regulatory factor-8 is indispensable for the expression of promyelocytic leukemia and the formation of nuclear bodies in myeloid cells. J. Biol. Chem. 282:5633–40 208. Rosenbauer F, Kallies A, Scheller M, Knobeloch KP, Rock CO, et al. 2002. Disabled-2 is transcriptionally regulated by ICSBP and augments macrophage spreading and adhesion. EMBO J. 21:211–20 209. Contursi C, Wang IM, Gabriele L, Gadina M, O’Shea J, et al. 2000. IFN consensus sequence binding protein potentiates STAT1-dependent activation of IFNγ-responsive promoters in macrophages. Proc. Natl. Acad. Sci. USA 97:91–96 210. Alter-Koltunoff M, Ehrlich S, Dror N, Azriel A, Eilers M, et al. 2003. Nramp1-mediated innate resistance to intraphagosomal pathogens is regulated by IRF-8, PU.1, and Miz-1. J. Biol. Chem. 278:44025–32 211. Levi BZ, Hashmueli S, Gleit-Kielmanowicz M, Azriel A, Meraro D. 2002. ICSBP/IRF-8 transactivation: a tale of protein-protein interaction. J. Interferon Cytokine Res. 22:153–60 212. Liu J, Ma X. 2006. Interferon regulatory factor 8 regulates RANTES gene transcription in cooperation with interferon regulatory factor-1, NF-κB, and PU.1. J. Biol. Chem. 281:19188–95 213. Fehr T, Schoedon G, Odermatt B, Holtschke T, Schneemann M, et al. 1997. Crucial role of interferon consensus sequence binding protein, but neither of interferon regulatory www.annualreviews.org • The IRF Family Transcription Factors
575
ANRV338-IY26-18
ARI
26 February 2008
214.
215.
Annu. Rev. Immunol. 2008.26:535-584. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
216.
217.
218.
219. 220.
221.
222. 223.
224. 225. 226.
227. 228.
229.
576
20:26
factor 1 nor of nitric oxide synthesis for protection against murine listeriosis. J. Exp. Med. 185:921–31 Scharton-Kersten T, Contursi C, Masumi A, Sher A, Ozato K. 1997. Interferon consensus sequence binding protein-deficient mice display impaired resistance to intracellular infection due to a primary defect in interleukin 12 p40 induction. J. Exp. Med. 186:1523– 34 Giese NA, Gabriele L, Doherty TM, Klinman DM, Tadesse-Heath L, et al. 1997. Interferon (IFN) consensus sequence-binding protein, a transcription factor of the IFN regulatory factor family, regulates immune responses in vivo through control of interleukin 12 expression. J. Exp. Med. 186:1535–46 Hein J, Kempf VA, Diebold J, Bucheler N, Preger S, et al. 2000. Interferon consensus sequence binding protein confers resistance against Yersinia enterocolitica. Infect. Immun. 68:1408–17 Ko J, Gendron-Fitzpatrick A, Splitter GA. 2002. Susceptibility of IFN regulatory factor-1 and IFN consensus sequence binding protein-deficient mice to brucellosis. J. Immunol. 168:2433–40 Abdollahi A, Lord KA, Hoffman-Liebermann B, Liebermann DA. 1991. Interferon regulatory factor 1 is a myeloid differentiation primary response gene induced by interleukin 6 and leukemia inhibitory factor: role in growth inhibition. Cell Growth Differ. 2:401–7 Testa U, Stellacci E, Pelosi E, Sestili P, Venditti M, et al. 2004. Impaired myelopoiesis in mice devoid of interferon regulatory factor 1. Leukemia 18:1864–71 Blanco JC, Contursi C, Salkowski CA, DeWitt DL, Ozato K, Vogel SN. 2000. Interferon regulatory factor (IRF)-1 and IRF-2 regulate interferon γ-dependent cyclooxygenase 2 expression. J. Exp. Med. 191:2131–44 Kamijo R, Harada H, Matsuyama T, Bosland M, Gerecitano J, et al. 1994. Requirement for transcription factor IRF-1 in NO synthase induction in macrophages. Science 263:1612–15 Kimura T, Nakayama K, Penninger J, Kitagawa M, Harada H, et al. 1994. Involvement of the IRF-1 transcription factor in antiviral responses to interferons. Science 264:1921–24 Hobart M, Ramassar V, Goes N, Urmson J, Halloran PF. 1997. IFN regulatory factor-1 plays a central role in the regulation of the expression of class I and II MHC genes in vivo. J. Immunol. 158:4260–69 Hida S, Tadachi M, Saito T, Taki S. 2005. Negative control of basophil expansion by IRF-2 critical for the regulation of Th1/Th2 balance. Blood 106:2011–17 Stellacci E, Testa U, Petrucci E, Benedetti E, Orsatti R, et al. 2004. Interferon regulatory factor-2 drives megakaryocytic differentiation. Biochem. J. 377:367–78 Cuesta N, Nhu QM, Zudaire E, Polumuri S, Cuttitta F, Vogel SN. 2007. IFN regulatory factor-2 regulates macrophage apoptosis through a STAT1/3- and caspase-1-dependent mechanism. J. Immunol. 178:3602–11 Cuesta N, Salkowski CA, Thomas KE, Vogel SN. 2003. Regulation of lipopolysaccharide sensitivity by IFN regulatory factor-2. J. Immunol. 170:5739–47 Salkowski CA, Kopydlowski K, Blanco J, Cody MJ, McNally R, Vogel SN. 1999. IL12 is dysregulated in macrophages from IRF-1 and IRF-2 knockout mice. J. Immunol. 163:1529–36 Zhang S, Thomas K, Blanco JC, Salkowski CA, Vogel SN. 2002. The role of the interferon regulatory factors, IRF-1 and IRF-2, in LPS-induced cyclooxygenase-2 (COX-2) expression in vivo and in vitro. J. Endotoxin Res. 8:379–88
Tamura et al.
Annu. Rev. Immunol. 2008.26:535-584. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-18
ARI
26 February 2008
20:26
230. Duncan GS, Mittrucker HW, Kagi D, Matsuyama T, Mak TW. 1996. The transcription factor interferon regulatory factor-1 is essential for natural killer cell function in vivo. J. Exp. Med. 184:2043–48 231. Ogasawara K, Hida S, Azimi N, Tagaya Y, Sato T, et al. 1998. Requirement for IRF-1 in the microenvironment supporting development of natural killer cells. Nature 391:700–3 232. Ohteki T, Yoshida H, Matsuyama T, Duncan GS, Mak TW, Ohashi PS. 1998. The transcription factor interferon regulatory factor 1 (IRF-1) is important during the maturation of natural killer 1.1+ T cell receptor-α/β +(NK1+ T) cells, natural killer cells, and intestinal intraepithelial T cells. J. Exp. Med. 187:967–72 233. Taki S, Sato T, Ogasawara K, Fukuda T, Sato M, et al. 1997. Multistage regulation of Th1-type immune responses by the transcription factor IRF-1. Immunity 6:673–79 234. Lohoff M, Duncan GS, Ferrick D, Mittrucker HW, Bischof S, et al. 2000. Deficiency in the transcription factor interferon regulatory factor (IRF)-2 leads to severely compromised development of natural killer and T helper type 1 cells. J. Exp. Med. 192:325–36 235. Taki S, Nakajima S, Ichikawa E, Saito T, Hida S. 2005. IFN regulatory factor-2 deficiency revealed a novel checkpoint critical for the generation of peripheral NK cells. J. Immunol. 174:6005–12 236. Cattoretti G, Shaknovich R, Smith PM, Jack HM, Murty VV, Alobeid B. 2006. Stages of germinal center transit are defined by B cell transcription factor coexpression and relative abundance. J. Immunol. 177:6930–39 237. Nelson N, Kanno Y, Hong C, Contursi C, Fujita T, et al. 1996. Expression of IFN regulatory factor family proteins in lymphocytes. Induction of Stat-1 and IFN consensus sequence binding protein expression by T cell activation. J. Immunol. 156:3711–20 238. Lu R, Medina KL, Lancki DW, Singh H. 2003. IRF-4,8 orchestrate the pre-B-to-B transition in lymphocyte development. Genes Dev. 17:1703–8 239. Ma S, Turetsky A, Trinh L, Lu R. 2006. IFN regulatory factor 4 and 8 promote Ig light chain κ locus activation in pre-B cell development. J. Immunol. 177:7898–904 240. Eisenbeis CF, Singh H, Storb U. 1995. Pip, a novel IRF family member, is a lymphoidspecific, PU.1-dependent transcriptional activator. Genes Dev. 9:1377–87 241. Marecki S, Fenton MJ. 2002. The role of IRF-4 in transcriptional regulation. J. Interferon Cytokine Res. 22:121–33 242. Falini B, Fizzotti M, Pucciarini A, Bigerna B, Marafioti T, et al. 2000. A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4 protein in a subset of germinal center B cells, plasma cells, and activated T cells. Blood 95:2084–92 243. Lee CH, Melchers M, Wang H, Torrey TA, Slota R, et al. 2006. Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein. J. Exp. Med. 203:63–72 244. Sciammas R, Shaffer AL, Schatz JH, Zhao H, Staudt LM, Singh H. 2006. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 25:225–36 245. Zhan F, Tian E, Bumm K, Smith R, Barlogie B, Shaughnessy J Jr. 2003. Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development. Blood 101:1128–40 246. Klein U, Casola S, Cattoretti G, Shen Q, Lia M, et al. 2006. Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat. Immunol. 7:773– 82 247. Shapiro-Shelef M, Calame K. 2005. Regulation of plasma-cell development. Nat. Rev. Immunol. 5:230–42 www.annualreviews.org • The IRF Family Transcription Factors
577
ARI
26 February 2008
20:26
248. Gupta S, Jiang M, Anthony A, Pernis AB. 1999. Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4. J. Exp. Med. 190:1837–48 249. White LC, Wright KL, Felix NJ, Ruffner H, Reis LF, et al. 1996. Regulation of LMP2 and TAP1 genes by IRF-1 explains the paucity of CD8+ T cells in IRF-1−/− mice. Immunity 5:365–76 250. Penninger JM, Sirard C, Mittrucker HW, Chidgey A, Kozieradzki I, et al. 1997. The interferon regulatory transcription factor IRF-1 controls positive and negative selection of CD8+ thymocytes. Immunity 7:243–54 251. Ohteki T, Maki C, Koyasu S. 2001. Overexpression of Bcl-2 differentially restores development of thymus-derived CD4–8+ T cells and intestinal intraepithelial T cells in IFN-regulatory factor-1-deficient mice. J. Immunol. 166:6509–13 252. Hida S, Ogasawara K, Sato K, Abe M, Takayanagi H, et al. 2000. CD8+ T cell-mediated skin disease in mice lacking IRF-2, the transcriptional attenuator of interferon-α/β signaling. Immunity 13:643–55 253. Matsuyama T, Grossman A, Mittrucker HW, Siderovski DP, Kiefer F, et al. 1995. Molecular cloning of LSIRF, a lymphoid-specific member of the interferon regulatory factor family that binds the interferon-stimulated response element (ISRE). Nucleic Acids Res. 23:2127–36 254. Fanzo JC, Hu CM, Jang SY, Pernis AB. 2003. Regulation of lymphocyte apoptosis by interferon regulatory factor 4 (IRF-4). J. Exp. Med. 197:303–14 255. Lohoff M, Mittrucker HW, Brustle A, Sommer F, Casper B, et al. 2004. Enhanced TCRinduced apoptosis in interferon regulatory factor 4-deficient CD4+ Th cells. J. Exp. Med. 200:247–53 256. Lohoff M, Ferrick D, Mittrucker HW, Duncan GS, Bischof S, et al. 1997. Interferon regulatory factor-1 is required for a T helper 1 immune response in vivo. Immunity 6:681– 89 257. Coccia EM, Passini N, Battistini A, Pini C, Sinigaglia F, Rogge L. 1999. Interleukin-12 induces expression of interferon regulatory factor-1 via signal transducer and activator of transcription-4 in human T helper type 1 cells. J. Biol. Chem. 274:6698–703 258. Galon J, Sudarshan C, Ito S, Finbloom D, O’Shea JJ. 1999. IL-12 induces IFN regulating factor-1 (IRF-1) gene expression in human NK and T cells. J. Immunol. 162:7256–62 259. Kano S, Sato K, Morishita Y, Vollstedt S, Kim S, et al. 2008. Contribution of the transcription factor IRF1 to the interferon-γ-interleukin-12 signaling axis and TH1 versus TH-17 differentiation of CD4+ T cells. Nat. Immunol. 9:34–41 260. Elser B, Lohoff M, Kock S, Giaisi M, Kirchhoff S, et al. 2002. IFN-γ represses IL-4 expression via IRF-1 and IRF-2. Immunity 17:703–12 261. Lohoff M, Mittrucker HW, Prechtl S, Bischof S, Sommer F, et al. 2002. Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4. Proc. Natl. Acad. Sci. USA 99:11808–12 262. Rengarajan J, Mowen KA, McBride KD, Smith ED, Singh H, Glimcher LH. 2002. Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J. Exp. Med. 195:1003–12 263. Tominaga N, Ohkusu-Tsukada K, Udono H, Abe R, Matsuyama T, Yui K. 2003. Development of Th1 and not Th2 immune responses in mice lacking IFN-regulatory factor-4. Int. Immunol. 15:1–10 264. Maldonado-Lopez R, De Smedt T, Pajak B, Heirman C, Thielemans K, et al. 1999. Role of CD8α+ and CD8α− dendritic cells in the induction of primary immune responses in vivo. J. Leukoc. Biol. 66:242–46
Annu. Rev. Immunol. 2008.26:535-584. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-18
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Tamura et al.
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ANRV338-IY26-18
ARI
26 February 2008
20:26
265. Pulendran B, Smith JL, Caspary G, Brasel K, Pettit D, et al. 1999. Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc. Natl. Acad. Sci. USA 96:1036–41 266. Hu CM, Jang SY, Fanzo JC, Pernis AB. 2002. Modulation of T cell cytokine production by interferon regulatory factor-4. J. Biol. Chem. 277:49238–46 267. Ingraham CR, Kinoshita A, Kondo S, Yang B, Sajan S, et al. 2006. Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6). Nat. Genet. 38:1335–40 268. Richardson RJ, Dixon J, Malhotra S, Hardman MJ, Knowles L, et al. 2006. Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch. Nat. Genet. 38:1329–34 269. Sil AK, Maeda S, Sano Y, Roop DR, Karin M. 2004. IκB kinase-α acts in the epidermis to control skeletal and craniofacial morphogenesis. Nature 428:660–64 270. Pivarcsi A, Bodai L, Rethi B, Kenderessy-Szabo A, Koreck A, et al. 2003. Expression and function of Toll-like receptors 2 and 4 in human keratinocytes. Int. Immunol. 15:721–30 271. Harada H, Kitagawa M, Tanaka N, Yamamoto H, Harada K, et al. 1993. Anti-oncogenic and oncogenic potentials of interferon regulatory factors-1 and -2. Science 259:971–74 272. Tanaka N, Ishihara M, Lamphier MS, Nozawa H, Matsuyama T, et al. 1996. Cooperation of the tumour suppressors IRF-1 and p53 in response to DNA damage. Nature 382:816–18 273. Pamment J, Ramsay E, Kelleher M, Dornan D, Ball KL. 2002. Regulation of the IRF-1 tumour modifier during the response to genotoxic stress involves an ATM-dependent signalling pathway. Oncogene 21:7776–85 274. Kano A, Haruyama T, Akaike T, Watanabe Y. 1999. IRF-1 is an essential mediator in IFN-γ-induced cell cycle arrest and apoptosis of primary cultured hepatocytes. Biochem. Biophys. Res. Commun. 257:672–77 275. Yim JH, Ro SH, Lowney JK, Wu SJ, Connett J, Doherty GM. 2003. The role of interferon regulatory factor-1 and interferon regulatory factor-2 in IFN-γ growth inhibition of human breast carcinoma cell lines. J. Interferon Cytokine Res. 23:501–11 276. Kirchhoff S, Schaper F, Hauser H. 1993. Interferon regulatory factor 1 (IRF-1) mediates cell growth inhibition by transactivation of downstream target genes. Nucleic Acids Res. 21:2881–89 277. Romeo G, Fiorucci G, Chiantore MV, Percario ZA, Vannucchi S, Affabris E. 2002. IRF-1 as a negative regulator of cell proliferation. J. Interferon Cytokine Res. 22:39–47 278. Tanaka N, Ishihara M, Kitagawa M, Harada H, Kimura T, et al. 1994. Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1. Cell 77:829–39 279. Strasser A, Harris AW, Jacks T, Cory S. 1994. DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2. Cell 79:329–39 280. Tamura T, Ishihara M, Lamphier MS, Tanaka N, Oishi I, et al. 1995. An IRF-1-dependent pathway of DNA damage-induced apoptosis in mitogen-activated T lymphocytes. Nature 376:596–99 281. Lallemand C, Palmieri M, Blanchard B, Meritet JF, Tovey MG. 2002. GAAP-1: a transcriptional activator of p53 and IRF-1 possesses proapoptotic activity. EMBO Rep. 3:153– 58 282. Kim EJ, Lee JM, Namkoong SE, Um SJ, Park JS. 2002. Interferon regulatory factor1 mediates interferon-γ-induced apoptosis in ovarian carcinoma cells. J. Cell. Biochem. 85:369–80 www.annualreviews.org • The IRF Family Transcription Factors
267, 268. Two papers that report that Irf6 null/mutant mice have abnormal skin, limb, and craniofacial development.
278. Provides for the first time definitive evidence of the tumor suppressive role of an IRF.
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283. Tomita Y, Bilim V, Hara N, Kasahara T, Takahashi K. 2003. Role of IRF-1 and caspase-7 in IFN-γ enhancement of Fas-mediated apoptosis in ACHN renal cell carcinoma cells. Int. J. Cancer 104:400–8 284. Horiuchi M, Yamada H, Akishita M, Ito M, Tamura K, Dzau VJ. 1999. Interferon regulatory factors regulate interleukin-1β-converting enzyme expression and apoptosis in vascular smooth muscle cells. Hypertension 33:162–66 285. Sanceau J, Hiscott J, Delattre O, Wietzerbin J. 2000. IFN-β induces serine phosphorylation of Stat-1 in Ewing’s sarcoma cells and mediates apoptosis via induction of IRF-1 and activation of caspase-7. Oncogene 19:3372–83 ´ ´ G, Redondo JM, Lopez´ 286. Ruiz-Ruiz C, Ruiz de Almodovar C, Rodr´ıguez A, Ortiz-Ferron Rivas A. 2004. The up-regulation of human caspase-8 by interferon-γ in breast tumor cells requires the induction and action of the transcription factor interferon regulatory factor-1. J. Biol. Chem. 279:19712–20 287. Clarke N, Jimenez-Lara AM, Voltz E, Gronemeyer H. 2004. Tumor suppressor IRF-1 mediates retinoid and interferon anticancer signaling to death ligand TRAIL. EMBO J. 23:3051–60 288. Weinberg RA. 1989. Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res. 49:3713–21 289. Passioura T, Dolnikov A, Shen S, Symonds G. 2005. N-ras-induced growth suppression of myeloid cells is mediated by IRF-1. Cancer Res. 65:797–804 290. Bouker KB, Skaar TC, Riggins RB, Harburger DS, Fernandez DR, et al. 2005. Interferon regulatory factor-1 (IRF-1) exhibits tumor suppressor activities in breast cancer associated with caspase activation and induction of apoptosis. Carcinogenesis 26:1527–35 291. Kim PK, Armstrong M, Liu Y, Yan P, Bucher B, et al. 2004. IRF-1 expression induces apoptosis and inhibits tumor growth in mouse mammary cancer cells in vitro and in vivo. Oncogene 23:1125–35 292. Kroger A, Dallugge A, Kirchhoff S, Hauser H. 2003. IRF-1 reverts the transformed phenotype of oncogenically transformed cells in vitro and in vivo. Oncogene 22:1045–56 293. Tanaka N, Ishihara M, Taniguchi T. 1994. Suppression of c-myc or fosB-induced cell transformation by the transcription factor IRF-1. Cancer Lett. 83:191–96 294. Nozawa H, Oda E, Nakao K, Ishihara M, Ueda S, et al. 1999. Loss of transcription factor IRF-1 affects tumor susceptibility in mice carrying the Ha-ras transgene or nullizygosity for p53. Genes Dev. 13:1240–45 295. Tan RS, Taniguchi T, Harada H. 1996. Identification of the lysyl oxidase gene as target of the antioncogenic transcription factor, IRF-1, and its possible role in tumor suppression. Cancer Res. 56:2417–21 296. Contente S, Kenyon K, Rimoldi D, Friedman RM. 1990. Expression of gene rrg is associated with reversion of NIH 3T3 transformed by LTR-c-H-ras. Science 249:796–98 297. Jeay S, Pianetti S, Kagan HM, Sonenshein GE. 2003. Lysyl oxidase inhibits ras-mediated transformation by preventing activation of NF-κB. Mol. Cell. Biol. 23:2251–63 298. Itoh S, Harada H, Nakamura Y, White R, Taniguchi T. 1991. Assignment of the human interferon regulatory factor-1 (IRF1) gene to chromosome 5q23-q31. Genomics 10:1097– 99 299. Willman CL, Sever CE, Pallavicini MG, Harada H, Tanaka N, et al. 1993. Deletion of IRF-1, mapping to chromosome 5q31.1, in human leukemia and preleukemic myelodysplasia. Science 259:968–71 300. Van den Berghe H, Vermaelen K, Mecucci C, Barbieri D, Tricot G. 1985. The 5qanomaly. Cancer Genet. Cytogenet. 17:189–255
Annu. Rev. Immunol. 2008.26:535-584. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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Tamura et al.
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ANRV338-IY26-18
ARI
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301. Boultwood J, Fidler C, Lewis S, MacCarthy A, Sheridan H, et al. 1993. Allelic loss of IRF1 in myelodysplasia and acute myeloid leukemia: retention of IRF1 on the 5q-chromosome in some patients with the 5q-syndrome. Blood 82:2611–16 302. Ogasawara S, Tamura G, Maesawa C, Suzuki Y, Ishida K, et al. 1996. Common deleted region on the long arm of chromosome 5 in esophageal carcinoma. Gastroenterology 110:52–57 303. Tamura G, Ogasawara S, Nishizuka S, Sakata K, Maesawa C, et al. 1996. Two distinct regions of deletion on the long arm of chromosome 5 in differentiated adenocarcinomas of the stomach. Cancer Res. 56:612–15 304. Nozawa H, Oda E, Ueda S, Tamura G, Maesawa C, et al. 1998. Functionally inactivating point mutation in the tumor-suppressor IRF-1 gene identified in human gastric cancer. Int. J. Cancer 77:522–27 305. Kondo T, Minamino N, Nagamura-Inoue T, Matsumoto M, Taniguchi T, Tanaka N. 1997. Identification and characterization of nucleophosmin/B23/numatrin which binds the antioncogenic transcription factor IRF-1 and manifests oncogenic activity. Oncogene 15:1275–81 306. Harada H, Kondo T, Ogawa S, Tamura T, Kitagawa M, et al. 1994. Accelerated exon skipping of IRF-1 mRNA in human myelodysplasia/leukemia; a possible mechanism of tumor suppressor inactivation. Oncogene 9:3313–20 307. Tzoanopoulos D, Speletas M, Arvanitidis K, Veiopoulou C, Kyriaki S, et al. 2002. Low expression of interferon regulatory factor-1 and identification of novel exons skipping in patients with chronic myeloid leukaemia. Br. J. Haematol. 119:46–53 308. Park JS, Kim EJ, Kwon HJ, Hwang ES, Namkoong SE, Um SJ. 2000. Inactivation of interferon regulatory factor-1 tumor suppressor protein by HPV E7 oncoprotein. Implication for the E7-mediated immune evasion mechanism in cervical carcinogenesis. J. Biol. Chem. 275:6764–69 309. Connett JM, Badri L, Giordano TJ, Connett WC, Doherty GM. 2005. Interferon regulatory factor 1 (IRF-1) and IRF-2 expression in breast cancer tissue microarrays. J. Interferon Cytokine Res. 25:587–94 310. Doherty GM, Boucher L, Sorenson K, Lowney J. 2001. Interferon regulatory factor expression in human breast cancer. Ann. Surg. 233:623–29 311. Giatromanolaki A, Koukourakis MI, Ritis K, Mimidis K, Sivridis E. 2004. Interferon regulatory factor-1 (IRF-1) suppression and derepression during endometrial tumorigenesis and cancer progression. Cytokine 26:164–68 312. Moriyama Y, Nishiguchi S, Tamori A, Koh N, Yano Y, et al. 2001. Tumor-suppressor effect of interferon regulatory factor-1 in human hepatocellular carcinoma. Clin. Cancer Res. 7:1293–98 313. Mori T, Anazawa Y, Iiizumi M, Fukuda S, Nakamura Y, Arakawa H. 2002. Identification of the interferon regulatory factor 5 gene (IRF-5) as a direct target for p53. Oncogene 21:2914–18 314. Hu G, Mancl ME, Barnes BJ. 2005. Signaling through IFN regulatory factor-5 sensitizes p53-deficient tumors to DNA damage-induced apoptosis and cell death. Cancer Res. 65:7403–12 315. Barnes BJ, Kellum MJ, Pinder KE, Frisancho JA, Pitha PM. 2003. Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death. Cancer Res. 63:6424–31 316. Hao SX, Ren R. 2000. Expression of interferon consensus sequence binding protein (ICSBP) is downregulated in Bcr-Abl-induced murine chronic myelogenous leukemialike disease, and forced coexpression of ICSBP inhibits Bcr-Abl-induced myeloproliferative disorder. Mol. Cell. Biol. 20:1149–61 www.annualreviews.org • The IRF Family Transcription Factors
581
ARI
26 February 2008
20:26
317. Deng M, Daley GQ. 2001. Expression of interferon consensus sequence binding protein induces potent immunity against BCR/ABL-induced leukemia. Blood 97:3491–97 ¨ 318. Ortmann CA, Burchert A, Holzle K, Nitsche A, Wittig B, et al. 2005. Down-regulation of interferon regulatory factor 4 gene expression in leukemic cells due to hypermethylation of CpG motifs in the promoter region. Nucleic Acids Res. 33:6895–905 319. Schmidt M, Hochhaus A, Konig-Merediz SA, Brendel C, Proba J, et al. 2000. Expression of interferon regulatory factor 4 in chronic myeloid leukemia: correlation with response to interferon alfa therapy. J. Clin. Oncol. 18:3331–38 320. Liu K, Abrams SI. 2003. Coordinate regulation of IFN consensus sequence-binding protein and caspase-1 in the sensitization of human colon carcinoma cells to Fas-mediated apoptosis by IFN-γ. J. Immunol. 170:6329–37 321. Yang D, Thangaraju M, Greeneltch K, Browning DD, Schoenlein PV, et al. 2007. Repression of IFN regulatory factor 8 by DNA methylation is a molecular determinant of apoptotic resistance and metastatic phenotype in metastatic tumor cells. Cancer Res. 67:3301–9 322. Heylbroeck C, Balachandran S, Servant MJ, DeLuca C, Barber GN, et al. 2000. The IRF-3 transcription factor mediates Sendai virus-induced apoptosis. J. Virol. 74:3781–92 323. Weaver BK, Ando O, Kumar KP, Reich NC. 2001. Apoptosis is promoted by the dsRNAactivated factor (DRAF1) during viral infection independent of the action of interferon or p53. FASEB J. 15:501–15 324. Kirshner JR, Karpova AY, Kops M, Howley PM. 2005. Identification of TRAIL as an interferon regulatory factor 3 transcriptional target. J. Virol. 79:9320–24 325. Hsu LC, Park JM, Zhang K, Luo JL, Maeda S, et al. 2004. The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4. Nature 428:341– 45 326. Kim T, Kim TY, Song YH, Min IM, Yim J, Kim TK. 1999. Activation of interferon regulatory factor 3 in response to DNA-damaging agents. J. Biol. Chem. 274:30686–89 327. Karpova AY, Trost M, Murray JM, Cantley LC, Howley PM. 2002. Interferon regulatory factor-3 is an in vivo target of DNA-PK. Proc. Natl. Acad. Sci. USA 99:2818–23 328. Duguay D, Mercier F, Stagg J, Martineau D, Bramson J, et al. 2002. In vivo interferon regulatory factor 3 tumor suppressor activity in B16 melanoma tumors. Cancer Res. 62:5148–52 329. Kim TY, Lee KH, Chang S, Chung C, Lee HW, et al. 2003. Oncogenic potential of a dominant negative mutant of interferon regulatory factor 3. J. Biol. Chem. 278:15272–78 330. Ronco LV, Karpova AY, Vidal M, Howley PM. 1998. Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev. 12:2061–72 331. Takaoka A, Hayakawa S, Yanai H, Stoiber D, Negishi H, et al. 2003. Integration of interferon-α/β signalling to p53 responses in tumour suppression and antiviral defence. Nature 424:516–23 332. Weihua X, Lindner DJ, Kalvakolanu DV. 1997. The interferon-inducible murine p48 (ISGF3γ) gene is regulated by protooncogene c-myc. Proc. Natl. Acad. Sci. USA 94:7227– 32 333. Passioura T, Shen S, Symonds G, Dolnikov A. 2005. A retroviral library genetic screen identifies IRF-2 as an inhibitor of N-ras-induced growth suppression in leukemic cells. Oncogene 24:7327–36 334. Nguyen H, Mustafa A, Hiscott J, Lin R. 1995. Transcription factor IRF-2 exerts its oncogenic phenotype through the DNA binding/transcription repression domain. Oncogene 11:537–44
Annu. Rev. Immunol. 2008.26:535-584. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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Tamura et al.
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ANRV338-IY26-18
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335. Yamamoto H, Lamphier MS, Fujita T, Taniguchi T, Harada H. 1994. The oncogenic transcription factor IRF-2 possesses a transcriptional repression and a latent activation domain. Oncogene 9:1423–28 336. Vaughan PS, Aziz F, van Wijnen AJ, Wu S, Harada H, et al. 1995. Activation of a cell-cycle-regulated histone gene by the oncogenic transcription factor IRF-2. Nature 377:362–65 337. Vaughan PS, van der Meijden CM, Aziz F, Harada H, Taniguchi T, et al. 1998. Cell cycle regulation of histone H4 gene transcription requires the oncogenic factor IRF-2. J. Biol. Chem. 273:194–99 338. Masumi A, Yamakawa Y, Fukazawa H, Ozato K, Komuro K. 2003. Interferon regulatory factor-2 regulates cell growth through its acetylation. J. Biol. Chem. 278:25401–7 339. Yamagata T, Nishida J, Tanaka S, Sakai R, Mitani K, et al. 1996. A novel interferon regulatory factor family transcription factor, ICSAT/Pip/LSIRF, that negatively regulates the activity of interferon-regulated genes. Mol. Cell. Biol. 16:1283–94 340. Mamane Y, Grandvaux N, Hernandez E, Sharma S, Innocente SA, et al. 2002. Repression of IRF-4 target genes in human T cell leukemia virus-1 infection. Oncogene 21:6751–65 341. Mamane Y, Loignon M, Palmer J, Hernandez E, Cesaire R, et al. 2005. Repression of DNA repair mechanisms in IRF-4-expressing and HTLV-I-infected T lymphocytes. J. Interferon Cytokine Res. 25:43–51 342. Iida S, Rao PH, Butler M, Corradini P, Boccadoro M, et al. 1997. Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma. Nat. Genet. 17:226– 30 343. Saito T, Yamagata T, Takahashi T, Honda H, Hirai H. 1999. ICSAT overexpression is not sufficient to cause adult T-cell leukemia or multiple myeloma. Biochem. Biophys. Res. Commun. 260:329–31 344. Leung TH, Hoffmann A, Baltimore D. 2004. One nucleotide in a κB site can determine cofactor specificity for NF-κB dimers. Cell 118:453–64 345. Janssens S, Tschopp J. 2006. Signals from within: the DNA-damage-induced NF-κB response. Cell Death Differ. 13:773–84 346. Karin M, Greten FR. 2005. NF-κB: linking inflammation and immunity to cancer development and progression. Nat. Rev. Immunol. 5:749–59 347. Imai KS, Hino K, Yagi K, Satoh N, Satou Y. 2004. Gene expression profiles of transcription factors and signaling molecules in the ascidian embryo: towards a comprehensive understanding of gene networks. Development 131:4047–58 348. Krause CD, Pestka S. 2005. Evolution of the Class 2 cytokines and receptors, and discovery of new friends and relatives. Pharmacol. Ther. 106:299–346 349. Miyamoto M, Fujita T, Kimura Y, Maruyama M, Harada H, et al. 1988. Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-β gene regulatory elements. Cell 54:903–13 350. Au WC, Moore PA, Lowther W, Juang YT, Pitha PM. 1995. Identification of a member of the interferon regulatory factor family that binds to the interferon-stimulated response element and activates expression of interferon-induced genes. Proc. Natl. Acad. Sci. USA 92:11657–61 351. Zhang L, Pagano JS. 1997. IRF-7, a new interferon regulatory factor associated with Epstein-Barr virus latency. Mol. Cell. Biol. 17:5748–57 352. Driggers PH, Ennist DL, Gleason SL, Mak WH, Marks MS, et al. 1990. An interferon γ-regulated protein that binds the interferon-inducible enhancer element of major histocompatibility complex class I genes. Proc. Natl. Acad. Sci. USA 87:3743–47 www.annualreviews.org • The IRF Family Transcription Factors
349. Reports the discovery and cloning of the first IRF family member, IRF1.
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353. Levy DE, Kessler DS, Pine R, Darnell JE Jr. 1989. Cytoplasmic activation of ISGF3, the positive regulator of interferon-α-stimulated transcription, reconstituted in vitro. Genes Dev. 3:1362–71 354. Kimura T, Kadokawa Y, Harada H, Matsumoto M, Sato M, et al. 1996. Essential and nonredundant roles of p48 (ISGF3 γ) and IRF-1 in both type I and type II interferon responses, as revealed by gene targeting studies. Genes Cells 1:115–24
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:535-584. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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Contents
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Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan1,3 and Ian Parker1,2 1
Department of Physiology and Biophysics, 2 Department of Neurobiology and Behavior, and 3 Center for Immunology, University of California, Irvine, California 92697; emails:
[email protected],
[email protected] Annu. Rev. Immunol. 2008. 26:585–626
Key Words
First published online as a Review in Advance on January 2, 2008
T cell, B cell, dendritic cell, chemokine, antigen, motility
The Annual Review of Immunology is online at immunol.annualreviews.org This article’s doi: 10.1146/annurev.immunol.24.021605.090620 c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0585$20.00
Abstract The immune system is the most diffuse cellular system in the body. Accordingly, long-range migration of cells and short-range communication by local chemical signaling and by cell-cell contacts are vital to the control of an immune response. Cellular homing and migration within lymphoid organs, antigen recognition, and cell signaling and activation are clearly vital during an immune response, but these events had not been directly observed in vivo until recently. Introduced to the field of immunology in 2002, two-photon microscopy is the method of choice for visualizing living cells deep within native tissue environments, and it is now revealing an elegant cellular choreography that underlies the adaptive immune response to antigen challenge. We review cellular dynamics and molecular factors that contribute to basal motility of lymphocytes in the lymph node and cellular interactions leading to antigen capture and recognition, T cell activation, B cell activation, cytolytic effector function, and antibody production.
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INTRODUCTION
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The immune system is designed for detection of foreign antigens that have never been encountered, for amplification of responses to previously encountered antigen, and for the delivery of coordinated effector responses ranging from mobilization of effector T cells, cytokine delivery, and antibody production. Each of these processes relies on cell-to-cell contact for initiation, followed by guided dispersal of effector cells and molecules to the appropriate location, while avoiding friendly fire that could result in autoimmune disease. Lymphocytes are potentially dangerous cells, and numerous cellular and molecular mechanisms avoid inappropriate triggering, dampen initial responses, and amplify responses to second and subsequent encounters with antigen, while at the same time optimizing sensitivity to minute quantities of antigen. Within the past five years, since publication of the first studies examining the motility of lymphocytes and thymocytes in native tissue environments (1–3), new imaging studies have appeared at an exponentially increasing rate. Two-photon microscopy has proved to be the method of choice for cellular immunoimaging, enabling visualization deep within intact organs and tissues while minimizing photodamage and bleaching. Efforts to map out the cellular choreography in vivo build upon a framework of in vitro studies of lymphocyte motility and response dynamics following contact with antigen-presenting cells (APCs). In this review, we first discuss the technology of two-photon microscopy as applied to immunoimaging and then focus on its applications to live-cell imaging of immune cells in the lymph node under basal conditions and in response to antigenic challenge. Collectively, two-photon microscopy is revealing an elaborate and elegant choreography of cell motility, antigen capture, and cell-cell interactions in a variety of in vivo settings and holds great promise for understanding the dynamic response to infectious agents.
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TWO-PHOTON IMAGING METHODOLOGY Imaging the single-cell dynamics of the immune system within an intact environment requires the ability to look deep inside intact tissues and organisms with spatial and temporal resolution adequate to track cell morphology, motility, and signaling processes, all the while minimizing perturbation of the system under study. Optical microscopy employing fluorescence techniques is highly suited for this purpose, permitting both labeling of specific cells, organelles, or proteins and functional readout of physiological events (4). However, conventional (single-photon) techniques such as wide-field and confocal microscopy suffer severe disadvantages, principally because the short wavelengths required for fluorescence excitation are subject to strong scattering in biological tissue and exacerbate phototoxicity. Nonlinear microscopy differs fundamentally from conventional techniques in that the elementary process involves near simultaneous interactions of two (or more) photons, so that the signal varies as the square (or higher power) of incident light intensity, rather than linearly. This nonlinear relationship leads to qualitatively new imaging modalities, of which fluorescence excitation by two-photon absorption and second harmonic generation have proved most useful for immunoimaging. The essence of two-photon microscopy is that a fluorophore is excited by the nearsimultaneous absorption of energy from two photons, each of which contributes one half of the energy required to induce fluorescence. Because excitation then increases as the square of the incident light intensity, fluorescence is essentially confined to the focal spot formed by a microscope objective, thereby providing an inherent optical sectioning effect, analogous (though involving a completely different mechanism) to confocal microscopy. To achieve practicable fluorescence signals, the photon density in the focal spot must be incredibly high, yet not so high as to damage the specimen. This is achieved by using
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femtosecond or picosecond pulsed lasers, which concentrate their output into brief bursts with enormous instantaneous power, yielding a two-photon advantage of ∼105 as compared with a continuous beam of the same average power. The continuing improvement of ultrafast pulsed lasers has been a key factor driving the adoption of two-photon microscopy by immunologists. In addition to its inherent optical sectioning effect, two-photon excitation has other major advantages for immunoimaging because the excitation wavelengths are roughly twice as long as would be used for conventional linear excitation by widefield or confocal microscopy. This use of long wavelength excitation is particularly advantageous for imaging deep into highly scattering biological tissues (5) because scattering decreases with increasing wavelength (6) and because absorption by hemoglobin and other proteins is minimized. Thus, the infrared wavelengths used for two-photon imaging enable a fivefold or deeper tissue penetration than does confocal imaging employing visible wavelengths (2, 7–9) and cause negligible photodamage or photobleaching. Long-term imaging is thereby facilitated because bleaching and damage processes (induced by nonlinear processes) are largely confined to those cells lying at the focal plane, whereas cells above and below experience only the innocuous infrared light. Nevertheless, the laser power must be kept below some sharp threshold value in order to maintain long-term viability of the preparation. Finally, the two-photon excitation spectra of most fluorophores are appreciably broader than for one-photon excitation (10), so a single excitation wavelength can be used efficiently to excite multiple probes simultaneously with distinct emission wavelengths. Moreover, the ease of tuning of the latest generations of femtosecond lasers facilitates selection of a wavelength that balances excitation of different fluorophores. In instances in which highly divergent excitation wavelengths are required, two independently tuned lasers may be used simultaneously (8).
In addition to multiphoton absorption, another nonlinear interaction that becomes prominent at very high light intensities is that of optical-harmonic generation, in which two (or more) photons are almost simultaneously scattered to generate a single photon with exactly twice (or higher multiples of ) the incoming energy (11). Second harmonic generation is produced by spatially ordered molecules and has proved especially useful for imaging ordered structural proteins such as collagen fibers (12) and microtubules (13) by detecting emitted light through a bandpass filter of twice the wavelength of the excitation light without the need for fluorescent labeling. Deep tissue imaging is currently limited by several factors, including the requirement for exponentially increasing excitation power at increasing depths to compensate for increasing scattering loss. Use of infrared-emitting dyes may be advantageous in reducing signal loss owing to scattering, and the advent of ever more powerful lasers extends the depth range but will be limited by thermal effects and excitation near the surface (5). Moreover, image quality (as well as brightness) degrades with transit through tissues with strongly varying refractive index but may be mitigated by correcting for wavefront distortions with deformable mirrors (14) or by applying depthdependent deconvolution algorithms to acquired images (15). Imaging yet deeper into thick tissues and organs will necessitate mechanical techniques, such as penetration or removal of overlying tissue, use of needle-like gradient index lenses to extend the range of otherwise bulky objectives (13), and development of miniaturized two-photon endoscopes (16, 17).
Fluorescent Labels and Probes The imaging techniques reviewed here rely primarily on the introduction of a fluorescent probe or label into cells or structures of interest, although useful information may also be gained from intrinsic signals such as
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autofluorescence and second harmonic generation. Extrinsic labeling may be accomplished in vitro using isolated cells that are then adoptively transferred into a recipient animal by introducing fluorophores directly into the animal or organ being imaged (e.g., to stain vasculature) or by genetically engineering expression of fluorescent proteins. The first in situ imaging studies of lymphocytes and dendritic cells (DCs) employed cell tracker fluorescent dyes, including CSFE (5,6-carboxyfluoresceine diacetate succinimidyl ester; green fluorescence) and CMTMR (chloromethylbenzoyl aminotetramethylrhodamine; red) for staining of adoptively transferred cells, and this method remains a mainstay. Such dyes have been used for many years by immunologists for flow cytometry and have the advantages of providing bright fluorescence signals while being relatively benign. Adoptive transfer of labeled cells typically results in 90 min (the usual limit for live-cell observation by two-photon microscopy). Although generally stable, clusters also exhibit dynamic changes, with DCs ripping T cells away from nearby DCs (96), suggesting one type of competition that could occur if a second wave of DCs arrived. This second, cluster stage is accompanied by IL2 production, indicating activation of NFAT (nuclear factor of activated T cells)-dependent downstream signaling leading to gene expression. From 16–24 h after initially encountering antigen, enlarged T cells dissociate from DC clusters and begin to swarm in looping patterns around DCs in a localized region. During this third stage, T cells again form transient contacts with additional DCs and later begin to proliferate. Motile T cell blasts that had previously separated from DCs round up and divide within 20–30 min. The daughter
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T cells are immediately motile with 2-D velocities of about 10 μm/min, and within five days T cells have divided up to eight times. T cell Ca2+ signal during antigen recognition. Progressing beyond an initial phenomenological description of cell behavior in the lymph node, the next challenge is to understand how cell interactions and signaling cascades within the cell are integrated to promote various immunological outcomes. Within a few seconds of TCR engagement, Ca2+ signaling is initiated by IP3 -induced Ca2+ release from the endoplasmic reticulum (ER) and is subsequently sustained by Ca2+ influx through store-operated Ca2+ releaseactivated Ca2+ (CRAC) channels. CRAC channels are formed by Orai1 multimers activated by STIM1; these STIM1 multimers function dually as the ER Ca2+ sensor and as the activator of CRAC channel activity (118– 120). Ca2+ signals must exceed 500 nM for at least 1–2 h to drive gene expression via the calcineurin-dependent NFAT transcription factor pathway (121–123). The Ca2+ signal may be oscillatory, spike-like, or sustained in individual cells. The frequency and pattern of Ca2+ signaling are important for activating various transcription factor pathways in a differential manner (124, 125). Although in vitro studies have revealed much about the molecular mechanism and patterns of T cell Ca2+ signaling that lead to downstream transcriptional activation, an important goal remains to monitor signaling in primary T cells within the physiological context of antigen presentation inside the lymph node. A recent paper (79) describes Ca2+ signaling in lymph node T cells under basal conditions, during nonspecific inflammatory conditions, and during antigen-specific responses. Under basal conditions, T cells migrate rapidly and have low cytosolic Ca2+ , showing only infrequent, small-amplitude Ca2+ spike activity associated with T cell slowing. Inflammation by itself reduces motility and nearly eliminates intermittent Ca2+ spiking without affecting average Ca2+ lev-
els. Antigen priming reduces velocities further and evokes strong Ca2+ signaling activity (79), evident as irregular transients to >500 nM. Cells with the strongest Ca2+ signals are associated with the lowest velocities. Those T cells observed in direct contact with labeled DCs have more pronounced Ca2+ signals, but the initiation and termination of DC contacts are not clearly correlated with any change in Ca2+ signaling. T cell Ca2+ signaling continues even after detachment from all visible DCs. These results define the pattern of the Ca2+ signal in naive T cells during antigen presentation under physiological conditions as consisting of persistent and irregular spike activity. Using confocal microscopy and a nonratiometric Ca2+ indicator, Skokos et al. (126) detected Ca2+ signals associated with T cell slowing in freshly homed T cells interacting with DC that had taken up DEC-205conjugated high-potency peptide under tolerizing conditions. Lower-potency peptides failed to elicit Ca2+ signaling, T cell arrest, and downstream proliferative responses, even though they elicited upregulation of CD69. Together, these first two Ca2+ imaging studies (79, 126) in lymph node emphasize the involvement of Ca2+ signaling in producing T cell arrest, regardless of T cell priming or tolerization, and herald a new phase of imaging that incorporates intracellular signaling responses together with tracking cell behavior in relation to functional outcomes. Stop signal. Calcium signaling during antigen recognition inhibits T lymphocyte motility in vitro (38, 127, 128). T cell motility in vitro is also inhibited by elevated Ca2+ when proximal TCR signaling is bypassed by the use of Ca2+ ionophores or by treatment with thapsigargin. Immunoimaging of T cells, B cells, and thymocytes indicates that the Ca2+ stop signal hypothesis also applies in vivo. Intermittent Ca2+ signaling in the absence of antigen is sufficient to reduce the velocity of T cell migration (57, 79). Furthermore, T cells
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and B cells produce Ca2+ signals and slow at sites of interaction with antigen-bearing DCs (79, 113). The most rigorous test was performed by Bhakta et al. (129), who showed that Ca2+ signaling is both necessary and sufficient for thymocytes to stop crawling in the thymic environment. Importantly, by changing the concentrations of Ca2+ and K+ ions in the medium, Bhakta et al. were able to restore the motility of arrested thymocytes by reducing Ca2+ influx. Using thapsigargin treatment, they showed that moderate Ca2+ levels stop cells reversibly, proving sufficiency. Lowering Ca2+ levels also inhibits Ca2+ signaling in a selecting environment and results in the resumption of motility, proving necessity. Like T cells interacting with APCs, the Ca2+ dependence of thymocyte motility prolongs interactions with stromal cells and promotes sustained Ca2+ signaling that in turn alters gene expression critical for deleting autoreactive thymocytes. Further validation of the Ca2+ stop signal hypothesis was obtained in recent work by Skokos et al. (126), who showed in the lymph node that, even under noninflammatory conditions, T cells decelerate and produce Ca2+ signals when responding to YFP-expressing DCs primed with the most potent in a series of altered peptide ligands. Together, these studies support the conclusion that Ca2+ signaling both in vitro and in vivo promotes the stability of T cell–APC interactions, an essential prerequisite for stabilizing the immunological synapse and downstream effector function. A potentially important new wrinkle in the stop signal hypothesis has been raised by Schneider et al. (130), who report that CTLA4 (cytotoxic lymphocyte antigen-4) increases basal T cell motility and overrides the TCRinduced stop signal required for stable conjugate formation between T cells and APC. CTLA-4 is well known as an inhibitory coreceptor on T cells that is induced upon activation and opposes costimulation by APC proteins CD80 and CD86 delivered to CD28 on the T cell. After separating CTLA-4+ and CTLA-4− cells among a preactivated pool of
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antigen-specific T cells, the authors distinguished their motility and response to subsequent antigen challenge. In the lymph node, CTLA-4+ cells do not arrest during antigen challenge, suggesting that CTLA-4 expression prevents cell arrest during contact with antigen-presenting DCs. On the basis solely of differences in T cell behavior, one may conclude that the differences in cell arrest between these preactivated populations are due to a lack of initial antigen recognition by CTLA-4+ cells and to a corresponding suppression of the Ca2+ signal to below what is needed for cell arrest (131).
Antigen Quality, Quantity, and Timing The initial descriptions of T cell–DC interactions (3, 49, 96, 114) have been extended in several studies that examined the consequences of varying conditions that alter T cell/DC dynamics and functional outcomes. When one considers the demonstrated effects of costimulatory signaling; antigen quality, quantity, and persistence; competition between cells for antigen; and timing of T cell and DC arrival to the lymph node, the potential complexities are enormous. Late T cell/DC encounters may provide a rationale for prolonging the stay inside a lymph node. During the days-long period of egress block (lymph node shutdown) during an antigen response, T cells may encounter DCs again and again to integrate signals delivered by successive waves of DCs migrating from the periphery. How these signals are integrated remains to be seen, but antigen persistence during the final days in the lymph node can also modulate T cell differentiation programs. Experiments tracking CD4+ T cell proliferation revealed that the presence of antigen throughout their expansion phase is essential for optimal activation (132). Furthermore, T cells induce antigen loss from the surface of DCs, resulting in high-affinity T cells outcompeting loweraffinity T cells during a response to antigenic challenge (133).
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Tolerance and Priming. Three studies imaged T cell–DC interactions under conditions that produced either priming or tolerizing immune responses (50, 134, 135). In a priming response, initiated usually by antigen in combination with an adjuvant containing TLR ligands such as lipopolysaccharide (LPS) to promote DC maturation, the subsequent exposure to antigen induces a more rapid and robust functional response, whereas a tolerizing regimen using antigen alone results in a diminished functional response. Hugues et al. (134) and Shakhar et al. (50) used DEC-205 (to facilitate antigen uptake by steady-state DCs) conjugated to ovalbumin in the presence or absence of LPS or anti-CD40 (mimicking DC costimulation) to induce priming or tolerance. Hugues et al. (134) found that in the tolerizing regimen, CD8+ T cells slow but do not arrest to the same degree during stage II as during priming. Differing from these results on CD8+ T cells, Shakhar et al. (50) found that CD4+ T cells arrest equally well in response to priming and tolerizing regimens but become more motile sooner during tolerization (at 18 h) compared with priming (at 24 h). Comparing oral priming with oral tolerance induction, Zinselmeyer et al. (135) found only minor differences in CD4+ T cell motility and clustering behavior, with larger and more stable clusters seen in the priming regimen. Common themes among all three studies are that priming and tolerizing routines do not lead to markedly different T cell behaviors, but that priming is associated with more prolonged and/or more stable cluster formation during stage II. Such subtle differences in T cell–DC interactions could influence or reflect costimulatory signals delivered during the interaction. The quality and context of pMHC presentation also matter. Skokos et al. (126) compared the dynamics and functional outcomes of steady-state DCs presenting high-, medium-, or low-potency pMHC complexes varying by only a single amino acid substitution in the peptide antigen conjugated with DEC-205 under tolerizing conditions.
All three peptide ligands induced CD69 upregulation and anergy, but only high-potency MHC complexes resulted in Ca2+ signaling, T cell arrest, and stable T cell–DC interactions that subsequently led to the strongest proliferative response and cytokine production. These latter responses, but not CD69 upregulation, were inhibitable by cyclosporin A. However, CD69 upregulation induced by low- and medium-potency pMHC was shown to be sufficient to produce T cell anergy that is not inhibited by cyclosporin A, suggesting that anergy can be induced by Ca2+ independent events that are activated during hit-and-run contacts with DCs. Together, these results emphasize the importance of stable T cell–DC interactions, during which effective Ca2+ signaling can take place, for proliferative responses and cytokine production in vivo.
Timing of DC arrival: sustaining the response. During the third stage of antigen presentation, CD4+ T cells resume their motility and swarm away from their clusters while making contact with additional DCs (117). The consequences of a subsequent late encounter with an additional wave of DCs have been evaluated by Celli et al. (136), who sent in reinforcements, i.e., antigen-bearing DCs, during an already developing immune response. Swarming T cell blasts found and reengaged this fresh set of recent DC immigrants, sometimes again forming long-lasting contacts. Activated T cells that reengaged fresh antigen-bearing DCs did not proliferate to a greater extent but were more likely to express the high-affinity IL-2 receptor CD25 and to secrete IFN-γ. As this cytokine secretes directionally into the immunological synapse (137), it may exert a localized effect on the DC. These results on CD4+ cell behavior differ from findings in CD8+ cells rechallenged with antigen; in the latter case, CD8+ cells did not reengage in long-lasting contacts following antigen delivered as a second wave at 20 h (134).
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Timing of T cell arrival: competition and antigen persistence. Using static methods and by blocking homing to inhibit the arrival of T cells, Catron et al. (138) compared outcomes for resident and late-arriving T cells that entered the lymph node after a specific antigen response was already underway. Although this was not imaged, the late arrivers engaged DCs that presumably would have already accumulated T cell clusters. Tracking the outcome of residents and late arrivers separately showed that competition results in a weaker proliferative response among the late arrivers and predestines them to become central memory T cells. The resident T cells that benefit from the full antigen load have a greater tendency to become fully differentiated effector cells. Garcia and colleagues (139) extended the theme of competition by sending in labeled T cells either alone or accompanied by a tenfold excess of identical but unlabeled cells. With low numbers of cognate T cells, competition for antigen-presenting DCs is reduced and the specific T cells form stable interactions with antigen-pulsed DCs for a longer period. At higher densities, competition among antigenspecific T cells for space on the DC surface is not limiting because the frequency of transient interactions with DCs increases when more cognate T cells are transferred. On a per cell basis, however, CD69 is less efficiently induced. As a direct test of whether the quantity of antigen is the limiting factor, i.v. injection of the peptide antigen restores long-duration late contacts 2 days after the initial exposure of antigen. Thus, competition for the quantity of antigen plays an important role in determining the stability of T cell/DC contacts and the duration of the second stage of stable T cell/DC clustering. The results emphasize that the initial phase of T cell expansion is limited by the quantity of antigen present. Furthermore, they imply that under the normal condition of low cognate T cell frequency, longer-duration conjugate T cell–DC interactions will form. As T cell expansion continues, competition for residual antigen by
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T cells becomes self-limiting. The latearriving T cells that have a greater likelihood of becoming central memory cells (138) may do so because they endure competition for antigen by early arrivers which are more likely to become fully differentiated effectors. Another form of negative feedback involves late-arriving cytolytic effector cells returning to the draining lymph node from the periphery. CD8+ effector cells (CCR7− Lselectin− ) return by targeted homing specifically to draining lymph nodes in a CXCR3dependent manner. Once inside the lymph node, these effectors were visualized making prolonged contacts with, and killing, antigen-bearing DCs, thereby providing negative feedback by eliminating specific antigenpresenting DCs (140).
CD4+ T Cell/CD8+ T Cell/DC Ternary Clusters During an immune response to whole antigen, both CD4+ and CD8+ T cells often become activated by contact with differing pMHC complexes on DCs. The activation of CD4+ cells augments CD8+ cell clonal expansion and differentiation to become memory and cytolytic effector CD8+ cells (141). The initial recognition of antigen by either CD4+ or CD8+ T cells may be understood in the sense of a stochastic mechanism by which T cells make numerous random contacts with DCs, but the problem is compounded by the need to get all three cell types together. To investigate mechanisms of help provided by CD4+ cells for the CD8+ response, two groups examined the dynamics of CD4+ and CD8+ T cells interacting with DCs during responses that engage both T cell subsets. Each group imaged ternary clusters with both CD4+ and CD8+ cells in direct contact with antigen-bearing DCs (142, 143). Clustering of CD8+ cells to DCs is enhanced by the presence of CD4+ cells that recognize their cognate peptide on the same DC. Notably, this tripartite interaction is diminished by several molecular interventions: blocking
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antibodies directed against either CCL3 or CCL4 (chemokines that are produced by T cells and DCs following their engagement); CCR5 genetic deletion in CD8+ T cells; and DCs lacking CD40. The assembly of the ternary cluster enhances high-affinity IL-2 receptor expression and promotes generation of CD8+ memory T cells (142, 143). A variation on this theme was shown recently by the demonstration that help to naive CD8+ cells can be provided by other CD8+ cells through preferential recruitment of polyclonal CD8+ T cells to specific CD8+ T cells responding to DCs (144). As with help delivered by CD4+ T cells, the tendency for increased clustering of nonspecific polyclonal CD8+ cells requires upregulation of CCR5, induced in CD8+ T cells by inflammation without the need for specific antigen stimulation. Such a mechanism would encourage greater vigilance in surveying the repertoire during an ongoing immune response. A key question is whether CD8+ cells are preferentially recruited or retained (or both) by the presence of CD4+ (or CD8+ ) cells in contact with DCs. Castellino et al. (143) present evidence suggesting that CD8+ cells are recruited to clusters through chemotaxis, by analyzing the hit rate of CD8+ cells making contact with DC clusters. Within 25 μm of a DC, the wild-type cells show a pronounced directional bias toward the DC, and they approach clusters more frequently and with greater velocity than do CCR5-knockout cells. Although a caveat remains that guidance may involve fine DC processes (nanotubes) below the limit of optical resolution, the results of this exciting paper suggest a scenario in which preferential recruitment of CD8+ cells is enabled by upregulation of the chemokine receptor CCR5 on CD8+ cells following antigen stimulation in the inflammatory environment, leading to chemotaxis in response to secretion of CCL3 and CCL4 by CD4+ /DC clusters. By favoring prolonged contacts between CD8+ T cells and DCs, the larger and longer-lasting resulting clusters would thus promote CD8+ cells to ex-
press high-affinity IL-2 receptors and to become memory CD8+ cells.
Dynamics of Target Cell Recognition and Lysis by Cytotoxic T Lymphocytes and NK Cells Activated CD8+ T lymphocytes and NK cells both possess the ability to recognize and kill target cells by triggered exocytosis of cytolytic granules. Two studies describe the dynamics of target cell lysis within the lymph node environment. In a beautiful, yet chilling, description of cellular genocide, Mempel and colleagues (145) imaged recognition and lysis of antigen-engaged B cells by in vivo primed CD8+ cytotoxic T lymphocytes (CTL). Freshly homed and motile B cells are sampled but ignored after a short-duration encounter by CTLs when the B cell suspect lacks specific antigen. CTLs latch onto genuine B cell targets in prolonged interactions only when these surrogate targets have previously taken up the specific antigen recognized by the CTL. Then, CTL cells are taken for a ride by the B cell, with the B cells leading the way in motile conjugate pairs analagous to helper T cells interacting with activated B cells (146). Motility arrest provides the first sign of the cellular murder that is taking place. After ∼10 min, the monogamous CTL/B pair stop abruptly, and 5–10 min afterward the dually labeled B cells bleed soluble CMTMR from the cytoplasm while nuclear staining remains intact. At this point, the CTL generally detaches from its victim and migrates away in search of another target. The B cell victims are observed blebbing, leaving fragments of the corpses. These cell fragments are later cleaned up by presumptive macrophages that carry fluorescent B cell body parts within granules. In a further fascinating part of this study, when antigen-specific regulatory T cells (Tregs) are present, CTLs recognize their targets and pair off in monogamous and highly motile conjugate pairs, but the targets are not killed, and the CTL/B cell conjugate pairs continue to migrate together until
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the CTL eventually detach, leaving the target unscathed. In contrast to CD8+ T lymphocytes, NK cells need no initial activation and priming step to recognize and kill their target. Target recognition is not antigen specific, although in both cases the lethal hit can be delivered by exocytosis of cytolytic granules or by ligandinduced death. NK cells are restrained from killing through engagement of inhibitory receptors that recognize self–MHC class I. Failure to recognize self–MHC I in combination with activating signals unleashes the lethal potential of NK cells, and their cytotoxic granule contents are released following contact. NK cells reject metastatic cells and bone marrow transplants from MHC-mismatched donors by this mechanism. In the lymph node, NK cells actively patrol the territory near B cell follicles, migrating at 6–7 μm/min (104). Garrod et al. (104) set up allogeneic foreign B cells as potential NK cell targets along with cotransferred syngeneic B cells. Both syngeneic and allogeneic cells migrate at 5– 7 μm/min, and NK cells sample both in a series of short contacts. When allogeneic MHC-mismatched B cells are recognized, NK interactions are prolonged and the B cell targets stop moving. Sometimes several NK cells swarmed a common B cell target. Shortly after dissociation of cognate NK cells, allogeneic B cell blebbing and fragmentation occurred.
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Regulatory T Cells Regulatory T cells (Tregs) modulate numerous types of immune responses and protect against autoimmunity by inhibiting activation responses during antigen priming through mechanisms that may require direct contact between Tregs and DCs and/or bystander effects mediated by cytokines (147–151). Three papers have applied immunoimaging techniques to investigate these processes in different settings of specific T cell priming by introducing Tregs as purified CD25+ cell populations [Foxp3 GFP cells (151) would 612
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be an attractive alternative but unfortunately have low fluorescence]. In a model of type 1 diabetes, CD4+ T (Th) cells specific for islet autoantigens are highly motile and migrate randomly in nondraining inguinal lymph node but swarm and arrest in pancreatic lymph nodes of prediabetic NOD (nonobese diabetic) animals (152). Antigenspecific Tregs behave similarly in both environments. In CD28−/− NOD hosts with fewer Tregs, autoimmune progression is more rapid, and the static clusters of Th cells are predominant. When cotransferred together with CD25+ Tregs, little change is evident, but Tregs transferred ahead of time inhibit swarming and cluster formation of diabetogenic Th cells. Imaging both cells together shows that the presence of Tregs prevents swarming and arrest of Th cells, but without apparent direct interactions. In pancreatic lymph node, where DCs were visible because they had taken up GFP released by dying β cells, dynamic but stable contacts between Th cells and DCs, as well as swarming activity, were observed, reminiscent of T cell/DC dynamics during CD4 T cell priming (117). Tregs also swarm and engage in long-lasting interactions with DCs, but their presence inhibits stable contacts of Th cells with DCs. These results point strongly to indirect actions of Tregs on Th cells, possibly mediated by DCs. Could it be that Tregs somehow reduce the quantity of specific antigen on DCs, or do they produce factors that inhibit antigen recognition by Th cells? Without visualizing Tregs directly, Tadokoro et al. (153) showed that the presence of Tregs inhibits stable contacts of autoreactive myelin basic protein-specific T cells with autoantigen presented in the lymph node following an immunization by injected myelin basic protein. The presence of Tregs in both systems favors robust, apparently normal motility of CD4+ T cells, despite the presence of autoantigens, by inhibition of antigen recognition and the stop signal subsequent to interaction with autoantigen-presenting DCs.
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A somewhat different picture of Treg action was obtained by Mempel and colleagues (145) while imaging the ability of CD8+ CTLs to interact with antigen-presenting target cells. Instead of altering the initial recognition and stable attachment to an APC, Tregs do not inhibit CTL recognition and stable interactions with B cell targets. Instead, Tregs profoundly inhibit the ability of CD8+ CTLs to release cytolytic granules and to lyse the targets (145). Despite being fully armed, potentially dangerous, and in contact with a target that would otherwise be destroyed, CTLs do not deliver the lethal hit. Tregs themselves were imaged in this study but did not interact directly with CD8+ effectors. The ability of Tregs to suppress CD8+ cytolytic function depends on TGF-β production. These results (145) indicate that Tregs can prevent the final cytolytic step of CTL-target interaction but do not interfere with all the previous steps, including the initial priming and subsequent recognition and long-lasting conjugate interaction of CTLs with their targets. A picture thus emerges from these imaging studies that Tregs can exert effects both on initial recognition with APCs and on subsequent activation events.
Activation of B Lymphocytes B cells exhibit great flexibility to capture and respond to antigen in varying contexts. B cells at the follicle edge acquire, sample, and respond to antigen diffusing in or held by macrophages and FDCs. B cells in the follicle interior sample FDCs for antigen captured and displayed on their surface, activate, and then migrate to the edge of the T cell area. In contrast, newly homed B cells sample, respond to, and capture whole antigen displayed on the surface of DCs in the paracortex. T cell help delivered to B cells by direct cell contact is required for B cell immunoglobulin class switching and hypermutation in germinal centers to become high-affinity antibody-producing plasma cells. Live-cell immunoimaging is now illuminating the
underlying choreography of each of these events. B cell–DC interaction. A recent paper presents a fascinating scenario for newly homed B cells on their way to the follicle to interact with cognate antigen-bearing DCs in the paracortex. When specific antigen corresponding to the BCR is present, B cell contact with DC results in B cell Ca2+ signaling, cell arrest, and antigen uptake by newly homed B cells. Qi et al. (113) show that B cells emerging from HEVs make contact with DCs immediately after homing. Soluble antigen, delivered through reticular conduits, is taken up by the DC and presented, in a form recognized by the BCR (i.e., without complete processing to small peptide fragments bound to MHC), to B cells on their way to the follicle. Ca2+ signaling is rapidly initiated, and the B cells fail to localize to the follicle but linger in direct contact with DCs while upregulating surface expression of the chemokine receptor CCR7 and CD86, the costimulatory ligand for CD28 on T cells. This hit-and-run robbery of antigen provides an opportunity for a localized m´enage a` trois, consisting of DCs, T cells, and B cells interacting together locally in the cortical ridge. Thus, DCs may provide a platform for localized T cell–B cell interaction that would potentially accelerate the delivery of T cell help to activating B cells. B cells seeking help by chemotaxis. B cells that are already in the follicle respond to the arrival of antigen in a very different manner. In the absence of antigen, B cells migrate inside the follicle at 6–7 μm/min and follow random trajectories (2). In order for B cells to receive T cell help during antigen challenge, they must make direct contact with CD4+ T cells by migrating to the edge of the follicle (follicular exclusion) after detecting the presence of antigen with their BCRs. Studies by Okada et al. (154) reveal that this is achieved by directed migration of antigen-engaged B cells, rather than by trapping of cells that randomly arrive at the follicle edge (146).
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Antigen induces a rapid upregulation of CCR7 expression that may permit the cells to detect and then migrate directionally along a CCL21 gradient (visualized by immunostaining) projecting from the T cell zone ∼150 μm into the follicle. Initially, antigenengaged B cells move at a reduced rate (4 μm/min) but then later migrate more rapidly, after 1 day, at 8–9 μm/min. Recent studies have confirmed the initial decline in B cell velocity upon antigen engagement, first seen by Okada et al. (146), by visualizing B cells following subcutaneous injection of antigen-coated small particles (112) or antigen-containing immune complexes (23). Okada et al. (146) then went on to show that upon reaching the CCL21 gradient by random migration, the B cells dither but then make consistent progress along more linear paths toward the T zone (a B-line, so to speak). Further supporting this interpretation, Okada et al. (154) showed that CCR7−/− antigen-specific B cells fail to relocate, as do CCR7+/+ in plt recipients that lack CCL19 and CCL21, consistent with conclusions from static imaging of fixed tissue (51). The directed migration of B cells may be the first example in which chemotaxis (or more properly haptotaxis) of lymphocytes has been clearly visualized in the lymph node.
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T cells delivering help: B cell/T cell waltz at the follicle edge. B cells that encounter activated T cells at the edge of the follicle form stable, motile conjugate pairs and migrate as partners, waltzing at the follicle edge with the characteristic velocity of an activated B cell (146). The B cell always leads, dragging the T cell behind as a rounded partner, sharing the dance floor with activated solitary T and B cells. Although generally stable (with contacts often lasting >45 min), conjugate pairs also undergo partner exchange, with single B or T cells cutting in on a motile pair. Activated solitary T and B cells that have not yet paired off migrate in the same region with conjugate pairs, the T cells more rapidly at ∼12 μm/min. During partner exchange, con614
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tact between two Bs and one T or between one B and two Ts (threesomes) rarely lasts more than a minute or two before the new T/B pair moves away (146), resulting in serial monogamy. Rare long-lasting threesomes do not migrate effectively. T cell help to B cells promotes differentiation of B cells to antibody-producing plasma cells. But what purpose might be served by the motility of cognate T/B pairs and by partner exchange? As B cells present antigen to T cells, the resultant T cell Ca2+ signaling will inhibit T cell motility, permitting coordinated motion to be led by the B cell. Polarized cytokine secretion by helper T cells in contact with B cells was discovered nearly 20 years ago (155), and more recently Huse and colleagues (137) showed that T cells can secrete certain cytokines locally toward the B cell, while releasing other cytokines and chemokines multidirectionally from the distal side of a T cell engaged with a B cell partner. Thus, polarized cytokine production in a motile conjugate pair may allow the T cell to secrete IL-2 and IFN-γ locally into the immunological synapse for a private conversation with the B cell, while at the same time broadcasting IL-4, tumor necrosis factor, and the chemokine CCL3 into the surrounding tissue. The motility of the conjugate pair would allow for more extensive distribution of inflammatory cytokines and chemokines than if the cells were immotile. Moreover, their motility may permit the conjugate pair to seek and colonize new territory, with B cells possibly carrying T cells into the follicle, and T cell/B cell partner exchange may optimize T/B cooperation during a mixed antigen response, thereby reducing the likelihood of ineffective T cell help being delivered to the B cell. Germinal center dynamics. Germinal centers are sites of organization for B cells and FDCs, and perhaps also T cells, to interact during a developing humoral immune response. In germinal centers, the humoral immune response becomes fine-tuned to produce high-affinity antibodies generated by
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hypermutation of the variable regions of the antibody locus and by selection of cells. It is thought that competition among newly arising clones underlies a survival advantage for those clones that produce the highest affinity BCR (99). Based on histological examination of fixed tissue, germinal centers are subdivided into dark zones close to the T cell region and more distal light zones. B cell blasts undergoing cell division predominate in the dark zone, and the light zone contains a network of FDCs with extensive fine processes that bind immune complexes. Three recent imaging studies have begun to examine cellular dynamics in germinal centers. All three groups imaged highly motile B cells within the light and dark zones (21, 156, 157). B cells exhibit an elongated, dendritic morphology and migrate similarly at 6 μm/min within both regions. Two populations of B cells, including motile cells that moved along straighter paths than naive B cells and relatively stationary B cells, were distinguished in one study (21). Clusters of relatively stationary B cells make contact with FDCs, sometimes through long membrane tethers. All three groups demonstrated bidirectional migration between light and dark zones, but detailed cell tracking in favorably situated germinal centers showed surprisingly little crossing of the border between light and dark zones in two of the studies (21, 156). Furthermore, episodes of B cell division and death were seen in both light and dark zones (21). Apoptotic B cells release blebs and larger cell fragments including nuclei; both are taken up by macrophages. B cell blebs are also acquired by motile T cells that are present, mainly in the light zone, and that are moving with higher velocity than B cells. T cells are seen to engage B cells only in short-duration contacts, suggesting limited delivery of help at this stage. One group saw frequent visits to the germinal center by follicular B cells (157); another saw B cells leaving toward the T cell area, but not toward the follicle mantle (21). These recent imaging studies are causing reevaluation of a classical model for affinity
maturation (158) to account for B cell proliferation and death in both light and dark zones and to consider the implications of a low incidence of interzonal migration (21, 99, 156). In a strict interpretation of the cyclic reentry model, somatic hypermutation during cell division in the dark zone and selection events in the light zone would require migration from the light zone to the dark zone and back to the light zone, necessitating double crossing of the zonal boundary (once in each direction) during each cell cycle. The relative infrequency of such border crossings and the corresponding primarily intrazonal pattern of migration may favor a model of intrazonal germinal center development in which B cells need not migrate to and fro in order to be selected (21). A revised cyclic reentry model would allow recombination and division in both subcompartments and considers competition for germinal center T cells to promote selection of favorable rearrangements (99). Direct tracking of antigen, along with longerterm and wider-field imaging, may help to distinguish these models or to reveal aspects of both in differing circumstances.
IMMUNOIMAGING APPLIED TO OTHER ORGANS: A BRIEF OVERVIEW In addition to enabling the dynamics of lymphocyte motility and cellular interactions to be imaged within lymph nodes, two-photon immunoimaging is being applied in several other sites. Page constraints prohibit a detailed account of these results, but two-photon imaging has been effectively performed in spleen (159–162), thymus (1, 24, 129), bone marrow (163–165), skin (166; D. Sen, M. Matheu, M.D. Cahalan, and I. Parker, unpublished observations), gut (167, 168), the central nervous system (169, 170), and tumors (171–174). Highlights particularly relevant to themes developed in this review include the mixture of randomly oriented and highly directional paths of developing thymocytes during positive selection in the thymus (24);
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gesticulation of dynamic DC dendrites into the gut lumen (168); extrusion of protoplatelets from megakaryocytes into blood vessels (165); random migration and arrest of encephalitogenic T cells invading the spinal cord and recognizing myelin autoantigens (170); and the random migration and stable target interactions of tumor-infiltrating lymphocytes (173) and cytotoxic T lymphocytes (171) in the tumor microenvironment. Random walks, chemokine receptors, antigen acquisition, cell recognition events, and stop signals no doubt apply in many of these settings.
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SUMMARY AND FUTURE DIRECTIONS The advent of two-photon microscopy allows us to visualize, in real-time and deep within intact organs and tissues, the ongoing cellular drama of the immune system under basal conditions and during responses to antigen. Although previous static imaging approaches had provided great insights, they may be likened to trying to understand the rules of baseball using only still photographs. Dynamic, multidimensional imaging is now helping us comprehend the cellular rules of the game inside the lymph node and other organs. The field has evolved beyond initial phenomenological descriptions, and quantitative analyses together with computer modeling and simulation are beginning to make sense of the apparently chaotic activity within lymph nodes as lymphocytes continually migrate amid the waving dendrites of DCs. At a macroscopic scale, random-walk motility prevails, constituting a swarm intelligence of autonomous cellular elements that enables efficient and highly sensitive scanning for rare antigens. However, at a microscopic level, the individual cell motions are clearly directed both by chemokine gradients and by structural elements, as, for example, with the antigen-induced march of the B cells toward the T cell area, the migration of CD8+ cells toward DC/T cell clusters, and 616
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the regulation of lymphocyte egress from the node. At least nine types of cellular close encounters have now been visualized by live-cell immunoimaging in the lymph node, providing fresh insight on modes of cell communication during basal migration, antigen capture, antigen recognition, cell activation, differentiation, and death. (a) Under basal conditions, T cells migrate along FRCs that provide haptokinetic signaling to enhance their velocity. (b) In their ongoing search for antigen, T cells scan dynamic DC dendrites in short-lived, randomly initiated encounters. (c) After emerging from the HEV into the paracortex, newly homed B cells scan the DC surface for whole antigen. (d ) Inside the follicle, B cells migrate in direct contact with FDCs, exchanging antigen back and forth. (e) B cells scan subcapsular macrophages and other B cells, capture immune complexes and particulate antigen, and convey the cargo to other sites. ( f ) Upon encountering specific antigen, both T and B cells undergo Ca2+ signaling, arrest, and upregulation of gene expression, which lead to directed migration, cytokine secretion, and cell proliferation. (g) After migrating to the follicle edge, B cells pair with T cells and waltz while receiving their help. (h) Foreign or tumor cells are killed by activated CD8+ cytolytic T cells. (i ) Foreign cells are killed by NK cells. The application of live-cell in vivo imaging to the immune system has just begun, and we can anticipate that technological advances in microscopy and design of improved morphological and functional probes will provide new opportunities. Purely descriptive studies are being supplanted by a new functional immunoimaging approach that takes advantage of targeted gene deletion or overexpression and the application of selective pharmacological agents or antibodies to pinpoint molecular targets. Particularly important developments will be to apply immunoimaging to visualize host/pathogen dynamics and to elucidate and refine the actions of therapeutic agents at the level of cellular dynamics. Ultimately,
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these methods may be applied to diagnose and treat human disease as well as continue
to illuminate cellular and molecular mechanisms in the immune response.
DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.
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ACKNOWLEDGMENTS The authors thank members of our joint laboratory group—Melanie Matheu, Debasish Sen, Ying Yu, and Kym Garrod—for their comments on the manuscript, and M. Matheu and Y. Yu for assistance in preparing figures. In addition, we wish to thank Mark Miller (Washington University) and David Fruman (University of California, Irvine) for their careful reading and helpful suggestions. This work is supported by grants from the National Institutes of Health (GM41514 to M.D.C. and GM-48071 to I.P.).
LITERATURE CITED 1. Bousso P, Bhakta NR, Lewis RS, Robey E. 2002. Dynamics of thymocyte-stromal cell interactions visualized by two-photon microscopy. Science 296:1876–80 2. Miller MJ, Wei SH, Parker I, Cahalan MD. 2002. Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. Science 296:1869–73 3. Stoll S, Delon J, Brotz TM, Germain RN. 2002. Dynamic imaging of T cell-dendritic cell interactions in lymph nodes. Science 296:1873–76 4. Petty HR. 2007. Fluorescence microscopy: established and emerging methods, experimental strategies, and applications in immunology. Microsc. Res. Tech. 70:687–709 5. Nimmerjahn A, Kirchhoff F, Helmchen F. 2005. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–18 6. Oheim M, Beaurepaire E, Chaigneau E, Mertz J, Charpak S. 2001. Two-photon microscopy in brain tissue: parameters influencing the imaging depth. J. Neurosci. Methods 111:29–37 7. Cahalan MD, Parker I, Wei SH, Miller MJ. 2002. Two-photon tissue imaging: seeing the immune system in a fresh light. Nat. Rev. Immunol. 2:872–80 8. Germain RN, Miller MJ, Dustin ML, Nussenzweig MC. 2006. Dynamic imaging of the immune system: progress, pitfalls and promise. Nat. Rev. Immunol. 6:497–507 9. Mempel TR, Scimone ML, Mora JR, von Andrian UH. 2004. In vivo imaging of leukocyte trafficking in blood vessels and tissues. Curr. Opin. Immunol. 16:406–17 10. Dickinson ME, Simbuerger E, Zimmermann B, Waters CW, Fraser SE. 2003. Multiphoton excitation spectra in biological samples. J. Biomed. Opt. 8:329–38 11. Mertz J. 2004. Nonlinear microscopy: new techniques and applications. Curr. Opin. Neurobiol. 14:610–16 12. Mohler W, Millard AC, Campagnola PJ. 2003. Second harmonic generation imaging of endogenous structural proteins. Methods 29:97–109 13. Levene MJ, Dombeck DA, Kasischke KA, Molloy RP, Webb WW. 2004. In vivo multiphoton microscopy of deep brain tissue. J. Neurophysiol. 91:1908–12 14. Booth MJ, Neil MA, Juskaitis R, Wilson T. 2002. Adaptive aberration correction in a confocal microscope. Proc. Natl. Acad. Sci. USA 99:5788–92 www.annualreviews.org • Cell Motility and Interaction Dynamics Imaged
617
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15. Niesner RA, Andresen V, Neumann J, Spiecker H, Gunzer M. 2007. The power of singleand multibeam 2-photon microscopy for high-resolution and high-speed deep tissue and intravital imaging. Biophys. J. 93:2519–29 16. Gobel W, Kerr JN, Nimmerjahn A, Helmchen F. 2004. Miniaturized two-photon microscope based on a flexible coherent fiber bundle and a gradient-index lens objective. Opt. Lett. 29:2521–23 17. Jung JC, Mehta AD, Aksay E, Stepnoski R, Schnitzer MJ. 2004. In vivo mammalian brain imaging using one- and two-photon fluorescence microendoscopy. J. Neurophysiol. 92:3121–33 18. Giepmans BN, Adams SR, Ellisman MH, Tsien RY. 2006. The fluorescent toolbox for assessing protein location and function. Science 312:217–24 19. Straight AF. 2007. Fluorescent protein applications in microscopy. Methods Cell Biol. 81:93–113 20. Spiess E, Bestvater F, Heckel-Pompey A, Toth K, Hacker M, et al. 2005. Two-photon excitation and emission spectra of the green fluorescent protein variants ECFP, EGFP and EYFP. J. Microsc. 217:200–4 21. Hauser AE, Junt T, Mempel TR, Sneddon MW, Kleinstein SH, et al. 2007. Definition of germinal-center B cell migration in vivo reveals predominant intrazonal circulation patterns. Immunity 26:655–67 22. Lindquist RL, Shakhar G, Dudziak D, Wardemann H, Eisenreich T, et al. 2004. Visualizing dendritic cell networks in vivo. Nat. Immunol. 5:1243–50 23. Phan TG, Grigorova I, Okada T, Cyster JG. 2007. Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells. Nat. Immunol. 8:992–1000 24. Witt CM, Raychaudhuri S, Schaefer B, Chakraborty AK, Robey EA. 2005. Directed migration of positively selected thymocytes visualized in real time. PLoS Biol. 3:1062–69 25. Bajenoff M, Egen JG, Koo LY, Laugier JP, Brau F, et al. 2006. Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity 25:989– 1001 26. Miller MJ, Wei SH, Cahalan MD, Parker I. 2003. Autonomous T cell trafficking examined in vivo with intravital two-photon microscopy. Proc. Natl. Acad. Sci. USA 100:2604–9 27. Sumen C, Mempel TR, Mazo IB, von Andrian UH. 2004. Intravital microscopy: visualizing immunity in context. Immunity 21:315–29 28. Gowans JL. 1959. The recirculation of lymphocytes from blood to lymph in the rat. J. Physiol. 146:54–69 29. Gowans JL, Knight EJ. 1964. The route of re-circulation of lymphocytes in the rat. Proc. R. Soc. London B Biol. Sci. 159:257–82 30. Marchesi VT, Gowans JL. 1964. The migration of lymphocytes through the endothelium of venules in lymph nodes: an electron microscope study. Proc. R. Soc. London B Biol. Sci. 159:283–90 31. Campbell DJ, Kim CH, Butcher EC. 2003. Chemokines in the systemic organization of immunity. Immunol. Rev. 195:58–71 32. Gallatin WM, Weissman IL, Butcher EC. 1983. A cell-surface molecule involved in organ-specific homing of lymphocytes. Nature 304:30–34 33. Gutman GA, Weissman IL. 1972. Lymphoid tissue architecture. Experimental analysis of the origin and distribution of T-cells and B-cells. Immunology 23:465–79 34. von Andrian UH, Mempel TR. 2003. Homing and cellular traffic in lymph nodes. Nat. Rev. Immunol. 3:867–78
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35. de Boisfleury-Chevance A, Rapp B, Gruler H. 1989. Locomotion of white blood cells: a biophysical analysis. Blood Cells 15:315–33 36. Haston WS, Shields JM, Wilkinson PC. 1982. Lymphocyte locomotion and attachment on two-dimensional surfaces and in three-dimensional matrices. J. Cell Biol. 92:747–52 37. Noble PB, Boyarsky A, Bentley KC. 1979. Human lymphocyte migration in vitro: characterization and quantitation of locomotory parameters. Can. J. Physiol. Pharmacol. 57:108– 12 38. Negulescu PA, Krasieva TB, Khan A, Kerschbaum HH, Cahalan MD. 1996. Polarity of T cell shape, motility, and sensitivity to antigen. Immunity 4:421–30 39. Groves JT, Dustin ML. 2003. Supported planar bilayers in studies on immune cell adhesion and communication. J. Immunol. Methods 278:19–32 40. Friedl P, den Boer AT, Gunzer M. 2005. Tuning immune responses: diversity and adaptation of the immunological synapse. Nat. Rev. Immunol. 5:532–45 41. Gunzer M, Schafer A, Borgmann S, Grabbe S, Zanker KS, et al. 2000. Antigen presentation in extracellular matrix: interactions of T cells with dendritic cells are dynamic, short lived, and sequential. Immunity 13:323–32 42. Gunzer M, Weishaupt C, Hillmer A, Basoglu Y, Friedl P, et al. 2004. A spectrum of biophysical interaction modes between T cells and different antigen-presenting cells during priming in 3-D collagen and in vivo. Blood 104:2801–9 43. Stachowiak AN, Wang Y, Huang YC, Irvine DJ. 2006. Homeostatic lymphoid chemokines synergize with adhesion ligands to trigger T and B lymphocyte chemokinesis. J. Immunol. 177:2340–48 44. Doh J, Irvine DJ. 2006. Immunological synapse arrays: patterned protein surfaces that modulate immunological synapse structure formation in T cells. Proc. Natl. Acad. Sci. USA 103:5700–5 45. Dustin ML, Bromley SK, Kan Z, Peterson DA, Unanue ER. 1997. Antigen receptor engagement delivers a stop signal to migrating T lymphocytes. Proc. Natl. Acad. Sci. USA 94:3909–13 46. Huang AY, Qi H, Germain RN. 2004. Illuminating the landscape of in vivo immunity: insights from dynamic in situ imaging of secondary lymphoid tissues. Immunity 21:331–39 47. Huang JH, Cardenas-Navia LI, Caldwell CC, Plumb TJ, Radu CG, et al. 2007. Requirements for T lymphocyte migration in explanted lymph nodes. J. Immunol. 178:7747–55 48. Worbs T, Mempel TR, Bolter J, von Andrian UH, Forster R. 2007. CCR7 ligands stimulate the intranodal motility of T lymphocytes in vivo. J. Exp. Med. 204:489–95 49. Mempel TR, Henrickson SE, Von Andrian UH. 2004. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427:154–59 50. Shakhar G, Lindquist RL, Skokos D, Dudziak D, Huang JH, et al. 2005. Stable T celldendritic cell interactions precede the development of both tolerance and immunity in vivo. Nat. Immunol. 6:707–14 51. Reif K, Ekland EH, Ohl L, Nakano H, Lipp M, et al. 2002. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature 416:94–99 52. Cyster JG. 2005. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu. Rev. Immunol. 23:127–59 53. Gretz JE, Anderson AO, Shaw S. 1997. Cords, channels, corridors and conduits: critical architectural elements facilitating cell interactions in the lymph node cortex. Immunol. Rev. 156:11–24 54. Anderson AO, Anderson ND. 1975. Studies on the structure and permeability of the microvasculature in normal rat lymph nodes. Am. J. Pathol. 80:387–418 www.annualreviews.org • Cell Motility and Interaction Dynamics Imaged
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55. Gretz JE, Norbury CC, Anderson AO, Proudfoot AE, Shaw S. 2000. Lymph-borne chemokines and other low molecular weight molecules reach high endothelial venules via specialized conduits while a functional barrier limits access to the lymphocyte microenvironments in lymph node cortex. J. Exp. Med. 192:1425–40 56. Katakai T, Hara T, Lee JH, Gonda H, Sugai M, Shimizu A. 2004. A novel reticular stromal structure in lymph node cortex: an immuno-platform for interactions among dendritic cells, T cells and B cells. Int. Immunol. 16:1133–42 57. Asperti-Boursin F, Real E, Bismuth G, Trautmann A, Donnadieu E. 2007. CCR7 ligands control basal T cell motility within lymph node slices in a phosphoinositide 3-kinaseindependent manner. J. Exp. Med. 204:1167–79 58. Friedman RS, Jacobelli J, Krummel MF. 2006. Surface-bound chemokines capture and prime T cells for synapse formation. Nat. Immunol. 7:1101–8 59. Weninger W, von Andrian UH. 2003. Chemokine regulation of naive T cell traffic in health and disease. Semin. Immunol. 15:257–70 60. Zlotnik A, Yoshie O, Nomiyama H. 2006. The chemokine and chemokine receptor superfamilies and their molecular evolution. Genome Biol. 7:243 61. Viola A, Contento RL, Molon B. 2006. T cells and their partners: the chemokine dating agency. Trends Immunol. 27:421–27 62. Rot A, von Andrian UH. 2004. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu. Rev. Immunol. 22:891–928 63. Woolf E, Grigorova I, Sagiv A, Grabovsky V, Feigelson SW, et al. 2007. Lymph node chemokines promote sustained T lymphocyte motility without triggering stable integrin adhesiveness in the absence of shear forces. Nat. Immunol. 8:1076–85 64. Okada T, Cyster JG. 2007. CC chemokine receptor 7 contributes to Gi-dependent T cell motility in the lymph node. J. Immunol. 178:2973–78 65. Han SB, Moratz C, Huang NN, Kelsall B, Cho H, et al. 2005. Rgs1 and Gnai2 regulate the entrance of B lymphocytes into lymph nodes and B cell motility within lymph node follicles. Immunity 22:343–54 66. Hwang IY, Park C, Kehrl JH. 2007. Impaired trafficking of Gnai2+/− and Gnai2−/− T lymphocytes: implications for T cell movement within lymph nodes. J. Immunol. 179:439– 48 67. Luther SA, Bidgol A, Hargreaves DC, Schmidt A, Xu Y, et al. 2002. Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J. Immunol. 169:424–33 68. Hogg N, Smith A, McDowall A, Giles K, Stanley P, et al. 2004. How T cells use LFA-1 to attach and migrate. Immunol. Lett. 92:51–54 69. Merlot S, Firtel RA. 2003. Leading the way: directional sensing through phosphatidylinositol 3-kinase and other signaling pathways. J. Cell Sci. 116:3471–78 70. Matheu MP, Deane JA, Parker I, Fruman DA, Cahalan MD. 2007. Class IA phosphoinositide 3-kinase modulates basal lymphocyte motility in the lymph node. J. Immunol. 179:2261–69 71. Reif K, Okkenhaug K, Sasaki T, Penninger JM, Vanhaesebroeck B, Cyster JG. 2004. Cutting edge: differential roles for phosphoinositide 3-kinases, p110γ and p110δ, in lymphocyte chemotaxis and homing. J. Immunol. 173:2236–40 72. Nombela-Arrieta C, Lacalle RA, Montoya MC, Kunisaki Y, Megias D, et al. 2004. Differential requirements for DOCK2 and phosphoinositide-3-kinase γ during T and B lymphocyte homing. Immunity 21:429–41 73. Hirsch E, Katanaev VL, Garlanda C, Azzolino O, Pirola L, et al. 2000. Central role for G protein-coupled phosphoinositide 3-kinase γ in inflammation. Science 287:1049–53
Annu. Rev. Immunol. 2008.26:585-626. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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ANRV338-IY26-19
ARI
16 February 2008
13:34
74. Li Z, Jiang H, Xie W, Zhang Z, Smrcka AV, Wu D. 2000. Roles of PLC-β2 and -β3 and PI3Kγ in chemoattractant-mediated signal transduction. Science 287:1046–49 75. Sasaki T, Irie-Sasaki J, Jones RG, Oliveira-dos-Santos AJ, Stanford WL, et al. 2000. Function of PI3Kγ in thymocyte development, T cell activation, and neutrophil migration. Science 287:1040–46 76. Nombela-Arrieta C, Mempel TR, Soriano SF, Mazo I, Wymann MP, et al. 2007. A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphatemediated egress. J. Exp. Med. 204:497–510 77. Shulman Z, Pasvolsky R, Woolf E, Grabovsky V, Feigelson SW, et al. 2006. DOCK2 regulates chemokine-triggered lateral lymphocyte motility but not transendothelial migration. Blood 108:2150–58 78. Fukui Y, Hashimoto O, Sanui T, Oono T, Koga H, et al. 2001. Haematopoietic cellspecific CDM family protein DOCK2 is essential for lymphocyte migration. Nature 412:826–31 79. Wei SH, Safrina O, Yu Y, Garrod KR, Cahalan MD, Parker I. 2007. Ca2+ signals in CD4+ T cells during early contacts with antigen-bearing dendritic cells in lymph node. J. Immunol. 179:1586–94 80. Revy P, Sospedra M, Barbour B, Trautmann A. 2001. Functional antigen-independent synapses formed between T cells and dendritic cells. Nat. Immunol. 2:925–31 81. Delon J, Stoll S, Germain RN. 2002. Imaging of T-cell interactions with antigen presenting cells in culture and in intact lymphoid tissue. Immunol. Rev. 189:51–63 82. Fischer UB, Jacovetty EL, Medeiros RB, Goudy BD, Zell T, et al. 2007. MHC class II deprivation impairs CD4 T cell motility and responsiveness to antigen-bearing dendritic cells in vivo. Proc. Natl. Acad. Sci. USA 104:7181–86 83. Wei SH, Parker I, Miller MJ, Cahalan MD. 2003. A stochastic view of lymphocyte motility and trafficking within the lymph node. Immunol. Rev. 195:136–59 84. Wei SH, Rosen H, Matheu MP, Sanna MG, Wang SK, et al. 2005. Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses. Nat. Immunol. 6:1228–35 85. Hargreaves DC, Hyman PL, Lu TT, Ngo VN, Bidgol A, et al. 2001. A coordinated change in chemokine responsiveness guides plasma cell movements. J. Exp. Med. 194:45– 56 86. Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, et al. 2002. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296:346– 49 87. Sanna MG, Liao J, Jo E, Alfonso C, Ahn MY, et al. 2004. Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J. Biol. Chem. 279:13839–48 88. Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, et al. 2004. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427:355–60 89. Rosen H, Goetzl EJ. 2005. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat. Rev. Immunol. 5:560–70 90. Rosen H, Sanna MG, Cahalan SM, Gonzalez-Cabrera PJ. 2007. Tipping the gatekeeper: S1P regulation of endothelial barrier function. Trends Immunol. 28:102–7 91. Sanna MG, Wang SK, Gonzalez-Cabrera PJ, Don A, Marsolais D, et al. 2006. Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nat. Chem. Biol. 2:434–41 www.annualreviews.org • Cell Motility and Interaction Dynamics Imaged
621
ARI
16 February 2008
13:34
92. Gonzalez-Cabrera PJ, Hla T, Rosen H. 2007. Mapping pathways downstream of sphingosine 1-phosphate subtype 1 by differential chemical perturbation and proteomics. J. Biol. Chem. 282:7254–64 93. Halin C, Scimone ML, Bonasio R, Gauguet JM, Mempel TR, et al. 2005. The S1Panalog FTY720 differentially modulates T-cell homing via HEV: T-cell-expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer patches. Blood 106:1314–22 94. Mempel TR, Junt T, von Andrian UH. 2006. Rulers over randomness: stroma cells guide lymphocyte migration in lymph nodes. Immunity 25:867–69 95. Westermann J, Bode U, Sahle A, Speck U, Karin N, et al. 2005. Naive, effector, and memory T lymphocytes efficiently scan dendritic cells in vivo: contact frequency in T cell zones of secondary lymphoid organs does not depend on LFA-1 expression and facilitates survival of effector T cells. J. Immunol. 174:2517–24 96. Miller MJ, Hejazi AS, Wei SH, Cahalan MD, Parker I. 2004. T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in the lymph node. Proc. Natl. Acad. Sci. USA 101:998–1003 97. Cyster JG, Ansel KM, Reif K, Ekland EH, Hyman PL, et al. 2000. Follicular stromal cells and lymphocyte homing to follicles. Immunol. Rev. 176:181–93 98. Kosco-Vilbois MH. 2003. Are follicular dendritic cells really good for nothing? Nat. Rev. Immunol. 3:764–69 99. Allen CD, Okada T, Cyster JG. 2007. Germinal-center organization and cellular dynamics. Immunity 27:190–202 100. Moretta A, Marcenaro E, Parolini S, Ferlazzo G, Moretta L. 2007. NK cells at the interface between innate and adaptive immunity. Cell Death Differ. In press 101. Chen S, Kawashima H, Lowe JB, Lanier LL, Fukuda M. 2005. Suppression of tumor formation in lymph nodes by L-selectin-mediated natural killer cell recruitment. J. Exp. Med. 202:1679–89 102. Martin-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, et al. 2004. Induced recruitment of NK cells to lymph nodes provides IFN-γ for T(H)1 priming. Nat. Immunol. 5:1260–65 103. Bajenoff M, Breart B, Huang AY, Qi H, Cazareth J, et al. 2006. Natural killer cell behavior in lymph nodes revealed by static and real-time imaging. J. Exp. Med. 203:619–31 104. Garrod KR, Wei SH, Parker I, Cahalan MD. 2007. Natural killer cells actively patrol peripheral lymph nodes forming stable conjugates to eliminate MHC-mismatched targets. Proc. Natl. Acad. Sci. USA 104:12081–86 105. Itano AA, McSorley SJ, Reinhardt RL, Ehst BD, Ingulli E, et al. 2003. Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity. Immunity 19:47–57 106. Sixt M, Kanazawa N, Selg M, Samson T, Roos G, et al. 2005. The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Immunity 22:19–29 107. Kissenpfennig A, Henri S, Dubois B, Laplace-Builhe C, Perrin P, et al. 2005. Dynamics and function of Langerhans cells in vivo dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells. Immunity 22:643–54 ¨ 108. Mart´ın-Fontecha A, Sebastiani S, Hopken UE, Uguccioni M, Lipp M, et al. 2003. Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J. Exp. Med. 198:615–21
Annu. Rev. Immunol. 2008.26:585-626. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-19
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ANRV338-IY26-19
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16 February 2008
13:34
109. Agrawal S, Agrawal A, Doughty B, Gerwitz A, Blenis J, et al. 2003. Cutting edge: different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. J. Immunol. 171:4984–89 110. Pulendran B. 2004. Modulating vaccine responses with dendritic cells and Toll-like receptors. Immunol. Rev. 199:227–50 111. Pape KA, Catron DM, Itano AA, Jenkins MK. 2007. The humoral immune response is initiated in lymph nodes by B cells that acquire soluble antigen directly in the follicles. Immunity 26:491–502 112. Carrasco YR, Batista FD. 2007. B cells acquire particulate antigen in a macrophage-rich area at the boundary between the follicle and the subcapsular sinus of the lymph node. Immunity 27:160–71 113. Qi H, Egen JG, Huang AY, Germain RN. 2006. Extrafollicular activation of lymph node B cells by antigen-bearing dendritic cells. Science 312:1672–76 114. Bousso P, Robey E. 2003. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes. Nat. Immunol. 4:579–85 115. Wei X, Tromberg BJ, Cahalan MD. 1999. Mapping the sensitivity of T cells with an optical trap: polarity and minimal number of receptors for Ca2+ signaling. Proc. Natl. Acad. Sci. USA 96:8471–76 116. Kaiser A, Donnadieu E, Abastado JP, Trautmann A, Nardin A. 2005. CC chemokine ligand 19 secreted by mature dendritic cells increases naive T cell scanning behavior and their response to rare cognate antigen. J. Immunol. 175:2349–56 117. Miller MJ, Safrina O, Parker I, Cahalan MD. 2004. Imaging the single cell dynamics of CD4+ T cell activation by dendritic cells in lymph nodes. J. Exp. Med. 200:847–56 118. Feske S. 2007. Calcium signalling in lymphocyte activation and disease. Nat. Rev. Immunol. 7:690–702 119. Cahalan MD, Zhang SL, Yeromin AV, Ohlsen K, Roos J, Stauderman KA. 2007. Molecular basis of the CRAC channel. Cell Calcium 42:133–44 120. Lewis RS. 2007. The molecular choreography of a store-operated calcium channel. Nature 446:284–87 121. Fanger CM, Hoth M, Crabtree GR, Lewis RS. 1995. Characterization of T cell mutants with defects in capacitative calcium entry: genetic evidence for the physiological roles of CRAC channels. J. Cell Biol. 131:655–67 122. Feske S, Giltnane J, Dolmetsch R, Staudt LM, Rao A. 2001. Gene regulation mediated by calcium signals in T lymphocytes. Nat. Immunol. 2:316–24 123. Negulescu PA, Shastri N, Cahalan MD. 1994. Intracellular calcium dependence of gene expression in single T lymphocytes. Proc. Natl. Acad. Sci. USA 91:2873–77 124. Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI. 1997. Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386:855–58 125. Dolmetsch RE, Xu K, Lewis RS. 1998. Calcium oscillations increase the efficiency and specificity of gene expression. Nature 392:933–36 126. Skokos D, Shakhar G, Varma R, Waite JC, Cameron TO, et al. 2007. Peptide-MHC potency governs dynamic interactions between T cells and dendritic cells in lymph nodes. Nat. Immunol. 8:835–44 127. Donnadieu E, Cefai D, Tan YP, Paresys G, Bismuth G, Trautmann A. 1992. Imaging early steps of human T cell activation by antigen-presenting cells. J. Immunol. 148:2643–53 128. Donnadieu E, Bismuth G, Trautmann A. 1994. Antigen recognition by helper T cells elicits a sequence of distinct changes of their shape and intracellular calcium. Curr. Biol. 4:584–95 www.annualreviews.org • Cell Motility and Interaction Dynamics Imaged
623
ARI
16 February 2008
13:34
129. Bhakta NR, Oh DY, Lewis RS. 2005. Calcium oscillations regulate thymocyte motility during positive selection in the three-dimensional thymic environment. Nat. Immunol. 6:143–51 130. Schneider H, Downey J, Smith A, Zinselmeyer BH, Rush C, et al. 2006. Reversal of the TCR stop signal by CTLA-4. Science 313:1972–75 131. Cahalan MD, Gutman GA. 2006. The sense of place in the immune system. Nat. Immunol. 7:329–32 132. Obst R, van Santen HM, Mathis D, Benoist C. 2005. Antigen persistence is required throughout the expansion phase of a CD4+ T cell response. J. Exp. Med. 201:1555–65 133. Kedl RM, Schaefer BC, Kappler JW, Marrack P. 2002. T cells down-modulate peptideMHC complexes on APCs in vivo. Nat. Immunol. 3:27–32 134. Hugues S, Fetler L, Bonifaz L, Helft J, Amblard F, Amigorena S. 2004. Distinct T cell dynamics in lymph nodes during the induction of tolerance and immunity. Nat. Immunol. 5:1235–42 135. Zinselmeyer BH, Dempster J, Gurney AM, Wokosin D, Miller M, et al. 2005. In situ characterization of CD4+ T cell behavior in mucosal and systemic lymphoid tissues during the induction of oral priming and tolerance. J. Exp. Med. 201:1815–23 136. Celli S, Garcia Z, Bousso P. 2005. CD4 T cells integrate signals delivered during successive DC encounters in vivo. J. Exp. Med. 202:1271–78 137. Huse M, Lillemeier BF, Kuhns MS, Chen DS, Davis MM. 2006. T cells use two directionally distinct pathways for cytokine secretion. Nat. Immunol. 7:247–55 138. Catron DM, Rusch LK, Hataye J, Itano AA, Jenkins MK. 2006. CD4+ T cells that enter the draining lymph nodes after antigen injection participate in the primary response and become central-memory cells. J. Exp. Med. 203:1045–54 139. Garcia Z, Pradelli E, Celli S, Beuneu H, Simon A, Bousso P. 2007. Competition for antigen determines the stability of T cell-dendritic cell interactions during clonal expansion. Proc. Natl. Acad. Sci. USA 104:4553–58 140. Guarda G, Hons M, Soriano SF, Huang AY, Polley R, et al. 2007. L-selectin-negative CCR7-effector and memory CD8+ T cells enter reactive lymph nodes and kill dendritic cells. Nat. Immunol. 8:743–52 141. Bevan MJ. 2004. Helping the CD8+ T-cell response. Nat. Rev. Immunol. 4:595–602 142. Beuneu H, Garcia Z, Bousso P. 2006. Cutting edge: cognate CD4 help promotes recruitment of antigen-specific CD8 T cells around dendritic cells. J. Immunol. 177:1406–10 143. Castellino F, Germain RN. 2007. Chemokine-guided CD4+ T cell help enhances generation of IL-6Rαhigh IL-7Rαhigh prememory CD8+ T cells. J. Immunol. 178:778–87 144. Hugues S, Scholer A, Boissonnas A, Nussbaum A, Combadiere C, et al. 2007. Dynamic imaging of chemokine-dependent CD8+ T cell help for CD8+ T cell responses. Nat. Immunol. 8:921–30 145. Mempel TR, Pittet MJ, Khazaie K, Weninger W, Weissleder R, et al. 2006. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25:129–41 146. Okada T, Miller MJ, Parker I, Krummel MF, Neighbors M, et al. 2005. Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells. PLoS Biol. 3:1047–61 147. Fontenot JD, Rudensky AY. 2005. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat. Immunol. 6:331–37
Annu. Rev. Immunol. 2008.26:585-626. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-19
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Cahalan
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ANRV338-IY26-19
ARI
16 February 2008
13:34
148. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. 1995. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155:1151–64 149. Shevach EM. 2000. Regulatory T cells in autoimmmunity. Annu. Rev. Immunol. 18:423– 49 150. von Boehmer H. 2005. Mechanisms of suppression by suppressor T cells. Nat. Immunol. 6:338–44 151. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. 2005. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22:329–41 152. Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, et al. 2006. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat. Immunol. 7:83–92 153. Tadokoro CE, Shakhar G, Shen S, Ding Y, Lino AC, et al. 2006. Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J. Exp. Med. 203:505–11 154. Okada T, Cyster JG. 2006. B cell migration and interactions in the early phase of antibody responses. Curr. Opin. Immunol. 18:278–85 155. Poo WJ, Conrad L, Janeway CA Jr. 1988. Receptor-directed focusing of lymphokine release by helper T cells. Nature 332:378–80 156. Allen CD, Okada T, Tang HL, Cyster JG. 2007. Imaging of germinal center selection events during affinity maturation. Science 315:528–31 157. Schwickert TA, Lindquist RL, Shakhar G, Livshits G, Skokos D, et al. 2007. In vivo imaging of germinal centres reveals a dynamic open structure. Nature 446:83–87 158. MacLennan IC. 1994. Germinal centers. Annu. Rev. Immunol. 12:117–39 159. Grayson MH, Hotchkiss RS, Karl IE, Holtzman MJ, Chaplin DD. 2003. Intravital microscopy comparing T lymphocyte trafficking to the spleen and the mesenteric lymph node. Am. J. Physiol. Heart Circ. Physiol. 284:H2213–26 160. Morelli AE, Larregina AT, Shufesky WJ, Zahorchak AF, Logar AJ, et al. 2003. Internalization of circulating apoptotic cells by splenic marginal zone dendritic cells: dependence on complement receptors and effect on cytokine production. Blood 101:611–20 161. Odoardi F, Kawakami N, Li Z, Cordiglieri C, Streyl K, et al. 2007. Instant effect of soluble antigen on effector T cells in peripheral immune organs during immunotherapy of autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 104:920–25 162. Wei SH, Miller MJ, Cahalan MD, Parker I. 2002. Two-photon imaging in intact lymphoid tissue. Adv. Exp. Med. Biol. 512:203–8 163. Cavanagh LL, Bonasio R, Mazo IB, Halin C, Cheng G, et al. 2005. Activation of bone marrow-resident memory T cells by circulating, antigen-bearing dendritic cells. Nat. Immunol. 6:1029–37 164. Cariappa A, Mazo IB, Chase C, Shi HN, Liu H, et al. 2005. Perisinusoidal B cells in the bone marrow participate in T-independent responses to blood-borne microbes. Immunity 23:397–407 165. Junt T, Schulze H, Chen Z, Massberg S, Goerge T, et al. 2007. Dynamic visualization of thrombopoiesis within bone marrow. Science 317:1767–70 166. Chakraverty R, Cote D, Buchli J, Cotter P, Hsu R, et al. 2006. An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues. J. Exp. Med. 203:2021–31 www.annualreviews.org • Cell Motility and Interaction Dynamics Imaged
625
ARI
16 February 2008
13:34
167. Tutsch E, Griesemer D, Schwarz A, Stallmach A, Hoth M. 2004. Two-photon analysis of calcium signals in T lymphocytes of intact lamina propria from human intestine. Eur. J. Immunol. 34:3477–84 168. Chieppa M, Rescigno M, Huang AY, Germain RN. 2006. Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J. Exp. Med. 203:2841–52 169. Nitsch R, Pohl EE, Smorodchenko A, Infante-Duarte C, Aktas O, Zipp F. 2004. Direct impact of T cells on neurons revealed by two-photon microscopy in living brain tissue. J. Neurosci. 24:2458–64 170. Kawakami N, Nagerl UV, Odoardi F, Bonhoeffer T, Wekerle H, Flugel A. 2005. Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion. J. Exp. Med. 201:1805–14 171. Boissonnas A, Fetler L, Zeelenberg IS, Hugues S, Amigorena S. 2007. In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor. J. Exp. Med. 204:345–56 172. Wolf K, Mazo I, Leung H, Engelke K, von Andrian UH, et al. 2003. Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J. Cell Biol. 160:267–77 173. Mrass P, Takano H, Ng LG, Daxini S, Lasaro MO, et al. 2006. Random migration precedes stable target cell interactions of tumor-infiltrating T cells. J. Exp. Med. 203:2749– 61 174. Skala MC, Squirrell JM, Vrotsos KM, Eickhoff JC, Gendron-Fitzpatrick A, et al. 2005. Multiphoton microscopy of endogenous fluorescence differentiates normal, precancerous, and cancerous squamous epithelial tissues. Cancer Res. 65:1180–86
Annu. Rev. Immunol. 2008.26:585-626. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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Annual Review of Immunology
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:585-626. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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Contents
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Annu. Rev. Immunol. 2008.26:627-650. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno Trudeau Institute, Saranac Lake, New York 12983; email:
[email protected] Annu. Rev. Immunol. 2008. 26:627–50
Key Words
The Annual Review of Immunology is online at immunol.annualreviews.org
lymphotoxin, homeostatic chemokine, lymphoid tissue inducer
This article’s doi: 10.1146/annurev.immunol.26.021607.090257
Abstract
c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0627$20.00
Secondary lymphoid organs develop during embryogenesis or in the first few weeks after birth according to a highly coordinated series of interactions between newly emerging hematopoietic cells and immature mesenchymal or stromal cells. These interactions are orchestrated by homeostatic chemokines, cytokines, and growth factors that attract hematopoietic cells to sites of future lymphoid organ development and promote their survival and differentiation. In turn, lymphotoxin-expressing hematopoietic cells trigger the differentiation of stromal and endothelial cells that make up the scaffolding of secondary lymphoid organs. Lymphotoxin signaling also maintains the expression of adhesion molecules and chemokines that govern the ultimate structure and function of secondary lymphoid organs. Here we describe the current paradigm of secondary lymphoid organ development and discuss the subtle differences in the timing, molecular interactions, and cell types involved in the development of each secondary lymphoid organ.
627
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INTRODUCTION ILF: isolated lymphoid follicle NALT: nasal associated lymphoid tissue LTi: lymphoid tissue inducer
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LTin: lymphoid tissue initiator
628
Primary immune responses are initiated in secondary lymphoid organs, including spleen, regional lymph nodes, Peyer’s patches, isolated lymphoid follicles (ILFs), tonsils, and nasal associated lymphoid tissue (NALT). These tissues are situated throughout the body at strategic sites where antigens from pathogens are most likely to be encountered. Regional lymph nodes are found along lymphatic vessels that collect antigen and antigenpresenting cells from nonlymphoid organs, whereas mucosal lymphoid organs, such as Peyer’s patches, ILFs, tonsils, and NALT, lack afferent lymphatics and acquire antigen directly across the mucosal epithelium. The spleen is also a secondary lymphoid organ and has evolved a unique structure to sample blood-borne antigens. All these secondary lymphoid organs have specialized architecture and microenvironments that promote the controlled interactions of immune cells in order to elicit a rapid and appropriate immune response to infectious agents (reviewed in 1–3). Most infectious agents gain entry to the body via the skin or mucosal epithelium, which comprise an extremely large surface area. Moreover, many infectious agents target nonlymphoid tissues and organs to complete their life cycle. Because the frequency of naive T or B lymphocytes specific for particular epitopes is in the order of 1 in 105 –106 , it would be very difficult for these few cells to monitor every inch of each peripheral tissue and organ for foreign antigens and pathogens. This problem is elegantly solved by secondary lymphoid organs, which recruit naive lymphocytes from the blood and attract activated, antigen-bearing antigen-presenting cells from regional tissues. In essence, lymphocytes recirculate from lymph node to lymph node and allow antigen to be delivered to them. As a result, the process of immune surveillance is much more efficient, and adaptive immune responses to infectious agents are initiated more quickly (reviewed in 1, 4, 5).
Randall
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Rangel-Moreno
Secondary lymphoid organs develop during embryogenesis or in the early postnatal period. This process occurs independently of antigen or pathogen recognition at predetermined sites throughout the body as a result of complex interactions between various hematopoietic, mesenchymal, and endothelial cells. Many, but by no means all, of the cellular and molecular interactions that are involved in secondary lymphoid organ development are understood, and some of these mechanisms are also involved in the maintenance of secondary lymphoid organ architecture in adults as well as the function of these organs during immune responses (previously reviewed in 6–11). Moreover, similar mechanisms govern the formation of tertiary lymphoid tissues, which develop in adults at sites of persistent infection or chronic inflammation. Because the formation and function of tertiary lymphoid organs has been recently reviewed (12, 13), this review focuses exclusively on the preprogrammed organogenesis of secondary lymphoid organs.
EARLY CELLULAR INTERACTIONS IN PEYER’S PATCH DEVELOPMENT Many of the cellular interactions that initiate secondary lymphoid organ development are well characterized, particularly with regard to Peyer’s patch development (11). Hematopoietic cells derived from precursors in the fetal liver first begin to colonize the gut between days E12.5 and E15.5 (14, 15). Although these cells are evenly distributed throughout the gut on day E15.5, they rapidly form clusters at sites of Peyer’s patch development (16). This is Step 1, as shown in Figure 1. These hematopoietic cells include a population of CD4+ CD3− IL-7Rα+ c-kit+ lymphoid tissue inducer (LTi) cells as well as a population of CD4− CD3− IL-7Rα− ckit+ CD11b+ CD11c+ lymphoid tissue initiator (LTin) cells (16, 17). Both the LTin and LTi cells cluster together with nonhematopoietic VCAM-1+ ICAM-1+ lymphoid tissue
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ARTN
LTin
Step 1
LTo
Rapid migration
LTαβ
TRANCE /IL-7 /chemokines
LTi
Step 2
LTo
Clustering of LTin, LTi, and LTo cells
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LTαβ /others?
TRANCE /IL-7 /chemokines
Step 3 LTi
Lymphocyte-independent initiation of follicle formation
LTo LTαβ /others?
IL-7 /chemokines
NK/T
Step 4
Stroma
Entry of lymphocytes and B/T segregation
LTαβ /others?
Chemokines
B
Step 5
FDC
Mature B cell follicle formation
TNF/LTαβ
Figure 1 General scheme of secondary lymphoid organ development. As noted in text, the details in the developmental pathways of Peyer’s patches and individual lymph nodes are often slightly different. Therefore, this scheme incorporates elements of both Peyer’s patch and lymph node development and outlines major steps that are likely to be in common in these pathways. Importantly, this scheme implies several events that are purely speculative. For example, it is unknown whether LTo cells are the direct precursors of mature stromal cells and follicular dendritic cells (FDCs). It is also unclear whether LTi cells and LTin cells are maintained in mature secondary lymphoid organs in adults. [Abbreviations: LTαβ, lymphotoxin-αβ; NK/T, natural killer and/or T cell; ARTN, artemin; TRANCE, TNF-related activation-induced cytokine; TNF, tumor necrosis factor.]
organizer (LTo) cells on the antimesenteric side of the small intestine and form the primitive anlagen of the Peyer’s patch (15, 16). The available evidence suggests that both LTin and LTi cells are important for the initial
stages of Peyer’s patch development. For example, mice depleted of CD11c+ cells during embryogenesis develop fewer Peyer’s patches, and mice lacking the tyrosine kinase receptor RET, which is expressed by LTin cells,
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completely lack Peyer’s patch anlagen (16). Interestingly, Ret−/− mice have normal numbers of LTin and LTi cells, although these cells do not aggregate nor do they trigger the differentiation of VCAM-1+ ICAM-1+ LTo cells (16). One of the ligands for RET, ARTN (artemin), is produced by nonhematopoietic VCAM-1+ cells—probably LTo cells—and promotes the clustering of LTin and LTi cells at sites of Peyer’s patch development. In fact, the ectopic application of ARTN to embryonic gut tissue leads to the clustering of both LTin and LTi cells, the local appearance of VCAM-1+ cells, and the formation of an ectopic Peyer’s patch anlagen (16). LTi cells are also important for secondary lymphoid organ development, as mice deficient for the transcription factor Id2 (18) and mice deficient for the nuclear hormone receptor RORγ (19) fail to develop IL7Rα+ CD4+ CD3− LTi cells and consequently lack lymph nodes and Peyer’s patches (18, 19). Furthermore, the adoptive transfer of purified LTi cells from normal mice into neonatal CXCR5−/− recipients promotes the development of Peyer’s patches (20), and the adoptive transfer of IL-7Rα+ CD4+ CD3− cells into neonatal Id2−/− mice induces the development of NALT (21). Mice lacking the transcription factor Ikaros also fail to develop lymph nodes (22, 23), a fact that is attributed to the loss of LTi cells. However, given the defects in the dendritic cell (DC) lineage in Ikaros mutant mice (24), it is possible that the development of LTin cells is also compromised in these animals and may contribute to the loss of lymphoid organs. Additional evidence for the involvement of LTi cells in lymphoid organ development comes from transgenic mice that overexpress IL-7 (25). These mice have abnormally high numbers of LTi cells and develop a much higher number of lymph nodes and Peyer’s patches than normal mice (25). However, IL-7 by itself is not sufficient to drive the development of these lymphoid organs because IL-7 transgenic mice crossed to Rorc−/− mice
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fail to produce LTi cells and do not develop any lymph nodes or Peyer’s patches (25). Thus, IL-7Rα+ CD4+ CD3− cells appear to be essential for lymphoid organ development. Despite the essential roles that LTin and LTi cells play in secondary lymphoid organ development, the lineage relationship between these cell types remains obscure. LTin cells seem to have some characteristics of DCs, including CD11c, CD11b, and MHC class II expression. However, they lack DEC205 and instead express NK1.1 and Gr1 (16). Importantly, they lack IL-7Rα, which is important for the expansion of LTi precursors and for the expression of lymphotoxinαβ (LTαβ) on LTi cells, particularly at mucosal sites. On the other hand, LTi cells are not easily categorized into a particular lineage. They arise from common lymphoid progenitors in the fetal liver (26) but lack any features of B or T lymphocytes. Under the appropriate conditions, they mature into NKlike cells and CD11c+ DCs (27), suggesting that they may give rise to CD11c+ LTin cells. However, it is currently unclear whether the development of LTin cells also requires RORγ or Id2; such a finding would provide better evidence that the two populations are related.
EARLY EVENTS IN LYMPH NODE DEVELOPMENT The early stages of lymph node development are slightly different that those of Peyer’s patch development. Unlike Peyer’s patches, lymph nodes are encapsulated by lymphatic endothelium, and their development occurs concurrently with the process of lymphatic vascularization. As first shown by ink injections and microdissection, lymph sacs form from endothelial cells, which bud from the veins during early development (28, 29). These primitive lymph sacs then form buds that branch and form the lymphatic network. This process is controlled by the transcription
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factor Prox1, which is expressed exclusively by lymphatic endothelial cells (30) and is essential for the formation of lymphatic vessels (31, 32). In fact, the early lymph node anlagen is bordered by a mix of endothelial cells that have characteristics of both lymphatic and blood vascular endothelial cells (33). Analogous to what happens in developing Peyer’s patches, CD4+ CD3− IL7Rα+ LTi cells aggregate near endothelial cells at sites of future lymph node development and trigger the differentiation of VCAM-1+ ICAM-1+ LTo cells to form the primitive lymph node anlagen (34). Although CD11c+ cells are also observed in developing lymph node anlagen (34), it is currently unclear whether these cells are the equivalent of CD11c+ LTin cells or whether RET/ARTN interactions are also important for the development of lymph nodes.
DIFFERENTIAL ROLE OF TRANCE AND IL-7 IN PEYER’S PATCH AND LYMPH NODE FORMATION The differences in Peyer’s patch and lymph node organogenesis are also illustrated by the differential roles of the TNF family member TRANCE and the cytokine IL-7 in these processes (34, 35). TRANCE (TNF-related activation-induced cytokine, also known as OPGL/ODF/RANKL/TNFSF11), its receptor, RANK (receptor activator of NF-κB, also known as TRANCE-R/ODFR/OFE), and a critical component of the TRANCE signaling pathway, TRAF6 (TNF receptorassociated factor 6), are all required for the formation of lymph nodes, but not of Peyer’s patches or NALT (35–38). Although Trance−/− mice do develop some cervical lymph nodes, those that form are small and poorly populated (35, 36). Moreover, Trance−/− mice have relatively few LTi cells, and those that are present fail to properly induce the differentiation of mesenchymal cells (35). TRANCE is expressed by mesenchy-
mal LTo cells in sites of lymph node development and functions to promote the differentiation and survival of LTi cells and to upregulate LTαβ on their surface (33, 34). In turn, the ligation of the LTβR on local mesenchymal cells triggers their differentiation and promotes the expression of CCL19, CCL21, and CXCL13 as well as VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) (34, 39). This is Step 2 as shown in Figure1. These chemokines and adhesion molecules promote LTi clustering and continue to recruit newly emerging lymphocytes to the developing lymph nodes. Therefore, in the absence of TRANCE, VCAM-1+ ICAM-1+ cells fail to appear in the lymph node anlagen and lymph nodes fail to complete their program of development. Conversely, IL-7Rα, IL-2Rγ, and JAK3 are required for the organogenesis of Peyer’s patches, but not lymph nodes (14, 15). This was initially surprising because the LTi cells in developing lymph nodes express IL-7Rα just as the LTi cells in developing Peyer’s patches (34). In fact, LTi cells in developing lymph nodes are capable of responding to IL-7, as the ectopic application of IL-7 to developing Traf6−/− embryos (which cannot signal through TRANCE) promotes the development of lymph nodes (34). Like TRANCE, IL-7 upregulates LTαβ on the surface of LTi cells (40), which leads to the expression of chemokines and adhesion molecules by LTo cells. Other cytokines that signal through the IL-2Rγ chain, such as IL-4, are also capable of triggering LTαβ expression on LTi cells. However, there is no evidence that these cytokines are involved in secondary lymphoid organ development, probably because these cytokines are not expressed in the developing embryo. Thus, TRANCE and IL-7 perform similar functions, and the reason that TRANCE is required for lymph node development and IL-7R is required for Peyer’s patch development is due to differential expression of these cytokines in lymph nodes and Peyer’s patches.
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Lymph node anlagen: the unstructured collection of hematopoietic and mesenchymal cells that initially forms at sites of secondary lymphoid organ development
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Although these data would suggest that the role for IL-7 in lymph node genesis is minimal, other data demonstrate that mice doubly deficient in CXCL13 and IL-7Rα completely fail to form lymph nodes (40), including mesenteric lymph nodes, which are normally present in Cxcl13−/− mice (40, 41). Moreover, the transgenic overexpression of IL-7 promotes the development of extra lymph nodes as a result of much higher numbers of LTi cells (25). Thus, IL-7 probably also plays a role in the expansion or development of LTi cells from common lymphoid progenitors and is also a critical inducer of LTαβ expression in some locations. The counterparts to LTi cells in the development of secondary lymphoid organs are LTo cells, which are mesenchymal in origin and form the stromal cell matrix of the developing lymphoid organ (14, 33, 39, 42). Just as there seem to be multiple types of hematopoietic cells that trigger lymphoid organ development, there are also multiple types of mesenchymal LTo cells, with different expression patterns of adhesion molecules, cytokines, and receptors (43). In fact, the VCAM-1+ ICAM-1+ LTo population can be divided into VCAM-1int ICAM1int and VCAM-1hi ICAM-1hi populations (33). Whereas both of these populations are present in peripheral and mesenteric lymph nodes, the frequency of VCAM-1int ICAM1int cells is dramatically lower in peripheral lymph nodes (33). Differences between these populations are also found in developing Peyer’s patches and mesenteric lymph nodes. In fact, the LTo cells found at sites of mesenteric lymph node and Peyer’s patch development express very different gene programs (43). For example, LTo cells at sites of mesenteric lymph node development express much higher levels of TGF-β and stem cell factor (the ligand for c-kit), whereas LTo cells at sites of Peyer’s patch development express higher levels of IL-6, TRANCE, CXCL1, CCL7, and CCL11 (43). These differences in gene expression may explain why
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various lymphoid organs have different requirements for cytokines and growth factors, such as the requirement for IL-7 in Peyer’s patch development and the requirement for TRANCE in lymph node development. However, it remains an open question whether all secondary lymphoid organs have slightly different populations of LTo cells and whether the differences in these populations are intrinsic or are caused by the local environment.
LYMPHOTOXIN SIGNALING AND SECONDARY LYMPHOID ORGAN DEVELOPMENT One of the key events in the development of secondary lymphoid organs is lymphotoxin signaling, which promotes the differentiation of mesenchymal LTo cells and leads to the expression of various chemokines and adhesion molecules that are necessary for secondary lymphoid organ development. The essential role of lymphotoxin is illustrated by Lta−/− mice, which lack Peyer’s patches and most lymph nodes, except for rudimentary mesenteric lymph nodes that occasionally appear in some mice (44, 45). This was initially somewhat surprising because LTα is a soluble cytokine that is structurally and functionally related to TNF (46). In fact, LTα binds to both TNFR1 and TNFR2, suggesting that the biological functions of LTα and TNF should be very similar (47). However, Tnf −/− mice have normal numbers of lymph nodes, albeit with some structural alterations (48, 49). Moreover, Tnfr1−/− and Tnfr2−/− mice also have normal numbers of lymph nodes (48, 50). However, there are some strains of Tnf−/− and Tnfr1−/− mice that completely lack Peyer’s patches (50a, 50b), suggesting that the type of genetic disruption at either the Tnf or the Tnfr1 locus may affect the sensitivity of Peyer’s patch development to the loss of TNF. The discrepancy between the activities of LTα and TNF was resolved by the observation that LTα also forms heterotrimers with
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LTβ, which is expressed as a transmembrane protein (51, 52). The LTαβ heterotrimer is expressed on the cell surface of lymphocytes (53) as well as on LTi and LTin cells (16) and binds to the LTβR. Because the organogenesis of secondary lymphoid organs is disrupted in Ltb−/− mice as well as in Ltbr−/− mice (54, 55), the surface form of LTαβ must be primarily responsible for triggering secondary lymphoid organ development. However, Ltb−/− mice still retain cervical and mesenteric lymph nodes (54), whereas Lta−/− mice lack these organs (44). Therefore, the soluble form of LTα must cooperate with surface LTαβ to contribute to the development of some lymph nodes. Furthermore, because all lymph nodes and Peyer’s patches are absent from Ltbr−/− mice (55), it is likely that another TNF family member, such as LIGHT (56, 57), acts through LTβR to facilitate the development of cervical and mesenteric lymph nodes. In fact, TNF, LTα, LTβ, and LIGHT all participate in secondary lymphoid organ development to some degree. For instance, mice treated in utero with soluble LTβR fused with the Fc portion of immunoglobulin (LTβR-Ig) retain mesenteric and cervical lymph nodes (58, 59), whereas mice treated in utero with both LTβR-Ig and TNFR1Ig do not develop these organs (60). Moreover, mice treated with LTβR-Ig and blocking antibodies against TNF also lack all lymph nodes and Peyer’s patches (60), indicating that TNF signaling through TNFR1 plays some role in mesenteric lymph node development. As discussed above, LIGHT also contributes to mesenteric lymph node development. Although both Light−/− and Ltb−/− mice have mesenteric lymph nodes (57), a portion of Light-Ltb−/− mice lack mesenteric lymph nodes (57), suggesting that LIGHT and LTβ cooperate to induce mesenteric lymph node formation. Furthermore, because all Ltbr−/− mice lack mesenteric lymph nodes (55), these results also suggest that there may be another ligand for the LTβR that facil-
itates mesenteric lymph node development. Thus, although LTαβ signaling through the LTβR is the major pathway through which secondary lymphoid organ development is triggered, other TNF family members also contribute to lymph node development. Despite the essential nature of interactions between LTαβ-expressing LTi cells and LTβR-expressing LTo cells, this interaction alone is not sufficient to promote secondary lymphoid organ development. For example, although the administration of an agonistic anti-LTβR antibody in utero promotes lymph node development in Lta−/− mice, the administration of this same antibody in Rorc−/− mice, which lack LTi cells, does not promote lymph node development (19). Furthermore, the administration of anti-LTβR to Cxcl13−/− mice also fails to promote lymph node development. These data demonstrate that LTi cells or possibly LTin cells provide additional signals to mesenchymal or stromal cells that are necessary for secondary lymphoid organ development. The identification of these additional signals is key to our future understanding of secondary lymphoid organ development. Most TNFR family members are coupled to the NF-κB signaling pathway (61), and, not surprisingly, molecules important in this signaling pathway are involved in LTβR signaling and lymphoid organ development. In particular, triggering of the LTβR induces the canonical pathway of NF-κB activation that involves IKKβ and IKKγ/NEMO and leads to the phosphorylation of IκB and the translocation of p50/RelA or p52/RelA complexes to the nucleus (62). In turn, these complexes control the expression of inflammatory proteins, including VCAM-1, CCL4, and CXCL1 (62). This pathway also promotes an increased production of the NF-κB2/p100 precursor (62). However, LTβR signaling also induces a second pathway that leads to the sequential activation of NIK and IKKα and leads to the processing of p100 to p52 (62, 63). In association with RelB, p52 translocates to the nucleus
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Homeostatic chemokines: chemokines that are constitutively expressed in secondary lymphoid organs and that control the steady-state recruitment and positioning of lymphocytes and DCs; their expression is often regulated by lymphotoxin Table 1
13:36
and activates transcription of molecules involved in secondary lymphoid organ development and homeostasis (62). These molecules include the homeostatic chemokines CCL19, CCL21, and CXCL13. Both pathways appear to be important in lymphoid organ development because mice homozygous for a natural mutation in NIK (alymphoplasia or aly/aly mice) (64, 65) as well as Tnfr1-Rela−/− mice lack lymph nodes and Peyer’s patches (66). Furthermore, RelB is essential for Peyer’s patch organogenesis and aspects of splenic architecture (67–69). These results partly explain why LTβR and NIK signaling pathways are essential for lymphoid organ development and also explain why signaling through
TNFR1 can facilitate lymph node development under some circumstances. (A list of mutations that impair secondary lymphoid organ development is provided in Table 1.)
LYMPHOTOXIN SIGNALING ELICITS CHEMOKINE AND ADHESION MOLECULE EXPRESSION BY STROMAL AND ENDOTHELIAL CELLS As mentioned above, interactions between LTαβ-expressing LTi and LTin cells promote the differentiation of LTβR-expressing mesenchymal and endothelial cells (7, 11, 34). As part of this differentiation pathway, the
Mutations that impair secondary lymphoid organ development mLNsa
pLNsb
PPsc
NALT
±d
−
−
±e
21, 44, 45, 110
stroma
±
−
−
±
21, 54, 110
stroma
−
−
−
±
21, 55, 110
LTβR
stroma
+
+
+
NDf
57
Light/Ltb−/−
LTβR
stroma
−
−
−
ND
57
Aly/aly
LTβR
stroma
−
−
−
±
21, 65, 110
Il7ra−/−
IL-7R
LTi
+
+
−
±
15, 21, 34, 110
Il2rg/rag−/−
IL-7R
LTi
+
+
−
−
86
Jak3−/−
IL-7R
LTi
+
+
−
ND
15, 34
Trance−/−
TRANCE-R
LTi
−
−
+
+
35, 37, 110
Rank−/−
TRANCE-R
LTi
−
−
+
ND
36
Traf6−/−
TRANCE-R
LTi
−
−
+
ND
38
Rorc−/−
LTi
−
−
−
+
10, 19, 110
Id2−/−
LTi
−
−
−
−
18, 21
Ikaros−/−
LTi
−
−
−
ND
23
Mutation
Signaling pathway
Cells affected
Lta−/−
LTβR
stroma
Ltb−/−
LTβR
Ltbr−/−
LTβR
Light−/−
References
Cxcl13−/−
CXCR5
LTi/B
−
−
−
±
40, 41
Cxcr5−/−
CXCR5
LTi/B
−
−
−
ND
74
Plt/plt
CCR7
LTi/B/T
+
+
+
+
40, 65
Ccr7−/−
CCR7
LTi/B/T
+
+
+
ND
129
Cxcl13/Ccl19/21−/−
CXCR5/CCR7
LTi/B/T
−
−
−
±
40
Ret−/−
RET
LTin
ND
ND
−
ND
16
Graf 51/51
RET
LTin
ND
ND
±
ND
16
a
mesenteric lymph nodes. peripheral lymph nodes. c Peyer’s patches. d small mLNs developed in a few mice. e small, disorganized NALT developed. f ND, Not determined. b
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mesenchymal cells express adhesion molecules, such as VCAM-1, ICAM-1, and MAdCAM (mucosal addressin cell adhesion molecule-1), as well as homeostatic chemokines, including CXCL13, CCL19, and CCL21. LTi cells and probably LTin cells express chemokine receptors, such as CXCR5, the receptor for CXCL13, and CCR7, the receptor for CCL19 and CCL21 (40). LTi cells also express the integrins α4β7 and α4β1 (27, 70), which bind to the vascular adhesion molecules MAdCAM and VCAM-1, respectively. Homeostatic chemokines, particularly CXCL13, are expressed in Peyer’s patch anlagen during development (39). This low-level expression attracts CXCR5-bearing IL-7Rα+ CD4+ CD3− cells to the Peyer’s patch anlagen and activates α4β1 integrin in order to facilitate adhesion to the local stroma (20). Once IL-7Rα+ CD4+ CD3− cells have arrived at the future sites of Peyer’s patch genesis, they provide surface LTαβ (27), which induces the expression of higher levels of chemokines as well as adhesion molecules on the mesenchymal cells (39, 71, 72). These newly expressed molecules then recruit lymphocytes, which provide a sustained source of surface lymphotoxin and induce the differentiation of local stromal cells (73). The chemokine receptors and integrins expressed by LTin cells are currently unknown. However, because LTin cells cluster with LTi cells in the developing Peyer’s patch at the same time, we can safely assume that they express similar chemokine receptors and adhesion molecules. Homeostatic chemokines do more than simply attract LTi cells to sites of secondary lymphoid organ development. Like IL-7 and TRANCE, they promote the expression of LTαβ on the surface of LTi cells and lymphocytes (40, 41). For example, CXCL13 promotes the expression of LTαβ on the surface of LTi cells as well as on mature B cells (41), whereas CCL21 and CCL19 promote the expression of LTαβ on LTi cells as well as on mature CD4 T cells (40). In fact, the expression of homeostatic chemokines and
lymphotoxin is codependent in a positivefeedback loop (41) in which lymphotoxin signaling triggers the expression of homeostatic chemokines by mesenchymal/stromal cells and chemokine signaling maintains expression of LTαβ on the surface of LTi cells and lymphocytes. The essential role of homeostatic chemokines in secondary lymphoid organ development is demonstrated by Cxcl13−/− mice, which fail to develop Peyer’s patches and most lymph nodes (41). Cxcr5−/− mice also lack Peyer’s patches and most lymph nodes (74). Although mice with a natural mutation (paucity of lymph node T cells, plt) that disrupts CCL19 and CCL21 generally form a full complement of secondary lymphoid organs (75–78), the lymph nodes and Peyer’s patches that do develop in plt/plt mice are small and poorly organized (75–77). In part, this is due to the reduced capacity of these organs to recruit mature lymphocytes from the blood and activated antigen-presenting cells from regional tissues (75–77, 79–81). However, CCL19 and CCL21 also play a role in the development of secondary lymphoid organs, as shown by mice triply deficient in CXCL13, CCL19, and CCL21, which exhibit a more frequent absence of facial and cervical lymph nodes than mice lacking CXCL13 alone (40). The loss of these additional lymph nodes is attributed to poor recruitment of LTi cells as well as to the failure of LTi cells to upregulate LTαβ and to promote the differentiation of local mesenchymal cells (40).
PROGRAMMED COLONIZATION AND DEVELOPMENT OF FOLLICULAR STRUCTURES IN DEVELOPING LYMPHOID ORGANS Although IL-7Rα+ CD4+ CD3− LTi cells and VCAM+ ICAM+ mesenchymal cells are initially arranged in homogenous clusters, they begin to segregate into follicular structures around day E18 (82). CD11c+ cells also
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segregate into follicular structures in the developing Peyer’s patches at this time (82), although it is not clear whether these cells are CD11c+ LTin cells or whether they are CD11c+ DCs that have differentiated in situ from LTi cells (27, 70). Regardless, the initial follicular formation requires LTαβ and occurs independently of B and T cells (82). Similar events are thought to take place during lymph node development (34). This is Step 3 in Figure 1. The last steps in the development of fully mature secondary lymphoid organs involve the recruitment of lymphocytes, the segregation of B and T cell areas, and the formation of mature B cell follicles. In mouse lymph nodes, this process is delayed until day 3 after birth (83) owing to the sequential expression of MAdCAM and PNAd on high endothelial venules (HEVs) (83, 84). Prior to day 3, MAdCAM-1 is the only vascular addressin expressed on HEVs (83). As a result, cells entering developing lymph nodes during this time must express α4β7, the receptor for MAdCAM. Cells that use this pathway include CD4+ CD3− LTi cells and γδ T cells (27, 70, 84). However, around day 3, MAdCAM expression is downregulated on the HEVs of lymph nodes and PNAd expression is upregulated, allowing the entry of mature naive B and T cells (83). This developmental switch is controlled in part by the de novo expression of CD34 and GlyCAM1 (83), which are substrates for the sulfation reaction that generates the PNAd epitope. After B and T cells start arriving in the developing lymph node, they begin to take over the role of CD4+ CD3− LTi cells by expressing LTαβ and maintaining the differentiation and survival of LTβR-expressing mesenchymal and stromal cells. When B cells first arrive in the developing lymph node, they do not respond to CXCL13 and lack surface LTαβ expression (85). At this time, CXCL13 expression is still dependent on LTαβ expressed by CD4+ CD3− LTi cells (85). The lymph node becomes more organized upon the entry of T cells, when B cells begin to
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segregate in the outer cortex. Interestingly, the initial segregation of T and B cells occurs independently of CXCL13. This is Step 4 in Figure 1. However, from day 4 on, the architectural changes are dependent on CXCL13 and CXCL13-responsive B cells. B cells also express LTαβ at this time (85), suggesting that LTαβ-expressing B cells play a major role in maintaining the architecture of secondary lymphoid organs. Consistent with the idea that LTαβ-expressing lymphocytes take over the role of LTαβ-expressing LTi cells, mice that lack NK, B, and T cells develop the initial lymph node anlagen, which persists for a while after birth before dissipating (86). Interestingly, the adoptive transfer of IL-7Rα+ T cells or NK cells, but not B cells, restores the final stages of lymph node development (86), suggesting that these cells have the ability to replace LTi cells as the source of LTαβ at this later stage. Although it is not totally understood why adoptively transferred NK and T cells would be more efficient at promoting lymph node maturation than B cells, the authors of this study speculate that IL-7-driven homeostatic expansion of NK and T cells may play a role (86).
ROLE OF LYMPHOTOXIN IN THE MAINTENANCE OF LYMPHOID ARCHITECTURE Lymphotoxin and TNF expression are also required for the maintenance of lymphoid architecture in adults as well as for the appropriate homing and segregation of B and T cells within secondary lymphoid organs (44, 45). For example, the spleens of Lta−/− mice lack organized B and T cell areas (44, 45), marginal zones (45, 87), and germinal centers (87, 88). Moreover, follicular dendritic cells (FDCs) fail to develop in the absence of lymphotoxin or TNF signaling (73, 89, 90). As in the developmental stages of secondary lymphoid organs, the expression of lymphotoxin and homeostatic chemokines are codependent in a positive-feedback loop in which lymphotoxin promotes the differentiation and
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survival of the stromal cells and DCs that express CXCL13, CCL21, and CCL19 (72), whereas chemokine receptor signaling controls the steady-state recruitment and positioning of naive B and T cells and maintains LTαβ expression on B and T cells (41, 72). Most evidence suggests that the expression of LTαβ and TNF on mature B cells is essential for the maintenance of CXCL13 expression and FDCs in the B cell follicle (73, 91). However, mice in which LTβ is genetically deleted specifically in the B cell lineage have normal levels of chemokines, FDCs, and B cell follicles in the lymph nodes (92, 93). In this case, LTαβ expression by T cells is sufficient to maintain these structures. Together, these data suggest that LTαβ expression on both B and T cells is important for the proper maintenance of lymphoid architecture in adults. In addition to maintaining B cell follicles and segregating B and T cells areas, lymphotoxin signaling is also important for maintaining DC numbers via homeostatic proliferation (94) and for the activation and maturation of DCs during immune responses (95). The development of gp38-expressing stromal cells in the spleen is also dependent on lymphotoxin-expressing B cells (96). Furthermore, the continued expression of the vascular addressins, PNAd and MAdCAM, on HEVs is dependent on lymphotoxin signaling (60, 97, 98). Interestingly, soluble LTα and membrane-bound LTαβ are responsible for different aspects of lymphoid architecture. For example, the defects in B and T cell separation are less severe in the spleens of Ltb−/− mice (54) than they are in the spleens of Lta−/− mice (45) and Ltbr−/− mice (55), suggesting that LTα signaling through TNFR1 as well as LTαβ signaling through LTβR are important for lymphocyte organization. In contrast, the presence of DCs in the spleen and the expression of MAdCAM and PNAd on HEVs and in marginal zone sinuses are controlled by surface LTαβ and the LTβR but not by TNF, LTα, or TNFR1 (59, 94). Finally, the differentiation of FDCs requires
TNF, LTα, and LTβ (49, 73, 90, 99). Thus, various aspects of lymphoid architecture are controlled by the overlapping, yet distinct, activities of soluble LTα, membrane LTαβ, and TNF.
SECONDARY LYMPHOID ORGANOGENESIS DEVELOPMENT IS STRICTLY CONFINED TO A DEVELOPMENTAL WINDOW The development of conventional secondary lymphoid organs occurs during a temporal window in embryogenesis that varies depending on the particular lymphoid organ (58). For example, mesenteric lymph nodes develop first (around day E9–E10), followed by brachial (day E13), axillary (day E15), inguinal (day E16), and popliteal lymph nodes (day E17) (58). Mucosal lymphoid organs, such as Peyer’s patches and NALT, appear to develop last, as disruption of lymphotoxin signaling just before birth blocks Peyer’s patch formation (58), whereas the adoptive transfer of LTi cells can restore the development of NALT in neonatal Id2−/− mice (21) and the development of Peyer’s patches in neonatal Cxcr5−/− mice (20). In fact, there is a strict developmental window within which the organogenesis of lymph nodes and Peyer’s patches must occur (58). Once this window has passed, the development of these organs cannot take place, regardless of whether lymphotoxin signaling is restored. There also seems to be a developmental window that restricts the formation of lymphoid tissues at ectopic sites, as demonstrated by the intradermal transfer of cells from dissociated lymph nodes to recipient mice (100). When given to adults, the transferred cells form disorganized clumps. However, when given to neonates, the transferred cells organize into follicular structures with segregated T cell zones and B cell follicles that contain FDCs (100). In contrast, there does not seem to be a fixed developmental window for the formation of ILFs. Although ILF development is dependent on
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lymphotoxin signaling (101, 102), these structures can be restored in adult Lta−/− mice by reconstitution with normal hematopoietic cells (102). Although it is unclear why these particular tissues lack a fixed developmental window, we do know that RORγ-expressing CD4+ CD3− LTi-like cells are found in the cryptopatches of adults (10). Thus, the developmental window for each lymphoid organ may be restricted by the availability of LTi cells in that location. Interestingly, there is even a developmental window that restricts the formation of some splenic structures, such as the gp38expressing stromal cells in the T cell areas of the spleen (96). The development of these stromal cells requires LTαβ-expressing B cells during the neonatal period (96). As a result, gp38+ stromal cells cannot be restored in the spleens of B cell–deficient or Lta−/− adult mice by reconstitution with normal bone marrow (96). However, most of the other defects in splenic architecture, including the differentiation of FDCs, expression of homeostatic chemokines, formation of the marginal zone, and the development of germinal centers after immunization, can be reversed upon reconstitution of Lta−/− mice with normal bone marrow (73, 87, 90, 99).
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A ROLE FOR CD4+ CD3− LTI CELLS AFTER LYMPHOID ORGANOGENESIS One of the most intriguing questions in lymphoid organogenesis is whether the sole purpose of CD4+ CD3− LTi cells is to promote secondary lymphoid organ development during a narrow temporal window in fetal and neonatal development or whether these cells are also present and functional in adults (103). Although LTi cells are easily located with relatively high frequency within the early anlagen of developing Peyer’s patches and lymph nodes (14, 34), they are difficult to locate in adults. In fact, the presence of LTi cells in adults remains a controversial point (104). However, RORγ+ LTi-like cells can be ob638
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served within the cryptopatches of the adult gut (105), where they are postulated to promote the development of ILFs in response to microbial stimulation (106). CD4+ CD3− LTi cells are also proposed to regulate Th2 responses in the spleen (107). CD4+ CD3− cells in adult spleens appear to have a program of gene expression similar to that in CD4+ CD3− cells found at sites of embryonic lymph node development. For example, CD4+ CD3− cells in adults express high levels of LTαβ and TNF (104). Moreover, the adoptive transfer of normal CD4+ CD3− cells from either embryonic or adult tissues into Lta−/− mice leads to the segregation of B and T cell areas and the expression of CCL21 (108). However, unlike embryonic LTi cells, adult CD4+ CD3− cells express high levels of OX40 ligand and CD30 ligand (109). Therefore, the precise lineage relationship between embryonic LTi cells and adult CD4+ CD3− cells remains unclear. To make matters even more complicated, there is evidence that LTi cells in embryo are not a single homogenous population. For example, the development of NALT occurs in the absence of RORγ (110), whereas it is completely dependent on Id2 (21). Because both RORγ and Id2 are thought to be essential for the differentiation of LTi cells (18, 19, 111) and because normal LTi cells restore NALT development in Id2−/− mice (21), these data suggest that there must be some populations of LTi cells that develop independently of RORγ. These different populations of LTi cells may express different patterns of chemokine receptors that preferentially attract them to particular sites of secondary lymphoid organ development. This corresponds with the idea that there are also different populations of mesenchymal LTo cells at sites of Peyer’s patch, mesenteric, and peripheral lymph node development that express different arrays of chemokines (43). Thus, the CD4+ CD3− LTi-like cells found in the spleens and cryptopatches of adults may simply be a few examples of the multiple types of these intriguing cells.
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EXCEPTIONS TO THE PARADIGM OF SECONDARY LYMPHOID ORGAN DEVELOPMENT Although Peyer’s patch organogenesis serves as an instructive model for the organogenesis of all lymphoid organs (11), the molecular requirements for the development of Peyer’s patches and other lymphoid organs are not identical. This is illustrated by the differential requirement of lymph nodes and Peyer’s patches for TRANCE and IL-7 (34, 35). Although these two cytokines seem to share a similar purpose in secondary lymphoid organ development (34), their differential expression at sites of Peyer’s patch and lymph node development leads to their differential importance in the development of these organs. In contrast, the development of some mucosal lymphoid tissues differs much more substantially from that of Peyer’s patches. For example, although NALT and Peyer’s patches share an architectural similarity, the development of these organs is very different. The organogenesis of NALT occurs during the first week or two after birth (21, 112), which is significantly later than that of Peyer’s patches. As in Peyer’s patch development, CD4+ CD3− LTi cells are among the first to appear in the developing NALT anlagen (21, 113). On the one hand, NALT development does not require RORγ-dependent LTi cells (110). On the other hand, it does require Id2-dependent LTi cells (21). In fact, the organogenesis of NALT can be restored in Id2−/− mice by the adoptive transfer of normal LTi cells to neonatal recipients (21). Most importantly, unlike the development of lymph nodes and Peyer’s patches, the development of NALT is not dependent on the lymphotoxin signaling pathway (21, 110). In fact, NALT is present in Lta−/− , Ltb−/− , Tnf-Lta−/− , Ltbr−/− , and Tnfr1−/− (21, 110). Moreover, NALT develops normally in mice treated in utero with both soluble LTβR and soluble TNFR1 (21), even though these mice do not develop any lymph nodes or Peyer’s patches. These data
argue that none of the ligands that bind to either the LTβR or the TNFR1, including the LTα homotrimer, the LTαβ heterotrimer, TNF, or LIGHT, are essential for NALT development. Furthermore, mice with mutations in the NF-κB signaling pathway, including aly/aly, Nfkb1−/− , Nfkb2−/− , and Relb−/− mice, all have NALT to some degree (114). Together, these data argue that the central feature in the paradigm of secondary lymphoid organ development—the interaction between LTαβ-expressing LTi cells and LTβRexpressing mesenchymal LTo cells—is not a part of the NALT developmental program. Although it is not clear why NALT development requires IL-7Rα+ CD4+ CD3− cells in Id2−/− mice but not in Rorc−/− mice, the difference may reflect the activities of additional cell types that facilitate NALT development. Because Id2−/− mice lack NK cells as well as multiple populations of DCs (18, 115, 116) and have defects in the CD8 T cell lineage (117), these cells may play important, although currently undefined, roles in NALT development in the absence of RORγ-dependent LTi cells. This would be consistent with other data showing that NK cells participate in the stabilization of lymph nodes during development (86). However, if CD4+ CD3− cells are a central component in the NALT developmental pathway, even in the absence of lymphotoxin signaling, then what signals might these cells provide during NALT organogenesis? It is clear from other studies that additional signals from LTi cells do play a role in lymph node development because agonistic antibodies to the LTβR do not promote lymph node development in Rorc−/− mice (19). Defining these interactions will be key to our future understanding of secondary lymphoid organ development. The discrepancy between Rorc−/− and Id2−/− mice in the relative importance of CD4+ CD3− cells in NALT development may also reflect diversity in the LTi population— with some LTi cells being formed independently of RORγ. Consistent with this idea,
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the LTi cells found in NALT express very low levels of CCR7 and CXCR5 relative to their levels on LTi cells from Peyer’s patches (113). Moreover, NALT develops in the absence of CXCL13, CCL19, and CCL21 (113, 118), and normal numbers of LTi cells migrate to the NALT of Cxcl13−/− or plt/plt mice just after birth (113). These data demonstrate that conventional LTi cells are probably not involved in NALT development and further suggest that additional, as yet undefined chemokines attract LTi cells to the NALT anlagen. One of these chemokines might be CCL20, which is normally expressed in the dome epithelium of NALT in a lymphotoxin-dependent manner (118). If CCL20 is required for NALT formation, possibly by recruiting CCR6-expressing LTi cells, then NALT development might be more analogous to the development of ILFs, which are highly dependent on CCR6 (119). Despite the fact that the initial stages of NALT development occur independently of the lymphotoxin signaling pathway, the structure of NALT is severely compromised in Lta−/− , Tnf-Lta−/− , and Ltbr−/− mice (110, 118). In fact, the B and T cells are not segregated into separate areas, FDCs and BP3+ stromal cells do not develop, HEVs cannot be found, and the normal array of homeostatic chemokines are not expressed in the NALT of Lta−/− mice (110, 118). However, the architectural defects in the NALT of adult Lta−/− mice can be repaired by the restoration of normal lymphotoxin-expressing hematopoietic cells (110). Again, this is dramatically different than other lymphoid organs, which cannot be reconstituted in Lta−/− mice, even after the transfer of normal bone marrow into irradiated recipients (120). Thus, the structural defects in the NALT of Lta−/− mice are primarily due to the failure of lymphotoxin to promote the differentiation of stromal and endothelial cells and to the loss of homeostatic chemokine expression. The development of ILFs is also different than that of Peyer’s patches, despite the similarity of their locations and presumably their
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functions in the small intestine. For example, the formation of ILFs is clearly dependent on lymphotoxin signaling, as ILFs are absent in Lta−/− and aly/aly mice (101, 102, 121). However, like NALT, ILFs are completely restored in Lta−/− mice after reconstitution with normal bone marrow (102, 122). Moreover, even though the treatment of mice in utero with LTβR-Ig or anti-IL-7R blocks Peyer’s patch development, it does not prevent the development of ILFs (101, 122). These data suggest that lymphotoxin signaling is important for the maintenance of ILFs after embryonic development rather than for the developmental formation of ILFs. This is probably analogous to the role of lymphotoxin in the formation of NALT, in which lymphotoxin is essential for the expression of chemokines and the differentiation of stromal and endothelial cells (118). An alternative explanation is that lymphotoxin is required for ILF development but that there is no temporal window in development during which ILF formation must occur. As it is in NALT, CCL20 is highly expressed in the dome epithelium of ILFs and seems to attract CCR6+ DCs as well as B and T cells to the dome region (119, 123). The central importance of CCR6/CCL20 interactions in the development of ILFs is demonstrated in Ccr6−/− mice, in which ILFs fail to develop properly (119). Like other homeostatic chemokines, CCL20 expression is dependent on LTα (118), suggesting that the lymphotoxin-induced expression of CCL20 may be the essential step in ILF formation. Although this might imply that LTi cells responsible for ILF formation must express CCR6 (124), it reflects instead a requirement for CCR6 on B cells (119). Given that LTαβ expression on B cells and not T cells is also required for the maturation of ILFs (125), one could speculate that there is a positive-feedback loop between CCL20 expression in the dome epithelium of ILFs and LTαβ expression on B cells. Interestingly, B cells in ILFs do not have to be antigen specific to mediate their effects. In fact, normal ILFs develop in mice in which all B
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cells express a transgenic BCR specific for lysozyme (125). Despite the central role of LTαβ+ CCR6+ B cells in ILF formation, ILF development is compromised in Rorc−/− mice (106), suggesting that LTi cells are important for ILF formation. However, it is unclear at this time whether LTi cells are attracted to sites of ILF development via CCL20 or other homeostatic chemokines, like CXCL13, which is also highly expressed in mature ILFs. Another unusual feature of ILF development, unlike that of any other secondary lymphoid organ, is that it is linked to microbial exposure (102, 125–127). For example, ILF formation is barely detectable in germ-free mice (102), and those ILFs that do develop have only small clusters of c-kit+ cells and essentially lack T cell zones or B cell follicles. However, other investigators find that ILFs (also known as solitary intestinal lymphoid tissue, or SILT) are present in normal numbers in germ-free mice but are very small and immature and lack identifiable B cell follicles (126, 127). Importantly, ILFs return to normal upon restoration of intestinal flora (102). These data argue that the location and number of ILFs is determined developmentally and cannot be altered by inflammation or infection. However, the final maturation and organization of ILFs depends on microbial stimuli and can even be enhanced by infection with pathogenic bacteria (128). Together, these data demonstrate that the de-
velopment of ILFs has some characteristics in common with the development of ectopic lymphoid follicles but have other characteristics of secondary lymphoid organs.
CONCLUDING REMARKS Our understanding of the programmed development of secondary lymphoid organs has progressed remarkably over the past decade. We now appreciate that interactions between newly emerging populations of LTi and LTin with immature mesenchymal LTo cells are instrumental in this process and that these interactions are orchestrated by a variety of homeostatic chemokines, cytokines, and growth factors. In particular, the lymphotoxin signaling pathway is centrally important for the initial differentiation of mesenchymal LTo cells and for the maintenance of architectural elements that comprise the scaffolding of secondary lymphoid organs. However, it is now apparent that the developmental pathways governing each secondary lymphoid organ are often subtly and sometimes dramatically different. These differences are reflected in the variety of cytokines and chemokines that are required for the development of each organ and in the various types of LTi cells and LTo cells that are present in each site. Understanding these differences and determining how they impact the ultimate structure and function of each secondary lymphoid organ will be the challenge for the next decade.
SUMMARY POINTS 1. The development of secondary lymphoid organs is initiated during embryogenesis by interactions between hematopoietic cells (CD4+ CD3− IL-7Rα+ α4β7+ LTi cells and CD4− CD3− IL-7Rα− CD11c+ LTin cells) that arise in the fetal liver and mesenchymal cells that are located at sites of future lymphoid organ development. 2. The development of LTi cells from precursors in the fetal liver and their local differentiation into lymphotoxin-αβ-expressing cells requires the activities of cytokines, such as TRANCE or IL-7. IL-7 seems to be most important for the differentiation of LTi cells at mucosal sites, such as the Peyer’s patches, whereas TRANCE is most important at sites of peripheral lymph node development.
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3. LTi cells are attracted to sites of lymphoid organ development by homeostatic chemokines, including CXCL13, CCL19, and CCL21. Like TRANCE and IL-7, these chemokines also maintain surface lymphotoxin-αβ expression on LTi cells. 4. The lymphotoxin signaling pathway plays a central role in the development of secondary lymphoid organs owing to its ability to trigger mesenchymal cell differentiation, elicit homeostatic chemokine expression, and promote the differentiation of HEVs, stromal cells, and DCs. 5. Signaling through the lymphotoxin-βR initiates both the canonical and alternative NF-κB signaling pathways. Annu. Rev. Immunol. 2008.26:627-650. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
6. The vascular addressins, MAdCAM and PNAd, are sequentially expressed during lymph node development so that LTi cells and mature lymphocytes are recruited in a temporally ordered fashion. 7. CD4+ CD3− cells can be found in adults and seem to have a function in facilitating follicular T cell responses. However, the lineage relationship between embryonic CD4+ CD3− LTi cells and those found in adults remains uncertain. 8. The developmental pathways for peripheral lymph nodes, mesenteric lymph nodes, and Peyer’s patches differ in their requirements for chemokines, cytokines, and growth factors. However, the pathways that govern the development of ILFs and NALT are dramatically different from those that govern conventional lymph nodes and Peyer’s patches.
FUTURE ISSUES 1. What is the relationship between CD4+ CD3− IL-7Rα+ LTi cells and CD4− CD3− IL7Rα− CD11c+ LTin cells? 2. Does each secondary lymphoid organ use slightly different populations of LTi and LTo cells for their development, and does this differential utilization of cell types explain why each lymphoid organ uses subtly different combinations of chemokines, growth factors, and cytokines for their development? 3. Other than the lymphotoxin signaling pathway, what pathways are used by LTi cells to trigger the differentiation of mesenchymal cells and initiate secondary lymphoid organ development? 4. Why is the development of most secondary lymphoid organs (lymph nodes, Peyer’s patches, and NALT) restricted to embryogenesis, when the development of ILFs can occur in adults? 5. Why does the development of NALT occur in the absence of lymphotoxin signaling and what pathways substitute for lymphotoxin signaling in this process?
DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review. 642
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ACKNOWLEDGMENTS This work was supported by the Trudeau Institute, by NIH grants HL69409 and AI072689, and by the Sandler Program for Asthma Research.
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LITERATURE CITED 1. Goodnow CC. 1997. Chance encounters and organized rendezvous. Immunol. Rev. 156:5– 10 2. Kiyono H, Fukuyama S. 2004. NALT- versus Peyer’s-patch-mediated mucosal immunity. Nat. Rev. Immunol. 4:699–710 3. Kunisawa J, Fukuyama S, Kiyono H. 2005. Mucosa-associated lymphoid tissues in the aerodigestive tract: their shared and divergent traits and their importance to the orchestration of the mucosal immune system. Curr. Mol. Med. 5:557–72 4. Butcher EC, Williams M, Youngman K, Rott L, Briskin M. 1999. Lymphocyte trafficking and regional immunity. Adv. Immunol. 72:209–53 5. Butcher EC, Picker LJ. 1996. Lymphocyte homing and homeostasis. Science 272:60–62 6. Drayton DL, Liao S, Mounzer RH, Ruddle NH. 2006. Lymphoid organ development: from ontogeny to neogenesis. Nat. Immunol. 7:344–53 7. Cupedo T, Kraal G, Mebius RE. 2002. The role of CD45+ CD4+ CD3− cells in lymphoid organ development. Immunol. Rev. 189:41–50 8. Cupedo T. 2003. Regulation of Lymphoid Organogenesis. Amsterdam: Vrije Univ. Amsterdam. 144 pp. 9. Cyster JG. 2003. Lymphoid organ development and cell migration. Immunol. Rev. 195:5– 14 10. Eberl G, Littman DR. 2003. The role of the nuclear hormone receptor RORγt in the development of lymph nodes and Peyer’s patches. Immunol. Rev. 195:81–90 11. Nishikawa S, Honda K, Vieira P, Yoshida H. 2003. Organogenesis of peripheral lymphoid organs. Immunol. Rev. 195:72–80 12. Aloisi F, Pujol-Borrell R. 2006. Lymphoid neogenesis in chronic inflammatory diseases. Nat. Rev. Immunol. 6:205–17 13. Carragher DM, Rangel-Moreno J, Randall TD. 2007. Ectopic lymphoid tissues and local immunity. Semin. Immunol. In press 14. Yoshida H, Honda K, Shinkura R, Adachi S, Nishikawa S, et al. 1999. IL-7Rα+ CD3− cells in the embryonic intestine induces the organizing center of Peyer’s patches. Int. Immunol. 11:643–55 15. Adachi S, Yoshida H, Honda K, Maki K, Saijo K, et al. 1998. Essential role of IL-7 receptor α in the formation of Peyer’s patch anlage. Int. Immunol. 10:1–6 16. Veiga-Fernandes H, Coles MC, Foster KE, Patel A, Williams A, et al. 2007. Tyrosine kinase receptor RET is a key regulator of Peyer’s patch organogenesis. Nature 446:547– 51 17. Fukuyama S, Kiyono H. 2007. Neuroregulator RET initiates Peyer’s-patch tissue genesis. Immunity 26:393–95 18. Yokoto Y, Mansouri A, Mori S, Sugawara S, Adachi S, et al. 1999. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 397:702–6 19. Sun Z, Unutmaz D, Zou Y-R, Sunshine MJ, Pierani A, et al. 2000. Requirement for RORγ in thymocyte survival and lymphoid organ development. Science 288:2369–73 www.annualreviews.org • Secondary Lymphoid Organ Development
643
ARI
16 February 2008
13:36
20. Finke D, Acha-Orbea H, Mattis A, Lipp M, Kraehenbuhl J. 2002. CD4+ CD3− cells induce Peyer’s patch development: role of α4β1 integrin activation by CXCR5. Immunity 17:363–73 21. Fukuyama S, Hiroi T, Yokota Y, Rennert PD, Yanagita M, et al. 2002. Initiation of NALT organogenesis is independent of the IL-7R, LTβR, and NIK signaling pathways but requires the Id2 gene and CD3− CD4+ CD45+ cells. Immunity 17:31–40 22. Georgopoulos K, Winandy S, Avitahl N. 1997. The role of the Ikaros gene in lymphocyte development and homeostasis. Annu. Rev. Immunol. 15:155–76 23. Wang JH, Nichogiannopoulou A, Wu L, Sun L, Sharpe AH, et al. 1996. Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity 5:537–49 24. Wu L, Nichogiannopoulou A, Shortman K, Georgopoulos K. 1997. Cell-autonomous defects in dendritic cell populations of Ikaros mutant mice point to a developmental relationship with the lymphoid lineage. Immunity 7:483–92 25. Meier D, Bornmann C, Chappaz S, Schmutz S, Otten LA, et al. 2007. Ectopic lymphoid-organ development occurs through interleukin 7-mediated enhanced survival of lymphoid-tissue-inducer cells. Immunity 26:643–54 26. Mebius RE, Miyamoto T, Christensen J, Domen J, Cupedo T, et al. 2001. The fetal liver counterpart of adult common lymphoid progenitors gives rise to all lymphoid lineages, CD45+ CD4+ CD3− cells, as well as macrophages. J. Immunol. 166:6593–601 27. Mebius RE, Rennert P, Weissman IL. 1997. Developing lymph nodes collect CD4+ CD3− LTβ+ cells that can differentiate to APC, NK cells, and follicular cells, but not T or B cells. Immunity 7:493–504 28. Sabin FR. 1908. Further evidence on the origin of lymphatic endothelium from the endothelium of the blood vasculature system. Anat. Rec. 2:46–55 29. Sabin FR. 1902. On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic ducts in the pig. Am. J. Anat. 1:367–81 30. Wilting J, Papoutsi M, Christ B, Nicolaides KH, von Kaisenberg CS, et al. 2002. The transcription factor Prox1 is a marker for lymphatic endothelial cells in normal and diseased human tissues. FASEB J. 16:1271–73 31. Wigle JT, Oliver G. 1999. Prox1 function is required for the development of the murine lymphatic system. Cell 98:769–78 32. Wigle JT, Harvey N, Detmar M, Lagutina I, Grosveld G, et al. 2002. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J. 21:1505–13 33. Cupedo T, Vondenhoff MF, Heeregrave EJ, De Weerd AE, Jansen W, et al. 2004. Presumptive lymph node organizers are differentially represented in developing mesenteric and peripheral nodes. J. Immunol. 173:2968–75 34. Yoshida H, Naito A, Inoue J, Satoh M, Santee-Cooper SM, et al. 2002. Different cytokines induce surface lymphotoxin-αβ on IL-7 receptor-α cells that differentially engender lymph nodes and Peyer’s patches. Immunity 17:823–33 35. Kim D, Mebius RE, MacMicking JD, Jung S, Cupedo T, et al. 2000. Regulation of peripheral lymph node genesis by the tumor necrosis factor family member TRANCE. J. Exp. Med. 192:1467–78 36. Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, et al. 1999. RANK is essential for osteoclast and lymph node development. Genes Dev. 13:2412–24 37. Kong Y, Yoshida H, Sarosi I, Tan H, Timms E, et al. 1999. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph node organogenesis. Nature 397:315–23
Annu. Rev. Immunol. 2008.26:627-650. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-20
644
Randall
·
Carragher
·
Rangel-Moreno
Annu. Rev. Immunol. 2008.26:627-650. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-20
ARI
16 February 2008
13:36
38. Naito A, Azuma S, Tanaka S, Miyazaki T, Takaki S, et al. 1999. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 4:353–62 39. Honda K, Nakano H, Yoshida H, Nishikawa S, Rennert P, et al. 2001. Molecular basis for hematopoietic/mesenchymal interaction during initiation of Peyer’s patch organogenesis. J. Exp. Med. 193:621–30 40. Luther SA, Ansel KM, Cyster JG. 2003. Overlapping roles of CXCL13, interleukin 7 receptor α, and CCR7 ligands in lymph node development. J. Exp. Med. 197:1191–98 41. Ansel KM, Ngo VN, Hayman PL, Luther SA, Forster R, et al. 2000. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406:309–14 42. Mebius RE. 2003. Organogenesis of lymphoid tissues. Nat. Rev. Immunol. 3:292–303 43. Okuda M, Togawa A, Wada H, Nishikawa S. 2007. Distinct activities of stromal cells involved in the organogenesis of lymph nodes and Peyer’s patches. J. Immunol. 179:804– 11 44. Banks TA, Rouse BT, Kerley MK, Blair PJ, Godfrey VL, et al. 1995. Lymphotoxin α deficient mice: effects on secondary lymphoid organ development and humoral immune responsiveness. J. Immunol. 155:1685–93 45. de Togni P, Goellner J, Ruddle NH, Streeter PR, Fick A, et al. 1994. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264:703–7 46. Banner DW, D’Arcy A, Janes W, Gentz R, Schoenfeld H-J, et al. 1993. Crystal structure of the soluble human 55 kd TNF receptor-human TNFβ complex: implications for TNF receptor activation. Cell 73:431–45 47. Aggarwal BB, Eessalu TE, Hass PE. 1985. Characterization of receptors for human tumour necrosis factor and their regulation by γ-interferon. Nature 318:665–67 48. Pasparakis M, Alexopoulou L, Grell M, Pfizenmaier K, Bluethmann H, Kollias G. 1997. Peyer’s patch organogenesis is intact yet formation of B lymphocyte follicles is defective in peripheral lymphoid organs of mice deficient for tumor necrosis factor and its 55-kDa receptor. Proc. Natl. Acad. Sci. USA 94:6319–23 49. Pasparakis M, Alexopoulou L, Episkopou V, Kollias G. 1996. Immune and inflammatory responses in TNFα-deficient mice: a critical requirement for TNFα in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J. Exp. Med. 184:1397–411 50. Erickson SL, de Sauvage FJ, Kikly K, Carver-Moore K, Pitts-Meek S, et al. 1994. Decreased sensitivity to tumor necrosis factor but normal T cell development in TNF receptor 2 deficient mice. Nature 372:560–63 50a. Kuprash DV, Tumanov AV, Liepinsh DJ, Koroleva EP, Drutskaya MS, et al. 2005. Novel tumor necrosis factor-knockout mice that lack Peyer’s patches. Eur. J. Immunol. 35:1592– 1600 50b. Neumann B, Luz A, Pfeffer K, Holzmann B. 1996. Defective Peyer’s patch organogenesis in mice lacking the 55-kD receptor for tumor necrosis factor. J. Exp. Med. 184:259–64 51. Androlewicz MJ, Browning JL, Ware CF. 1992. Lymphotoxin is expressed as a heteromeric complex with a distinct 33− kDa glycoprotein on the surface of an activated human T cell hybridoma. J. Biol. Chem. 267:2542–47 52. Browning JL, Ngam-ek A, Lawton P, DeMarinis J, Tizard R, et al. 1993. Lymphotoxin β, α novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell 72:847–56 53. Ware CF, Crowe PD, Grayson MH, Androlewicz MJ, Browning JL. 1992. Expression of surface lymphotoxin and tumor necrosis factor on activated T, B and natural killer cells. J. Immunol. 149:3881–88 www.annualreviews.org • Secondary Lymphoid Organ Development
645
ARI
16 February 2008
13:36
54. Koni PA, Sacca R, Lawton P, Browning JL, Ruddle NH, Flavell RA. 1997. Distinct roles in lymphoid organogenisis for lymphotoxins α and β revealed in lymphotoxin β deficient mice. Immunity 6:491–500 55. Futterer A, Mink K, Luz A, Kosco-Vilbois MH, Pfeffer K. 1998. The lymphotoxin β receptor controls organogenisis and affinity maturation in peripheral lymphoid tissues. Immunity 9:59–70 56. Wang J, Foster A, Chin R, Yu P, Sun Y, et al. 2002. The complementation of lymphotoxin deficiency with LIGHT, a newly discovered TNF family member, for the restoration of secondary lymphoid structure and function. Eur. J. Immunol. 32:1969–79 57. Scheu S, Alferink J, Potzel T, Barchet W, Kalinke U, Pfeffer K. 2002. Targeted disruption of LIGHT causes defects in costimulatory T cell activation and reveals cooperation with lymphotoxin β in mesenteric lymph node genesis. J. Exp. Med. 195:1613–24 58. Rennert PD, Browning JL, Mebius RE, Mackay F, Hochman PS. 1996. Surface lymphotoxin α complex is required for the development of peripheral lymphoid organs. J. Exp. Med. 184:1999–2006 59. Rennert PD, Browning JL, Hochman PS. 1997. Selective disruption of lymphotoxin ligands reveals a novel set of mucosal lymph nodes and unique effects on lymph node cellular organization. Int. Immunol. 9:1627–39 60. Rennert PD, James D, Mackay F, Browning JL. 1998. Lymph node genesis is induced by signaling through the lymphotoxin β receptor. Immunity 9:71–79 61. Pomerantz JL, Baltimore D. 2002. Two pathways to NF-κB. Mol. Cell 10:693–95 62. Dejardin E, Droin NM, Delhase M, Haas E, Cao Y, et al. 2002. The lymphotoxin-β receptor induces different patterns of gene expression via two NF-κB pathways. Immunity 17:525–35 63. Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, et al. 2001. Activation by IKKa of a second, evolutionary conserved, NF-κB signaling pathway. Science 293:1495–99 64. Shinkura R, Kitada K, Matsuda F, Tashiro K, Ikuta K, et al. 1999. Alymphoplasia is caused by a point mutation in the mouse gene encoding NFκB-inducing kinase. Nat. Genet. 22:74–77 65. Miyawaki S, Nakamura Y, Suzuka H, Koba M, Yasumizu R, et al. 1994. A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice. Eur. J. Immunol. 24:429–34 66. Alcamo E, Hacohen N, Schulte LC, Rennert PD, Hynes RO, Baltimore D. 2002. Requirement for the NF-κB family member RelA in the development of secondary lymphoid organs. J. Exp. Med. 195:233–44 67. Yilmaz ZB, Weih DS, Sivakumar V, Weih F. 2003. RelB is required for Peyer’s patch development: differential regulation of p52-RelB by lymphotoxin and TNF. EMBO J. 22:121–30 68. Weih DS, Yilmaz ZB, Weih F. 2001. Essential role of RelB in germinal center and marginal zone formation and proper expression of homing chemokines. J. Immunol. 167:1909–19 69. Weih F, Carrasco D, Durham SK, Barton DS, Rizzo CA, et al. 1995. Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-κB/Rel family. Cell 80:331–40 70. Yoshida H, Kawamoto H, Santee SM, Hashi H, Honda K, et al. 2001. Expression of α4 β7 integrin defines a distinct pathway of lymphoid progenitors committed to T cells, fetal intestinal lymphotoxin producer, NK, and dendritic cells. J. Immunol. 167:2511–21
Annu. Rev. Immunol. 2008.26:627-650. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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Randall
·
Carragher
·
Rangel-Moreno
Annu. Rev. Immunol. 2008.26:627-650. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-20
ARI
16 February 2008
13:36
71. Cuff CA, Schwartz J, Bergman CM, Russell KS, Bender JR, Ruddle NH. 1998. Lymphotoxin α3 induces chemokines and adhesion molecules: insight into the role of LT α in inflammation and lymphoid organ development. J. Immunol. 161:6853–60 72. Ngo VN, Korner H, Gunn MD, Schmidt KN, Riminton DS, et al. 1999. Lymphotoxin α and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen. J. Exp. Med. 189:403–12 73. Endres R, Alimzhanov MB, Plitz T, Futterer A, Kosco-Vilbois MH, et al. 1999. Mature follicular dendritic cell networks depend on expression of lymphotoxin β receptor by radioresistant stromal cells and of lymphotoxin β and tumor necrosis factor by B cells. J. Exp. Med. 189:159–67 74. Forster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M. 1996. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87:1037–47 75. Nakano H, Tamura T, Yoshimoto T, Yagita H, Miyasaka M, et al. 1997. Genetic defect in T lymphocyte-specific homing into peripheral lymph nodes. Eur. J. Immunol. 27:215–21 76. Nakano H, Mori S, Yonekawa H, Nariuchi H, Matsuzawa A, Kakiuchi T. 1998. A novel mutant gene involved in T-lymphocyte-specific homing into peripheral lymphoid organs on mouse chromosome 4. Blood 91:2886–95 77. Nakano H, Gunn MD. 2001. Gene duplications at the chemokine locus on mouse chromosome 4: multiple strain-specific haplotypes and the deletion of secondary lymphoidorgan chemokine and EBI-1 ligand chemokine genes in the plt mutation. J. Immunol. 166:361–69 78. Luther SA, Tang HL, Hyman PL, Farr AG, Cyster JG. 2000. Coexpression of the chemokines ELC and SLC by T zone stromal cells and deletion of the ELC gene in the plt/plt mouse. Proc. Natl. Acad. Sci. USA 97:12694–99 79. Gunn MD, Kyuwa S, Tam C, Kakiuchi T, Matsuzawa A, et al. 1999. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J. Exp. Med. 189:451–60 80. Vassileva G, Soto H, Zlotnik A, Nakano H, Kakiuchi T, et al. 1999. The reduced expression of 6Ckine in the plt mouse results from the deletion of one of two 6Ckine genes. J. Exp. Med. 190:1183–88 81. Okada T, Ngo VN, Ekland EH, Forster R, Lipp M, et al. 2002. Chemokine requirements for B cell entry to lymph nodes and Peyer’s patches. J. Exp. Med. 196:65–75 82. Hashi H, Yoshida H, Honda K, Fraser S, Kubo H, et al. 2001. Compartmentalization of Peyer’s patch anlagen before lymphocyte entry. J. Immunol. 166:3702–9 83. Mebius RE, Streeter PR, Michie S, Butcher EC, Weissman IL. 1996. A developmental switch in lymphocyte homing receptor and endothelial vascular addressin expression regulates lymphocyte homing and permits CD4+ CD3− cells to colonize lymph nodes. Proc. Natl. Acad. Sci. USA 93:11019–24 84. Mebius RE, Schadee-Eestermans IL, Weissman IL. 1998. MAdCAM-1 dependent colonization of developing lymph nodes involves a unique subset of CD4+ CD3− hematolymphoid cells. Cell Adhes. Commun. 6:97–103 85. Cupedo T, Lund FE, Ngo VN, Randall TD, Jansen W, et al. 2004. Initiation of cellular organization in lymph nodes is regulated by non-B cell-derived signals and is not dependent on CXC chemokine ligand 13. J. Immunol. 173:4889–96 86. Coles MC, Veiga-Fernandes H, Foster KE, Norton T, Pagakis SN, et al. 2006. Role of T and NK cells and IL7/IL7r interactions during neonatal maturation of lymph nodes. Proc. Natl. Acad. Sci. USA 103:13457–62 www.annualreviews.org • Secondary Lymphoid Organ Development
647
ARI
16 February 2008
13:36
87. Matsumoto M, Mariathasan S, Nahm MH, Baranyay F, Peschon JJ, Chaplin DD. 1996. Role of lymphotoxin and the type 1 TNF receptor in the formation of germinal centers. Science 271:1289–91 88. Matsumoto M, Lo SF, Carruthers CJL, Min J, Mariathasan S, et al. 1996. Affinity maturation without germinal centers in lymphotoxin α deficient mice. Nature 382:462–66 89. Fu Y-X, Huang G, Wang Y, Chaplin DD. 1998. B lymphocytes induce the formation of follicular dendritic cell clusters in a lymphotoxin α dependent fashion. J. Exp. Med. 187:1009–18 90. Hir ML, Bluethmann H, Kosco-Vilbois MH, Muller M, di Padova F, et al. 1996. Differentiation of follicular dendritic cells and full antibody responses require tumor necrosis factor receptor 1 signaling. J. Exp. Med. 183:2367–72 91. Fu Y-X, Huang G, Matsumoto M, Molina H, Chaplin DD. 1997. Independent signals regulate development of primary and secondary follicular structure in spleen and mesenteric lymph node. Proc. Natl. Acad. Sci. USA 94:5739–43 92. Tumanov AV, Kuprash DV, Mach JA, Nedospasov SA, Chervonsky AV. 2004. Lymphotoxin and TNF produced by B cells are dispensable for maintenance of the follicleassociated epithelium but are required for development of lymphoid follicles in the Peyer’s patches. J. Immunol. 173:86–91 93. Tumanov A, Kuprash D, Lagarkova M, Grivennikov S, Abe K, et al. 2002. Distinct role of surface lymphotoxin expressed by B cells in the organization of secondary lymphoid tissues. Immunity 17:239–50 94. Wu Q, Wang Y, Wang J, Hedgeman EO, Browning JL, Fu X-Y. 1999. The requirement on membrane lymphotoxin for the presence of dendritic cells in lymphoid tissues. J. Exp. Med. 190:629–38 95. Summers-DeLuca LE, McCarthy DD, Cosovic B, Ward LA, Lo CC, et al. 2007. Expression of lymphotoxin-αβ on antigen-specific T cells is required for DC function. J. Exp. Med. 204:1071–81 96. Ngo VN, Cornall RJ, Cyster JG. 2001. Splenic T zone development is B cell dependent. J. Exp. Med. 194:1649–60 97. Eugster H-P, Muller M, Karrer U, Car BD, Schnyder B, et al. 1996. Multiple immune abnormalities in tumor necrosis factor and lymphotoxin-α double deficient mice. Int. Immunol. 8:23–36 98. Browning JL, Allaire N, Ngam-Ek A, Notidis E, Hunt J, et al. 2005. Lymphotoxin-β receptor signaling is required for the homeostatic control of HEV differentiation and function. Immunity 23:539–50 99. Fu Y-X, Molina H, Matsumoto M, Huang G, Min J, Chaplin DD. 1997. Lymphotoxin α (LTα) supports development of splenic follicular structure that is required for IgG responses. J. Exp. Med. 185:2111–20 100. Cupedo T, Jansen W, Kraal G, Mebius RE. 2004. Induction of secondary and tertiary lymphoid structures in the skin. Immunity 21:655–67 101. Hamada H, Hiroi T, Nishiyama Y, Takahashi H, Masunaga Y, et al. 2002. Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine. J. Immunol. 168:57–64 102. Lorenz RG, Chaplin DD, McDonald KG, McDonough JS, Newberry RD. 2003. Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin β receptor, and TNF receptor I function. J. Immunol. 170:5475–82 103. Lane PJ, Gaspal FM, Kim MY. 2005. Two sides of a cellular coin: CD4+ CD3− cells regulate memory responses and lymph-node organization. Nat. Rev. Immunol. 5:655–60
Annu. Rev. Immunol. 2008.26:627-650. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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Randall
·
Carragher
·
Rangel-Moreno
Annu. Rev. Immunol. 2008.26:627-650. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-20
ARI
16 February 2008
13:36
104. Kim MY, Toellner KM, White A, McConnell FM, Gaspal FM, et al. 2006. Neonatal and adult CD4+ CD3− cells share similar gene expression profile, and neonatal cells up-regulate OX40 ligand in response to TL1A (TNFSF15). J. Immunol. 177:3074–81 105. Eberl G, Littman DR. 2004. Thymic origin of intestinal αβ T cells revealed by fate mapping of RORγt+ cells. Science 305:248–51 106. Ivanov II, Diehl GE, Littman DR. 2006. Lymphoid tissue inducer cells in intestinal immunity. Curr. Top. Microbiol. Immunol. 308:59–82 107. Kim MY, Gaspal FM, Wiggett HE, McConnell FM, Gulbranson-Judge A, et al. 2003. CD4+ CD3− accessory cells costimulate primed CD4 T cells through OX40 and CD30 at sites where T cells collaborate with B cells. Immunity 18:643–54 108. Kim MY, McConnell FM, Gaspal FM, White A, Glanville SH, et al. 2007. Function of CD4+ CD3− cells in relation to B- and T-zone stroma in spleen. Blood 109:1602–10 109. Kim MY, Anderson G, White A, Jenkinson E, Arlt W, et al. 2005. OX40 ligand and CD30 ligand are expressed on adult but not neonatal CD4+ CD3− inducer cells: evidence that IL-7 signals regulate CD30 ligand but not OX40 ligand expression. J. Immunol. 174:6686–91 110. Harmsen A, Kusser K, Hartson L, Tighe M, Sunshine MJ, et al. 2002. Organogenesis of nasal associated lymphoid tissue (NALT) occurs independently of lymphotoxin-α (LTα) and retinoic acid receptor-related orphan receptor-γ, but the organization of NALT is LTα-dependent. J. Immunol. 168:986–90 111. Eberl G, Marmon S, Sunshine MJ, Rennert PD, Choi Y, Littman DR. 2004. An essential function for the nuclear receptor RORγ(t) in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol. 5:64–73 112. Ying X, Chan K, Shenoy P, Hill M, Ruddle NH. 2005. Lymphotoxin plays a crucial role in the development and function of nasal-associated lymphoid tissue through regulation of chemokines and peripheral node addressin. Am. J. Pathol. 166:135–46 113. Fukuyama S, Nagatake T, Kim DY, Takamura K, Park EJ, et al. 2006. Cutting edge: uniqueness of lymphoid chemokine requirement for the initiation and maturation of nasopharynx-associated lymphoid tissue organogenesis. J. Immunol. 177:4276–80 114. Weih F, Caamano J. 2003. Regulation of secondary lymphoid organ development by the nuclear factor-κB signal transduction pathway. Immunol. Rev. 195:91–105 115. Ikawa T, Fujimoto S, Kawamoto H, Katsura Y, Yokota Y. 2001. Commitment to natural killer cells requires the helix-loop-helix inhibitor Id2. Proc. Natl. Acad. Sci. USA 98:5164– 69 116. Hacker C, Kirsch RD, Ju XS, Hieronymus T, Gust TC, et al. 2003. Transcriptional profiling identifies Id2 function in dendritic cell development. Nat. Immunol. 4:380–86 117. Kusunoki T, Sugai M, Katakai T, Omatsu Y, Iyoda T, et al. 2003. TH2 dominance and defective development of a CD8+ dendritic cell subset in Id2-deficient mice. J. Allergy Clin. Immunol. 111:136–42 118. Rangel-Moreno J, Moyron-Quiroz J, Kusser K, Hartson L, Nakano H, Randall TD. 2005. Role of CXC chemokine ligand 13, CC chemokine ligand (CCL) 19, and CCL21 in the organization and function of nasal-associated lymphoid tissue. J. Immunol. 175:4904– 13 119. McDonald KG, McDonough JS, Wang C, Kucharzik T, Williams IR, Newberry RD. 2007. CC chemokine receptor 6 expression by B lymphocytes is essential for the development of isolated lymphoid follicles. Am. J. Pathol. 170:1229–40 120. Moyron-Quiroz JE, Rangel-Moreno J, Kusser K, Hartson L, Sprague F, et al. 2004. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat. Med. 10:927–34 www.annualreviews.org • Secondary Lymphoid Organ Development
649
ARI
16 February 2008
13:36
121. Taylor RT, Patel SR, Lin E, Butler BR, Lake JG, et al. 2007. Lymphotoxin-independent expression of TNF-related activation-induced cytokine by stromal cells in cryptopatches, isolated lymphoid follicles, and Peyer’s patches. J. Immunol. 178:5659–67 122. Kweon MN, Yamamoto M, Rennert PD, Park EJ, Lee AY, et al. 2005. Prenatal blockage of lymphotoxin β receptor and TNF receptor p55 signaling cascade resulted in the acceleration of tissue genesis for isolated lymphoid follicles in the large intestine. J. Immunol. 174:4365–72 123. Wang C, McDonald KG, McDonough JS, Newberry RD. 2006. Murine isolated lymphoid follicles contain follicular B lymphocytes with a mucosal phenotype. Am. J. Physiol. Gastrointest. Liver Physiol. 291:G595–604 124. Lugering A, Kucharzik T. 2006. Induction of intestinal lymphoid tissue: the role of cryptopatches. Ann. N. Y. Acad. Sci. 1072:210–17 125. McDonald KG, McDonough JS, Newberry RD. 2005. Adaptive immune responses are dispensable for isolated lymphoid follicle formation: antigen-naive, lymphotoxinsufficient B lymphocytes drive the formation of mature isolated lymphoid follicles. J. Immunol. 174:5720–28 126. Pabst O, Herbrand H, Friedrichsen M, Velaga S, Dorsch M, et al. 2006. Adaptation of solitary intestinal lymphoid tissue in response to microbiota and chemokine receptor CCR7 signaling. J. Immunol. 177:6824–32 127. Pabst O, Herbrand H, Worbs T, Friedrichsen M, Yan S, et al. 2005. Cryptopatches and isolated lymphoid follicles: dynamic lymphoid tissues dispensable for the generation of intraepithelial lymphocytes. Eur. J. Immunol. 35:98–107 128. Halle S, Bumann D, Herbrand H, Willer Y, Dahne S, et al. 2007. Solitary intestinal lymphoid tissue provides a productive port of entry for Salmonella enterica serovar Typhimurium. Infect Immun. 75:1577–85 129. Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, et al. 1999. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99:23–33
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:627-650. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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Immunity to Citrullinated Proteins in Rheumatoid Arthritis 1,2 ¨ Lars Klareskog,1 Johan Ronnelid, Karin Lundberg,3 Leonid Padyukov,1 and Lars Alfredsson4 1
Rheumatology Unit, Department of Medicine, Karolinska Institutet/Karolinska University Hospital, SE-171 76, Stockholm, Sweden
2
Clinical Immunology Unit, Uppsala University/Uppsala University Hospital, SE-751 85, Uppsala, Sweden
3
Kennedy Institute of Rheumatology, Imperial College London, W6 8LH, London, United Kingdom
4
Institute of Environmental Medicine, Karolinska Institutet, SE-171 77, Stockholm, Sweden; email:
[email protected],
[email protected],
[email protected],
[email protected],
[email protected] Annu. Rev. Immunol. 2008. 26:651–75
Key Words
First published online as a Review in Advance on January 2, 2008
genes, environment, autoimmunity, smoking, HLA-DR
The Annual Review of Immunology is online at immunol.annualreviews.org This article’s doi: 10.1146/annurev.immunol.26.021607.090244 c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0651$20.00
Abstract Antibodies to citrullinated proteins (ACPA), i.e., to peptides posttranslationally modified by the conversion of arginine to citrulline, are specific serological markers for rheumatoid arthritis (RA). Studies on anticitrulline immunity, summarized in this review, demonstrate that the criterion-based syndrome RA should be subdivided into at least two distinct subsets (ACPA-positive and ACPA-negative disease). A new etiological model is proposed for ACPA-positive RA, built on MHC class II–dependent activation of adaptive immunity. Fundamentals of this model include the following: (a) ACPA antedate onset of arthritis; (b) ACPA may aggravate arthritis in rodents; (c) ACPA are triggered in the context of genes that confer susceptibility to RA (HLA-DRB1 SE) and by environmental agents triggering RA (smoking or bacterial stimuli); (d ) ACPA may complex with citrullinated proteins present in target tissue as part of a multistep process for arthritis development. The model provides a new basis for molecular studies on the pathogenesis of ACPA-positive arthritis.
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BACKGROUND RA: rheumatoid arthritis RF: rheumatoid factors MHC: major histocompatibility complex
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ACPA: antibodies to citrullinated protein antigens CII: collagen type II
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Rheumatoid arthritis (RA) is a disease defined by criteria (1) that have been useful in harmonizing clinical trials and clinical practice but that are not based on what is now known about its etiology or pathogenesis. It follows that any studies on the molecular pathogenesis of arthritis as defined by these criteria should consider the possibility that the findings are relevant only for a subset of RA. RA is often denoted an “autoimmune” disease, largely based on the presence of rheumatoid factors (RF) (2), one of the seven classification criteria. However, the presence of RF is not specific for RA but is rather a general consequence of immune activation in the context of immune complex formation (3, 4); no experimental studies have demonstrated any proarthritogenic effects of RF. However, other data favor a role for adaptive immunity and possibly for autoimmune reactions in the disease. Such features are the genetic linkage to MHC class II genes (5, 6), the pattern of immune cells and MHC class II molecules in inflamed synovium (7), and the presence of activated T and B cells in the joint (7–9). Taken together, these observations underscore a pathogenetic role for MHC class II–dependent immune activation in RA (7, 10). The nature of such specific immune reactions has, however, been surprisingly difficult to define. In recent years, advances in research and therapy within the field of cytokine regulation and cytokine-directed therapy have largely dominated the research field of RA (11–14), illustrating how therapeutic progress is possible even though the role of adaptive immunity in this disease is not fully understood. In parallel with this progress, there has also been a major development in the field of immunity focused on antibody reactivity to proteins modified by citrullination, i.e., an enzyme-mediated posttranslational modification of peptidylarginine to peptidylcitrulline. Notably, epidemiological and genetic studies of RA in relation to the anticitrulline immunity have redefined RA phenotypes, demonstrating major differences Klareskog et al.
in genetic and environmental risk factors, and thus probably in molecular pathogenesis too, between RA patients with and without the presence of antibodies to citrullinated proteins (ACPA). The implication for immunological studies of RA is that meaningful molecular studies on RA, particularly when dealing with adaptive immunity, should no longer be performed in patients with “RA” but rather in subsets of patients, grouped according to serology as well as to genetic, environmental, and clinical determinants. A short summary of studies from many groups over the past 10 years tells us that (a) antibodies to citrullinated proteins can be found in approximately 60% of RA patients (15–19). These antibodies are highly specific for RA, i.e., they exist in around 2% of normal populations (15) and are also quite rare in other inflammatory conditions (15). (b) The occurrence of ACPA is seen several years before onset of disease (20–23), and very few patients with RA develop ACPA after onset of their symptoms (24, 25). (c) The occurrence of ACPA is closely linked to the presence of MHC class II alleles that predispose for RA (26, 27); most notably, the association of HLA-DRB1 alleles is seen exclusively for the ACPA-positive subset of disease but not for the ACPA-negative variant (26, 27). (d ) Immunity toward citrullinated self proteins contributes to arthritis in rodents. The two experiments supporting this conclusion demonstrated that transfer of monoclonal antibodies to citrullinated fibrinogen can enhance arthritis development in mice at the same time as tolerization against citrullinated antigens diminishes arthritis severity (28), and that immunization with the citrullinated self antigen type II collagen (CII) leads to a more severe arthritis than immunization with the same noncitrullinated protein (29). These studies have renewed interest in the field of adaptive immunity in RA by focusing on a defined subset of the disease. This review summarizes this research and suggests potential directions for research into the etiology of selected RA subpopulations. By dissecting the
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syndrome now called RA, we might be able to devise immunotherapies specifically adapted to individual arthritis subpopulations.
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CITRULLINATION, A POSTTRANSLATIONAL PROTEIN MODIFICATION OF LARGELY UNKNOWN SIGNIFICANCE Deimination of the charged peptidyl arginine to the neutral peptidylcitrulline is an enzymatic process in mammals mediated by a series of enzymes denoted peptidyl arginine deiminases (PADs) (30, 31). The activity of these enzymes is dependent on high concentrations of calcium, and deimination can occur intracellularly in conjunction with apoptosis (32) as well as extracellularly given high enough Ca2+ concentrations (33). In addition, certain proteins present in the stratum corneum of outer epidermis (34) and in the CNS in conjunction with astrocytes appear to be constitutively citrullinated (35, 36). The precise physiological function of citrullination is incompletely understood. From the fact that the deimination changes the charge of critical residues of a protein, it is H
O
H
N
Peptidyl arginine deiminase (PAD)
known that citrullination often makes proteins more prone to degradation by proteolytic enzymes (33) (Figure 1). An interesting recent finding is that proteins undergoing processing in antigenpresenting cells (APCs) can be citrullinated before presentation to T cells (37). The functional consequence of this intriguing observation is not yet understood but warrants further consideration. In human disease, increased citrullination was first demonstrated to take place in lining and sublining cells in the joints of patients with RA (32). Subsequently, citrullinated proteins were detected by immunohistochemistry in a number of inflamed tissues, including arthritic joints in several different forms of arthritis (38), lungs (26, 39), extraarticular inflammatory sites in RA (39), human brain (40), and inflamed muscle as well as inflamed lymphoid organs (41). No selectivity of citrullination for certain argininecontaining proteins has been demonstrated to date, and citrullination has been observed in many different synovial proteins, including fibrinogen (42), vimentin (43, 44), and CII (M. Hermansson, unpublished observation); furthermore, α-enolase (45) has been demonstrated to colocalize with citrullination in conjunction with joint inflammation. O
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L-arginine residue (+ charged)
PAD: peptidyl arginine deiminase
Change in charge
Different folding More sensitive to degradation
NH2
L-citrulline residue (neutral)
Deimination
Deiminated protein
Figure 1 Deimination of peptidylarginine to peptidylcitrulline is a posttranslational process, also known as citrullination, driven by the calcium-dependent enzyme peptidyl arginine deiminase (PAD). The enzymatic conversion results in the loss of one positive charge for every arginine residue converted to a neutral citrulline. This causes changes in intra- and intermolecular interactions, which could lead to altered protein folding, enhanced degradation by proteases, and exposure of cryptic epitopes. www.annualreviews.org • Immunity to Citrullinated Proteins in Rheumatoid Arthritis
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CCP: cyclic citrullinated peptides
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IMMUNITY TO CITRULLINATED PROTEIN ANTIGENS IN RA AND RELATED CONDITIONS
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The first demonstration that antibodies in RA patients display a preferential reactivity with proteins modified by citrullination came from work by two groups, in France and in the Netherlands. Guy Serre’s group in Toulouse investigated the molecular basis of antibodies that reacted with keratin in the skin (45) and with perinuclear cellular structures (46), which were both used in RA diagnostics, and showed that filaggrin was the common target of these antibodies (47, 48). Walther van Venrooij’s group in Nijmegen subsequently demonstrated that the filaggrin-specific reactivity of RA sera is dependent on deimination (“citrullination”) of arginine residues in filaggrin-derived peptides (49). This failure to see reactivity against recombinant filaggrin produced for evaluation in potential immunoassays for RA led to the recognition that the reactivity was dependent on posttranslational citrullination (49). Initially, these findings were mainly used to develop better diagnostic markers for RA, and several assays were developed that increased the specificity and sensitivity for RA. The assays most widely used were those with cyclic citrullinated peptides as substrates for the detection of antibodies (15, 18, 50). The initial studies on ACPA reactivity were performed on in vivo citrullinated filaggrin molecules, and then on intact fibrinogen where arginines had been deiminated in vitro using PAD (51). Investigations on larger groups of RA patients showed comparable reactivity patterns when cyclic citrullinated peptides (CCP), citrullinated filaggrin (16), or fibrinogen (52) were used as substrates for assays focusing on IgG antibody reactivities. Further studies have demonstrated RA-specific reactivities against a wide range of citrullinated peptides and proteins. Reactivity to vimentin was originally observed as the so-called antiSa reactivity (53–55), and subsequent assays
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using a mutated variant of vimentin showed reactivities similar to, or with even better sensitivity than, those toward CCP (56) and fibrinogen (44). Reactivities to citrullinated α-enolase represent one recent observation (57), of interest because α-enolase is widely expressed in RA joints and, in immunohistochemical analysis, it colocalizes with citrulline staining. The antibody reactivity to citrullinated CII represents a specific challenge because CII is the major structural protein in hyaline cartilage and because native CII is the classic autoantigen used to provoke polyarthritis in rodents (58, 59). The relatively low frequency of antibody reactivity to native CII in sera of patients with RA has argued against a pathogenetic role of anticollagen immunity in human disease (60), although there are some reports of higher frequencies of immunity against native CII in joints of patients with RA (61, 62). The current demonstration of a high frequency of antibodies against the citrullinated variants of CII in sera of RA patients, especially certain citrullinated peptides (63), provides a new angle on collagen immunity in RA. The extent to which reactivities of single antibodies are directed toward private epitopes on different citrullinated peptides or proteins and the extent to which they react with public epitopes common to many citrullinated peptides/proteins are incompletely understood, as is the isotype distribution of the ACPA (see Reference 64 for an initial description). The most remarkable features of the data emerging from investigations of different ACPA are the high specificity for RA and the fact that they define a distinct subset of RA. Most of these studies have been performed using CCP-based assays. Typically, 50%–70% of early RA patients are anti-CCP positive (18, 19), and the phenotype is thereafter very stable, i.e., very few patients shift from being anti-CCP positive to being anti-CCP negative or vice versa, even after treatment with disease-modifying antirheumatic drugs
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(24, 25). This qualitative phenotypic stability is also seen after treatment with TNFblocking agents, although ACPA concentrations remain stable in some (65, 66), but not in all (67–69), studies. Comparatively few individuals (typically approximately 2%) in a population of healthy controls are positive for anti-CCP antibodies. In contrast to RF, antiCCP antibodies are rather specific for RA. Thus, only relatively few patients with systemic inflammatory diseases, such as systemic lupus erythematosus (SLE), mixed connective ¨ tissue disease (MCTD), Sjogren’s syndrome, or myositis, have anti-CCP antibodies; most investigators have reported fewer than 10% of such patients to be anti-CCP positive. When patients with these diagnoses are subgrouped according to anti-CCP phenotype, those with detectable anti-CCP antibodies often present with RA-like features (including polyarthritic disease, erosions, RF, and HLA association) or can be classified as RA in addition to other diagnoses. This ambiguity has also been described for patients with psoriatic arthritis (70–73), juvenile idiopathic arthritis (74–77), SLE (78), and MCTD (79). These data suggest a potential new classification of arthritis, as some patients with polyarthritis and concomitant features of other systemic rheumatic conditions might well share etiologic features with ACPA-positive classical RA. Further studies of common genetic and environmental determinants for ACPA-positive arthritides may suggest a new ACPA-related classification that has a wider inclusion than only those patients who fulfill today’s classification criteria for RA (1).
EVIDENCE THAT ACPA-POSITIVE AND ACPA-NEGATIVE RA CONSTITUTE TWO CLINICALLY AND GENETICALLY DISTINCT SUBSETS OF RA One of the more exciting features of current work on ACPA in RA is the evidence that
ACPA-positive and ACPA-negative RA constitute two distinct subsets of this criterionbased disease. The first confirmation is purely clinical in the sense that ACPA-positive RA patients have a disease course considerably more severe than that of ACPA-negative patients, irrespective of treatment (24, 25, 80, 81). In particular, erosiveness is highly linked to an ACPA-positive status (81–83). A second verification comes from treatment, where a recently published study demonstrated how methotrexate induced remission in ACPApositive early arthritis patients but had no effect in ACPA-negative subjects (84). The most compelling data from a pathophysiological perspective, however, demonstrate large differences concerning susceptibility genes for ACPA-positive and ACPA-negative disease. By the late 1970s, the MHC class II genes (5, 6, 85) were already identified as the major genetic risk factor for RA. Numerous studies on the association between HLA class II genes, in particular the HLA-DRB1∗ shared epitope (SE) alleles and RA, have provided a strong rationale for MHC class II–dependent T cell activation and thus for adaptive immunity having a pathogenic role in RA. This association also differentiated RA from other MHC class II–associated arthritic diseases such as ankylosing spondylitis, psoriatic arthritis, and reactive arthritis (86). The genetic association of RA to HLADRB1 SE has recently been shown to be entirely confined to the ACPA-positive subset (87, 88). This finding indicates that the implication of MHC class II–dependent T cell activation in the pathogenesis should be limited to ACPA-positive RA and to anticitrulline immunity (see below). In contrast, two studies suggested that ACPA-negative RA may be associated with HLA-DRB1∗ 03, an allele not previously associated with disease susceptibility in the unstratified RA population (64, 89). Following this initial demonstration of a genetic distinction between ACPA-positive and ACPA-negative RA for HLA-DR genes, a second major genetic risk factor for RA, the
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HLA-DRB1 SE: HLA-DRB1 shared epitope
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polymorphism in PTPN22 gene, was also shown to be associated only with the ACPApositive disease (90–92). Other genetic risk factors, in particular variations in the interferon regulating factor 5 (IRF-5) (93) but also polymorphisms in a newly identified risk gene in the C-type lectin complex (94), were associated exclusively with ACPA-negative disease (93). Taken together, the descriptive studies of disease course and genetic linkages strongly indicate that ACPA reactivity splits RA into two major and clinically relevant subsets of disease. Thus ACPA-positive and ACPAnegative RA should be treated as separate entities when studying the molecular pathophysiology of RA.
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EVIDENCE THAT ANTICITRULLINE IMMUNITY CAN CONTRIBUTE TO DEVELOPMENT OF ARTHRITIS The key issue related to anticitrulline immunity is whether the observed autoantibodies are causally related to the disease, consequences of the disease, or just epiphenomena. Two groups of experiments suggest that anticitrulline immunity may contribute to arthritis. That ACPA may precede clinical RA by years was first demonstrated from studies of blood repositories in northern Sweden, where individuals who subsequently developed arthritis had donated blood samples several years before onset of disease. Anti-CCP antibodies were demonstrated up to nine years before clinical onset of RA, and increased frequencies of higher concentrations of antibodies were seen as the individuals approached onset of disease (22). These studies were well in line with a series of earlier investigations from Kimmo Aho and associates in Finland; these authors had shown that rheumatoid factors (95) as well as antikeratin (20) and antifilaggrin antibodies (21) preceded RA development. An independent study from the Netherlands further corroborated the finding that most individuals who would de656
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velop ACPA-positive RA had already developed their autoantibodies before disease onset (23). Little is yet known about the evolution of ACPA epitope specificities during arthritis development, information that might shed light on the pathogenic role of different ACPAs. However, the time sequence of ACPA development pre-RA and, in particular, the finding that very few patients develop ACPA after disease onset, provide indirect evidence for the contribution of anticitrulline immunity, or some other concomitant immunity, in the pathogenesis of ACPA-positive RA. Studies of immunoglobulin isotypes and IgG subclasses in early and long-standing RA also indicate that the isotype repertoire is fully developed by the time of arthritis development, but shows a sustained presence of IgM antiCCP, interpreted as a continuous activation of ACPA-reactive B cells (64). The second line of evidence in support of a direct pathogenic role for anticitrulline immunity comes from experimental animal models. In the mouse, Kristine Kuhn and collaborators found that transfer of monoclonal antibodies to citrullinated fibrinogen enhanced a mild arthritis that was initiated with anti-CII antibody transfer (28). However, antibodies to citrullinated fibrinogen alone were not able to cause arthritis in naive animals with no joint lesions. Furthermore, mice immunized with native CII developed anticitrulline immunity, i.e., reactivity to native as well as citrullinated CII, and administration of citrullinated peptides in a tolerogenic protocol ameliorated the collagen-induced arthritis (CIA). These latter data thus suggested that citrullination of collagen and/or additional proteins might be involved in CIA. In two different reports in the rat, citrullination was shown to enable otherwise nonimmunogenic self molecules to trigger autoantibody production against albumin, CII (29), and fibrinogen (96). Neither the immunity to citrullinated albumin (29) nor to fibrinogen (96) was able to cause arthritis, whereas the immunity to citrullinated CII enhanced
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arthritis in Lewis 1AV1 rats (29). Taken together, these papers document how citrullination may change the immunogenicity of self antigens and suggest that immunity to some citrullinated proteins may contribute to arthritis development. More detailed studies are needed to determine which cells, specificities, and mechanisms are involved in this process (see below).
WHEN AND HOW IS ANTICITRULLINE IMMUNITY TRIGGERED? The data summarized above indicate that antibodies to autoantigens that have been modified by citrullination may contribute to arthritis. As citrullination is a common process in many physiological events, including apoptosis and inflammation, the rate-limiting steps appear to be whether and when immunity is triggered against these modified proteins and which epitopes of which proteins are being recognized. Most information on how genes and environmental determinants interact in increasing risk for ACPA-negative as well as ACPApositive RA comes from case control studies in which population-based RA cohorts were compared with healthy individuals from the same population. The most striking finding from these studies overall is the dichotomy between ACPA-positive and ACPA-negative RA concerning both genetic and environmental determinants. Thus, as noted above, both the major genes, i.e., HLA-DRB1 SE and PTPN22 alleles that predispose for RA, were shown to be risk factors for ACPA-positive disease, but not for ACPA-negative disease. For HLA-DRB1, the susceptibility alleles DRB1∗ 0401 and ∗ 0404 were also closely linked to frequencies as well as levels of ACPA, measured with the CCP assay (87, 88), indicating not only that these genes were susceptibility factors for the disease, but also that they directly influenced ACPA production. The PTPN22 codes for a tyrosine phosphatase
that is present in many cells, and the allelic difference influences susceptibility (97) by altering the threshold for activation of PTPN22expressing cells. This is true not only for T cells but also for a number of other cell types (98). The PTPN22 1858 T polymorphism (620W) is specifically associated with antiCCP-positive RA in many (91, 99, 100), but not in all (101), studies. Recently, a striking gene-gene interaction was demonstrated between HLA-DRB1 SE alleles and the susceptibility allele of the PTPN22 gene, where the combination of two SE alleles and the 620W allele of PTPN22 increased the risk for ACPA-positive RA 20-fold compared to individuals with none of these genetic risk factors (92). These data indicated that both molecular pathways involving MHC class II–dependent T cell activation and tyrosine phosphatase–mediated cell activation are of pathogenic importance in ACPA-positive RA. More recently, additional genetic determinants, notably one gene in the TRAF1-C5 region, have also been shown to associate with ACPA-positive RA (102), but not with ACPAnegative disease (103). Although the susceptibility gene(s) has not yet been definitely identified, its possible relation to TRAF1- or C5-mediated functions makes it an additional determinant influencing a pathway related to adaptive immunity and antibody-mediated effector functions. Smoking, long known to be the major environmental factor in increased risk for RA (104–107), was recently demonstrated to be a significant influence on RF+ disease (104, 106, 108–110). Smoking used to be considered as an unspecific risk factor, of interest mainly from a public health perspective, rather than a reasonably well-defined trigger of RA, and studies of its actions could help elucidate the molecular pathology of RA. Our investigations showed a striking gene-environment interaction between smoking and the presence of the HLA-DRB1 SE risk alleles as risk factors first for RF+ disease (110), and then even more pronounced for ACPA-positive RA (26) (Figure 2). The relative risk of developing
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Figure 2 (a) A major gene-environment interaction between HLA-DR SE and smoking is present in the ACPA-positive RA subpopulation (left) but not in the ACPA-negative RA subpopulation (right). Smoking only confers an increased risk of developing ACPA-positive RA, as does possessing a single copy of the HLA-SE allele or, even more so, two copies of the HLA-SE alleles (RR, relative risk). (Original data published in Reference 26.) (b) The two panels demonstrate the combined effects of the three risk factors (HLA-DRB1 SE, PTPN22 620W allele, and smoking) in ACPA-positive RA (left) and the complete absence of effect of any of these three factors in ACPA-negative RA (right). (Original data published in Reference 92.)
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ACPA-positive RA was over 20 times higher for smokers carrying two copies of the HLADRB1 SE alleles than for nonsmokers with no SE alleles. On the other hand, no increased risk was discerned for development of ACPAnegative RA (26). This gene-environment interaction has subsequently been replicated both in a Dutch study of ACPA-positive and ACPA-negative cases only (27) and in a Danish case control (111) study, which found even higher risk ratios for the combination of smoking and HLA-DRB1 SE than in our original study. Notably, in our continued studies in the Swedish cohorts, we extended the data for gene-environment interactions between smoking and HLA-DRB1 by showing the dose-dependency of smoking, with a combined relative risk of ACPA-positive RA of close to 50 times higher in heavy smokers carrying two copies of HLA-DRB1 SE alleles than in nonsmokers lacking these variations (112). However, no interaction was found between the PTN22 risk alleles and smoking (92). In a recently published study from North America, a more mixed picture emerged on the interaction between smoking and HLADRB1 SE, indicating that other genes or environmental factors may also influence the risk of RA development (113). The studies described above provide one of the most striking examples of geneenvironment interaction in the risk of developing a specific diagnosis, where this risk is strictly confined to an immunologically defined subgroup of patients. These observations provide an obvious basis for further molecular studies that would explain the observed effects of genes and environment as well as provide a more general insight into the pathogenesis of ACPA-positive RA. As a first step, we initiated studies to determine if and how smoking may influence citrullination of proteins in lungs. We showed initially that smoking is associated with an increased presence of citrullinated proteins in bronchoalveolar lavage (BAL) cells from healthy smokers and smokers with pulmonary inflammation (26). Subsequently, we extended this study to
demonstrate that this increased citrullination may be due to increased expression of PADs, in particular PAD2 in BAL cells from smokers ¨ L. Klareskog, (D. Makrygiannikos, M. Skold, and A. Catrina, submitted for publication). We then proposed the following model for how immunity to citrullinated proteins might be triggered by smoking and how the geneenvironment interactions might be explained (26, 114): Smoking may cause PAD activation and subsequent citrullination in lungs, at the same time as components in smoke act as unspecific adjuvants activating APCs in the pulmonary compartment. In individuals carrying immune response genes that predispose to a strong immune reaction against certain citrullinated peptides, and where other genetic variants are also present (such as the PTPN22coded tyrosine phosphatase), an immune response with antibody production to citrullinated proteins might be triggered. The validity of this model was further strengthened by a report in a mouse model that immunity to a citrullinated vimentin peptide may be restricted by HLA-DRB1 SE alleles (115).
A POSSIBLE ETIOLOGIC MODEL FOR ARTHRITIS THAT INVOLVES CITRULLINATION AND IMMUNITY TO CITRULLINATED PROTEINS The studies described above provide a framework for molecular studies of adaptive immunity in RA. In the remainder of this review, we use this framework to discuss a potential model for an etiology of ACPA-positive RA that could perhaps be extended to other cases of ACPA-positive arthritis. Notably, most of the issues related to specificity and regulation of anticitrulline immunity have still been incompletely investigated. The epidemiologic and longitudinal studies referred to above have also produced data to suggest the existence of different stages in a multistep process that leads to ACPA-positive RA. An outline of this model that we discuss below is provided in Figure 3.
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Figure 3 A three-stage etiologic model for the development of ACPA-positive RA. Stage 1, the immune response: Environmental risk factors, such as smoking, may induce citrullination of proteins in the lungs. An altered antigen uptake, processing, and presentation of citrullinated antigens could, in genetically susceptible individuals (i.e., HLA-DR SE positive), lead to the production of ACPA. Stage 2, the pathologic inflammatory response: An unspecific arthritis, accompanied by citrullination of proteins in the joints, develops at a later stage. Recruitment of ACPA from the circulation results in the formation of immune complexes. Stage 3, chronic RA: The generation of citrullinated proteins, the influx of immune cells, and the production of cytokines and autoantibodies, as a result of the immune complex formation, perpetuate the joint inflammation into chronic RA.
Stage 1: Citrullination and Triggering of Immunity to Citrullinated Proteins Key to understanding anticitrulline autoimmunity in arthritis is the determination of conditions that trigger the occurrence of (a) citrullination and (b) immunity to citrullinated proteins. Activation of PADs and citrullination occurs in inflammatory conditions as well as in apoptosis, and many different cells including macrophages and neutrophils can express PADs (30) (Figures 4 and 5). Active immunization with citrullinated self proteins can trigger antibodies directed to citrullinated as well as to the corresponding noncitrullinated proteins. The conditions required to trigger immunity to citrullinated proteins in a more physiological context are less well known. From the relatively rare occurrence of anticitrulline antibodies in healthy individuals (human as 660
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well as mouse) and the frequent occurrence of citrullination already in utero (116) and in inflammation (41), the brake of tolerance to citrullinated proteins should be a relatively rare event. In many respects, the occurrence of immunity to citrullinated proteins can be compared with immunity to molecules exposed to the immune system during apoptosis. Here, immunity toward DNA and other constituents of apoptotic blebs may be triggered under certain relatively rare conditions, where both genetic and environmental factors are important (117). We know from studies described above in humans that at least some anticitrulline immunity may be preferentially triggered in the context of certain MHC class II genetic variants, but also other genetic factors should be studied, preferably in a context where anticitrulline immunity can be investigated per se and independently of its possible later involvement in RA pathogenesis.
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Stage 1: Immune response a Influx of cells into the lung
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Figure 4 Stage 1 in the etiological model for the development of ACPA-positive RA: the immune response. (a) Heavy cigarette smoking stimulates an influx of cells into the lungs. (b) Toxic components in the smoke activate the cells and (c, d ) render them more prone to apoptosis. (e) PAD becomes activated during the apoptotic process and ( f ) deiminates proteins present in the lungs. (g) In genetically predisposed individuals, such as those carrying the HLA-DR SE alleles, presentation of citrullinated peptides or other neo-epitopes from citrullinated proteins could (h) activate autoreactive T cells, which in turn could induce B cell help and (i) stimulate the production of ACPA.
Functional polymorphisms in genes coding for the PADs are obvious candidates, and a polymorphism in the PADI4 gene has been reported to increase risk for RA in Japanese (118) and Korean (119) populations, but probably not in Western European populations (120–123). It is, however, not yet formally proven that this polymorphism affects anticitrulline immunity; other possible molecules in pathways related to the citrullination may have variations that predispose to the disease. Of particular interest is whether anti-PAD can be triggered in conjunction with citrullination. A few small studies suggest the exis-
tence of anti-PAD2 and anti-PAD4 antibodies in RA (124). This line of research warrants further attention, particularly given its attractive parallels to the situation in celiac disease, in which the complex of transglutaminase and gluten modified by this enzyme constitutes the immunogenic protein complex (125). In the ACPA parallel, the entire complex of PAD and a citrullinated antigen may constitute the nonself antigen complex. The possible association between citrullination in lungs and smoking—and the possible triggering of anticitrulline immunity in this context—is a challenging concept. But
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g IC formation Figure 5 Stage 2 in the etiological model for the development of ACPA-positive RA: the pathologic inflammatory response. (a) A second, joint-specific inflammatory event is initiated by an unknown and unspecific stimulus, for example, infection or trauma. (b) Inflammatory cells are recruited to the joint, (c) activated by the unknown “trigger,” and in this inflammatory milieu (d ) PAD becomes activated and (e) deiminates proteins present in the joint. ( f ) Circulating ACPA enter the joint, bind to the citrullinated proteins, and (g) form immune complexes (IC).
the model should not be limited to smoking. We might instead consider inflammation in lungs driven by various exposures as a potential trigger of citrullination within the airways and development of anticitrulline immunity. Silica dust and mineral oil exposure have both been linked to an increased risk for ACPA-positive RA (L. Klareskog, J. ¨ Ronnelid, K. Lundberg, L. Padyukov, and L. Alfredsson, unpublished results). Several other factors, including air pollutants and maybe also charcoal as in Caplan’s syndrome (126), are also possible agents. The fact that IgA anticitrulline immunity is seen early dur662
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ing development of an anticitrulline immune response (64) indicates that immunity triggered from mucosal surfaces such as the lungs may be involved in triggering of anticitrulline immunity (Figure 4). The nonequal importance of genetic variations in the PADI4 gene for risk of RA in Asian and in Caucasian populations (118–123) is an indication of possible multiple genetic and environmental factors that lead to the production of ACPA. Another trigger of citrullination and citrulline immunity could be infections. Although many pathogens are suggested to be involved in triggering of RA, no solid evidence exists linking infectious agents to RA. The discovery of ACPA provides new opportunities to reinvestigate this issue. Pratesi and colleagues, for example, have recently shown reactivity to citrullinated Epstein-Barr nuclear antigen-1 in RA patients (127). Another pathogen of interest is Porphyromonas gingivalis, the causal agent of adult periodontitis, a disease with many features in common with RA, of which the most striking is an HLASE association (128, 129). Given that P. gingivalis is the only bacterium known to express a functional PAD enzyme, one could hypothesize that infection by P. gingivalis could induce local citrullination and subsequent citrullineimmunity in susceptible individuals, which could lead to the development of RA in a fashion similar to that described for smoking. The seroconversion of a healthy individual from an ACPA-negative to an ACPA-positive state is quantitatively and “risk-wise” the most important step in the series of events that may lead to RA. Thus, for a healthy individual who is positive for ACPA, measured with an antiCCP test, the risk of developing RA in the future is 100-fold greater than that for the general population. This risk is further increased to over 100-fold if HLA-DRB1 and PTPN22 genes are taken into account (100). Little is known to date about the specificity, as well as affinity maturation, of antibodies during the pre-RA stage of development and whether there is a dynamic in the
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fine specificity and levels of antibodies during this time. It is of prime importance that such features be investigated, similar to the way studies were conducted in lupus (130). As described above, even less is known for T cell reactivities.
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Stage 2: Development of Unspecific Arthritis and the Possible Further Progression to RA A major feature in the proposed RA scenario is that antibodies to citrullinated proteins occur before onset of disease, and that the occurrence of these antibodies is associated with substantially increased risk of developing RA, even though most individuals with these antibodies do not develop disease. This observation is also compatible with the mouse data described above, in which transfer of anticitrullinated fibrinogen antibodies alone was not able to cause arthritis in naive mice but could enhance arthritis in mice with a lowgrade arthritis caused by other means (28). Antibodies as well as T cells typically cause inflammation at sites where the autoantigen(s) is present. No citrullination has yet been demonstrated in normal, uninflamed joints or other uninflamed tissues (41) except at sites that are relatively inaccessible for the immune system in the stratum corneum (34) or in the CNS (35). A number of different unspecific proinflammatory stimuli appear to cause citrullination in joints, including trauma and postinfectious events (D. Makryannikos, L. Klareskog, A. Catrina, unpublished observations). This suggests that some autoantibodies that are triggered outside the joints, e.g., in the lungs, may bind to autoantigens in joints after an unspecific “second strike” has caused joint inflammation and citrullination. Such a scenario is compatible with observations in both human and mouse: ACPApositive patients with unspecific mild arthritis are much more likely to develop chronic and long-lasting arthritis than are patients without these antibodies (17, 131). This clinical experience can be compared to the mice that
were subjected to mild CIA and that developed more severe disease after transfer of antibodies to citrullinated fibrinogen (28). Antibodies reacting with citrullinated proteins in the joint may thus enhance arthritis development in human as in mouse. This scenario would favor a three-stage development of ACPA-positive RA: the formation of antibodies, followed by the actual development and chronicity of arthritis (see Figure 6). The hypothesis that immunity to citrullinated proteins in joints may contribute to development of arthritis raises a fundamental question: Why does immunity to citrullinated but ubiquitously expressed proteins such as fibrinogen cause arthritis but not inflammation at other sites? Two tentative explanations can be offered: First, the main target molecule for the autoimmune attack may indeed be tissue specific, whereas reactivities to other proteins are epiphenomena, partly due to crossreactivities. This possibility is nicely illustrated in the putative case of CII immunity and in reports that citrullinated CII is recognized by antibodies from RA patients. This line of reasoning would reactivate the issue of collagen- and cartilage autoimmunity in RA and provide new relevance to the CIA model and collagen autoimmunity. All of this supports calls for greater emphasis in this line of research. The second assumption is that immunity to citrullinated proteins such as fibrinogen, vimentin, and α-enolase, which appear to be present in many sites of inflammation, can cause or enhance arthritis. In this scenario, we have to describe how immunity to such common proteins can cause a tissue-specific inflammation in joints. This problem might be parallel to how antibodies to the ubiquitous protein glucose phosphate isomerase (GPI) were shown to cause tissue-specific joint inflammation (132) and to how an initially T cell–driven pathology subsequently became driven by antibodies. A possible explanation for this tissue specificity (133) is that certain immune complexes containing antibodies
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Stage 3: Chronic rheumatoid arthritis a IC-mediated activation of APCs
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Figure 6 Stage 3 in the etiological model for the development of ACPA-positive RA: the chronic RA. (a) Immune complexes of ACPA and citrullinated proteins further stimulate antigen-presenting cells (APCs), by binding to complement and Fc receptors (not shown). Activated APCs present more citrullinated antigens, activate more T and B cells, increase the ACPA production but also (b) RF production. (c) Increased production of proinflammatory cytokines, including TNF, IL-1, and IL-6, in turn recruits more immune cells into the joint (d ), perpetuating the inflammatory process. Activation of PAD generates more citrullinated proteins, establishing a vicious cycle that ultimately leads to (e) the development of chronic RA.
to ubiquitous self molecules may preferentially accumulate in joint tissue. If also valid in human, such a mechanism would provide an option for antibodies to citrullinated forms of ubiquitous proteins to preferentially accumulate in joints and thereby contribute to arthritis development or perpetuation. Further comparative studies between anti-GPI-induced and ACPA-induced arthritis in rodents may show the extent to which lessons from anti-GPI-induced arthritis could help us understand ACPA-associated joint inflammation. 664
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Stage 3: Chronicity of Joint Inflammation and Fulfillment of the Diagnostic Criteria for RA Most cases of joint inflammation in human, such as synovitis in conjunction with trauma and postinfectious events, are transient and do not lead to chronic disease or to permanent joint damage. There have been some systematic studies of joint inflammation in a broad setting, i.e., including a very broad set of individuals with joint inflammation in early arthritis clinics. Strikingly, these studies demonstrate that most unspecific arthritides
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resume spontaneously (134). Patients with early arthritis also demonstrate huge differences in prognosis depending on initial ACPA status (17, 131, 135), as ACPA-positive subjects were more likely to develop RA, whereas ACPA-negative individuals with a clinically comparable picture often went into spontaneous remission. These data are of major clinical interest, as they allow a new clinically relevant classification of patients with early unspecific arthritis. In a biological context, these data support the notion that anticitrulline immunity may indeed enhance development of unspecific and otherwise transient arthritis into a chronic disease. Notably, chronicity (more than six weeks of disease) is an inherent part of the classification criteria for RA (1). It is therefore feasible that a capacity to enhance and/or prolong an otherwise transient arthritis may provide a causative role of anticitrulline immunity.
CONCLUDING REMARKS AND RESEARCH DIRECTIONS The principal message we hope to convey in this review is how knowledge gained from genetic epidemiology and longitudinal studies of the syndrome called RA can be used to provide a new basis for molecular studies of this disease. The lessons learned are as follows:
RA should be divided into at least two very different subsets, where multiple genetic and environmental determinants distribute dichotomously between the ACPA-positive and ACPAnegative variants of RA. Fundamentally different molecular pathologies must also be assumed for these two variants of disease. Analysis of gene-gene and geneenvironment interaction can provide precise leads to further molecular studies on etiology as well as therapy of distinct subgroups of arthritis. In the case of ACPA-positive RA, these studies point to the contribution of MHC
class II– and T cell–dependent adaptive immunity involving immune reactions toward proteins modified by citrullination. Longitudinal analyses, from pre-disease states to late disease, help in elucidating potential distinct breakpoints, where progression to disease may depend on different determinants in each of these stages. Future studies of ACPA-positive arthritis should be separate from ACPAnegative RA subjects, as discussed above. To be complete, however, ACPA-positive subjects with RA-like features, but who have other primary diagnoses (70–79), should also be included.
Notably, these lessons have been derived using information from only a very limited part of the mammalian genome, from a very limited set of antibody reactivities, and from limited data on environmental exposures. With new information on genetic variants over the entire genome now burgeoning (102, 136), as well as that from systems detecting multiple antibody reactivities (137), further insight into the molecular pathways involved in various subgroups of RA can be expected. This new information should be incorporated into our models and experimental systems. The implication is thus that any type of experiment aimed at understanding molecular events in RA, in particular when related to adaptive immunity, should be performed using biological specimens or patients’ clinical data for which we have precise knowledge of the profile of ACPA status, genetic determinants, and, if possible, pre-existing environmental triggers, and for which the investigated patients have been subgrouped accordingly. If these measures are taken, the possibilities will be better than ever before to define arthritis-specific immune reactions that take place at distinct time periods in disease development. This ability, in turn, should enable
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us to apply the experience garnered from different animal models to the more precise study of pathogenesis and therapies in different groups of RA patients. We conclude that studies on citrullination and immunity against citrullinated proteins, taken together,
may furnish critical knowledge that will allow us to understand and modulate adaptive immunity in newly defined sets of arthritis, including a major subset of RA that is characterized by the presence of antibodies to citrulline-modified proteins.
SUMMARY POINTS
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1. Antibodies to citrullinated protein antigens (ACPA) constitute a relatively specific diagnostic tool for RA, as they are present in approximately 60% of an early RA cohort and in approximately 2% of the general population. 2. ACPA-positive and ACPA-negative RA constitute two very different subpopulations of RA concerning the role of major susceptibility genes (HLA-DRB1 and PTPN22) and major environmental risk factors (smoking) as well as clinical course. These two subpopulations, which most likely also have different molecular pathogenesis, should be treated as separate entities in further immunological studies of RA. 3. Antibodies to citrulline-modified proteins may be causatively involved in the development of arthritis. Support for this proposal comes from data showing the emergence of ACPA before onset of disease and from animal model studies showing that immunity against citrulline-modified self molecules, such as fibrinogen or collagen type II, can enhance development of arthritis. 4. A new model has been proposed to explain the contributions from genetics and environment (smoking) in causing ACPA and the onset of arthritis. This model includes citrullination induced by environmental agents such as smoking, induction of ACPA in individuals with RA susceptibility genes (including HLA-DRB1 SE), and citrullination of molecules in target tissues. 5. The new model provides a framework for studies of adaptive immunity and of interactions between innate and adaptive immunity in RA. The data and the model emphasize the need to use data on genetic features, on environmental exposures, and on clinical course to subdivide RA in subpopulations before embarking on molecular studies on pathogenesis and treatment.
FUTURE ISSUES 1. The evidence from genetic epidemiology demonstrating the presence of at least two very distinct subsets of RA should be used to define relevant subsets of arthritis. Hypotheses on etiology in the different subsets of RA, should be tested in molecular immunology using information from genetic epidemiology to properly subdivide patients. 2. Different animal models for arthritis should be used to study different subsets of RA, where these subsets are defined by their genetic, environmental, and clinical characteristics.
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3. Prospective studies on the evolution of citrullination, anticitrulline immunity, and arthritis are needed to determine the different stages and breakpoints, initiation of ACPA, initiation of arthritis, and progression into chronic RA. 4. Further therapeutic and preventive studies can be directed toward molecular pathways defined from increased knowledge on citrullination and anti-citrulline immunity.
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DISCLOSURE STATEMENT The authors do not declare any conflicts of interest. The studies from the authors’ laboratories and clinics were supported from multiple and noncommercial sources, including the Swedish Research Council, the Swedish Council for Working Life and Social Research, King Gustaf ¨ V’s 80-Year Foundation, the Swedish Rheumatism Association, the Soderberg Foundation, FAMRI (Flight Attendants Medical Research Academy), the insurance company AFA, and the EU-supported project AutoCure. These sponsors had no influence on the writing of this manuscript.
LITERATURE CITED 1. Arnett FC, Edworthy SM, Block DA, McShane DJ, Fries JF, et al. 1988. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31:315–24 2. Waaler E. 1940. On the occurrence of a factor in human serum activating the specific agglutination of sheep blood corpuscles. Acta Pathol. Microbiol. Scand. 17:172 3. Nemazee D. 1985. Immune complexes can trigger specific T-cell dependent autoanti-IgG antibody production in mice. J. Exp. Med. 161:242 4. Tarkowski A, Czerkinsky C, Nilsson LA. 1985. Simultaneous induction of rheumatoid factor- and antigen-specific antibody-secreting cells during the secondary immune response in man. Clin. Exp. Immunol. 61:379–87 5. Stastny P. 1978. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N. Engl. J. Med. 298:869–71 6. Gregersen PK, Silver J, Winchester RJ. 1987. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30:1205–13 7. Klareskog L, Forsum U, Scheynius A, Kabelitz D, Wigzell H. 1982. Evidence in support of a self-perpetuating HLA-DR-dependent delayed-type cell reaction in rheumatoid arthritis. Proc. Natl. Acad. Sci. USA 79:3632–36 8. Burmester GR, Yu DT, Irani AM, Kunkel HG, Winchester RJ. 1981. Ia+ T cells in synovial fluid and tissues of patients with rheumatoid arthritis. Arthritis Rheum. 24:1370– 76 9. Edwards JC, Cambridge G. 2001. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology 40:205–11 10. Skapenko A, Lipsky PE, Schulze-Koops H. 2006. T cell activation as starter and motor of rheumatic inflammation. Curr. Top. Microbiol. Immunol. 305:195–211 11. Feldmann M, Brennan FM, Williams RO, Woody JN, Maini RN. 2004. The transfer of a laboratory based hypothesis to a clinically useful therapy: the development of anti-TNF therapy of rheumatoid arthritis. Best Pract. Res. Clin. Rheumatol. 18:59–80 www.annualreviews.org • Immunity to Citrullinated Proteins in Rheumatoid Arthritis
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12. McInnes IB, Liew FY. 2005. Cytokine networks—toward new therapies for rheumatoid arthritis. Nat. Clin. Pract. Rheumatol. 1:31–39 13. Firestein GS. 2005. Immunologic mechanisms in the pathogenesis of rheumatoid arthritis. J. Clin. Rheumatol. 11:S39–44 14. Tak PP. 2006. Chemokine inhibition in inflammatory arthritis. Best Pract. Res. Clin. Rheumatol. 20:929–39 15. Schellekens GA, Visser H, de Jong BA, van den Hoogen FH, Hazes JM, et al. 2000. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 43:155–63 16. Vincent C, Nogueira L, Sebbag M, Chapuy-Regaud S, Arnaud M, et al. 2002. Detection of antibodies to deiminated recombinant rat filaggrin by enzyme-linked immunosorbent assay: a highly effective test for the diagnosis of rheumatoid arthritis. Arthritis Rheum. 46:2051–58 17. van Gaalen FA, Linn-Rasker SP, van Venrooij WJ, de Jong BA, Breedveld FC, et al. 2004. Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study. Arthritis Rheum. 50:709–15 18. Avouac J, Gossec L, Dougados M. 2006. Diagnostic and predictive value of anticyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review. Ann. Rheum. Dis. 65:845–51 19. Nishimura K, Sugiyama D, Kogata Y, Tsuji G, Nakazawa T, et al. 2007. Meta-analysis: diagnostic accuracy of anticyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann. Intern. Med. 146:797–808 20. Kurki P, Aho K, Palosuo T, Heliovaara M. 1992. Immunopathology of rheumatoid arthritis. Antikeratin antibodies precede the clinical disease. Arthritis Rheum. 35:914–17 21. Aho K, Palosuo T, Heliovaara M, Knekt P, Alha P, von Essen R. 2000. Antifilaggrin antibodies within “normal” range predict rheumatoid arthritis in a linear fashion. J. Rheumatol. 27:2743–46 22. Rantap¨aa¨ -Dahlqvist S, de Jong BA, Berglin E, Hallmans G, Wadell G, et al. 2003. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 48:2741–49 23. Nielen MM, van Schaardenburg D, Reesink HW, van de Stadt RJ, van der HorstBruinsma IE, et al. 2004. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50:380– 86 24. Kastbom A, Strandberg G, Lindroos A, Skogh T. 2004. Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project). Ann. Rheum. Dis. 63:1085–89 ¨ 25. Ronnelid J, Wick MC, Lampa J, Lindblad S, Nordmark B, et al. 2005. Longitudinal analysis of anticitrullinated protein/peptide antibodies (anti-CP) during 5 year follow-up in early rheumatoid arthritis: anti-CP status is a stable phenotype that predicts worse disease activity and greater radiological progression. Ann. Rheum. Dis. 64:1744–49 26. Klareskog L, Stolt P, Lundberg K, K¨allberg H, Bengtsson C, et al. 2006. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 54:38–46 27. van der Helm-van Mil AH, Verpoort KN, le Cessie S, Huizinga TW, de Vries RR, Toes RE. 2007. The HLA-DRB1 shared epitope alleles differ in the interaction with smoking
Annu. Rev. Immunol. 2008.26:651-675. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-21
668
Klareskog et al.
ANRV338-IY26-21
28.
29.
30.
Annu. Rev. Immunol. 2008.26:651-675. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
31.
32.
33. 34. 35.
36.
37. 38.
39. 40.
41. 42.
43.
44.
ARI
16 February 2008
15:51
and predisposition to antibodies to cyclic citrullinated peptide. Arthritis Rheum. 56:425– 32 Kuhn KA, Kulik L, Tomooka B, Braschler KJ, Arend WP, et al. 2006. Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J. Clin. Invest. 116:961–73 Lundberg K, Nijenhuis S, Vossenaar ER, Palmblad K, van Venrooij WJ, et al. 2005. Citrullinated proteins have increased immunogenicity and arthritogenicity and their presence in arthritic joints correlates with disease severity. Arthritis Res. Ther. 7:R458– 67 Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ. 2003. PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. BioEssays 25:1106–18 Chavanas S, Mechin MC, Takahara H, Kawada A, Nachat R, et al. 2004. Comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved noncoding segments and a new human gene, PADI6. Gene 330:19–27 Baeten D, Peene I, Union A, Meheus L, Sebbag M, et al. 2001. Specific presence of intracellular citrullinated proteins in rheumatoid arthritis synovium: relevance to antifilaggrin autoantibodies. Arthritis Rheum. 44:2255–62 Gyorgy B, Toth E, Tarcsa E, Falus A, Buzas EI. 2006. Citrullination: a posttranslational modification in health and disease. Int. J. Biochem. Cell Biol. 38:1662–77 Kubilus J, Waitkus RW, Baden HP. 1979. The presence of citrulline in epidermal proteins. Biochim. Biophys. Acta 581:114–21 Nicholas AP, King JL, Sambandam T, Echols JD, Gupta KB, et al. 2003. Immunohistochemical localization of citrullinated proteins in adult rat brain. J. Comp. Neurol. 459:251–66 Moscarello MA, Mastronardi FG, Wood DD. 2007. The role of citrullinated proteins suggests a novel mechanism in the pathogenesis of multiple sclerosis. Neurochem. Res. 32:251–56 Ireland J, Herzog J, Unanue ER. 2006. Cutting edge: unique T cells that recognize citrullinated peptides are a feature of protein immunization. J. Immunol. 177:1421–25 Vossenaar ER, Smeets TJ, Kraan MC, Raats JM, van Venrooij WJ, Tak PP. 2004. The presence of citrullinated proteins is not specific for rheumatoid synovial tissue. Arthritis Rheum. 50:3485–94 Bongartz T, Cantaert T, Atkins SR, Harle P, Myers JL, et al. 2007. Citrullination in extra-articular manifestations of rheumatoid arthritis. Rheumatology 46:70–75 Nicholas AP, Whitaker JN. 2002. Preparation of a monoclonal antibody to citrullinated epitopes: its characterization and some applications to immunohistochemistry in human brain. Glia 37:328–36 ¨ Makrygiannakis D, af Klint E, Lundberg IE, Lofberg R, Ulfgren AK, et al. 2006. Citrullination is an inflammation-dependent process. Ann. Rheum. Dis. 65:1219–22 Masson-Bessiere C, Sebbag M, Girbal-Neuhauser E, Nogueira L, Vincent C, et al. 2001. The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the α- and β-chains of fibrin. J. Immunol. 166:4177–84 Vossenaar ER, Despres N, Lapointe E, van der Heijden A, Lora M, et al. 2004. Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin. Arthritis Res. Ther. 6:R142–50 ¨ Bang H, Egerer K, Gauliard A, Luthke K, Rudulph PE, et al. 2007. Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis. Arthritis Rheum. 56:2503–11 www.annualreviews.org • Immunity to Citrullinated Proteins in Rheumatoid Arthritis
669
ARI
16 February 2008
15:51
45. Young BJ, Mallya RK, Leslie RD, Clark CJ, Hamblin TJ. 1979. Anti-keratin antibodies in rheumatoid arthritis. Br. Med. J. 2:97–99 46. Nienhuis RL, Mandena E. 1964. A new serum factor in patients with rheumatoid arthritis, the antiperiuclear factor. Ann. Rheum. Dis. 23:202–5 47. Simon M, Girbal E, Sebbag M, Gomes-Daudrix V, Vincent C, et al. 1993. The cytokeratin filament-aggregating protein filaggrin is the target of the so-called “antikeratin antibodies,” autoantibodies specific for rheumatoid arthritis. J. Clin. Invest. 92:1387– 93 48. Sebbag M, Simon M, Vincent C, Masson-Bessiere C, Girbal E, et al. 1995. The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid arthritis-specific autoantibodies. J. Clin. Invest. 95:2672–79 49. Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ. 1998. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J. Clin. Invest. 101:273–81 50. Nijenhuis S, Zendman AJ, Vossenaar ER, Pruijn GJ, van Venrooij WJ. 2004. Autoantibodies to citrullinated proteins in rheumatoid arthritis: clinical performance and biochemical aspects of an RA-specific marker. Clin. Chim. Acta. 350:17–34 51. Girbal-Neuhauser E, Durieux JJ, Arnaud M, Dalbon P, Sebbag M, et al. 1999. The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. J. Immunol. 162:585–94 52. Vander Cruyssen B, Cantaert T, Nogueira L, Clavel C, De Rycke L, et al. 2006. Diagnostic value of antihuman citrullinated fibrinogen ELISA and comparison with four other anticitrullinated protein assays. Arthritis Res. Ther. 8:R122 53. Despres N, Boire G, Lopez-Longo FJ, Menard HA. 1994. The Sa system: a novel antigenantibody system specific for rheumatoid arthritis. J. Rheumatol. 21:1027–33 54. Hayem G, Chazerain P, Combe B, Elias A, Haim T, et al. 1999. Anti-Sa antibody is an accurate diagnostic and prognostic marker in adult rheumatoid arthritis. J. Rheumatol. 26:7–13 55. Hueber W, Hassfeld W, Smolen JS, Steiner G. 1999. Sensitivity and specificity of anti-Sa autoantibodies for rheumatoid arthritis. Rheumatology 38:155–59 56. Dejaco C, Klotz W, Larcher H, Duftner C, Schirmer M, Herold M. 2006. Diagnostic value of antibodies against a modified citrullinated vimentin in rheumatoid arthritis. Arthritis Res. Ther. 8:R119 57. Kinloch A, Tatzer V, Wait R, Peston D, Lundberg K, et al. 2005. Identification of citrullinated α-enolase as a candidate autoantigen in rheumatoid arthritis. Arthritis Res. Ther. 7:R1421–29 58. Trentham DE, Townes AS, Kang AH. 1977. Autoimmunity to type II collagen an experimental model of arthritis. J. Exp. Med. 146:857–68 59. Holmdahl R, Bockermann R, Backlund J, Yamada H. 2002. The molecular pathogenesis of collagen-induced arthritis in mice—a model for rheumatoid arthritis. Ageing Res. Rev. 1:135–47 60. Terato K, Shimozuru Y, Katyama K, Takemitzu Y, Yamashita I, et al. 1990. Specificity of antibodies to type II collagen in rheumatoid arthritis. Arthritis Rheum. 33:1493– 500 61. Tarkowski A, Klareskog L, Carlsten H, Herberts P, Koopman WJ. 1989. Secretion of antibodies to types I and II collagen by synovial tissue cells in patients with rheumatoid arthritis. Arthritis Rheum. 32:1087–92
Annu. Rev. Immunol. 2008.26:651-675. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-21
670
Klareskog et al.
Annu. Rev. Immunol. 2008.26:651-675. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-21
ARI
16 February 2008
15:51
¨ ¨ 62. Ronnelid J, Lysholm J, Engstrom-Laurent A, Klareskog L, Heyman B. 1994. Local antitype II collagen antibody production in rheumatoid arthritis synovial fluid. Evidence for an HLA-DR4-restricted IgG response. Arthritis Rheum. 37:1023–29 63. Burkhardt H, Sehnert B, Bockermann R, Engstrom A, Kalden JR, Holmdahl R. 2005. Humoral immune response to citrullinated collagen type II determinants in early rheumatoid arthritis. Eur. J. Immunol. 35:1643–52 64. Verpoort KN, Jol-van der Zijde CM, Papendrecht-van der Voort EA, Ioan-Facsinay A, Drijfhout JW, et al. 2006. Isotype distribution of anticyclic citrullinated peptide antibodies in undifferentiated arthritis and rheumatoid arthritis reflects an ongoing immune response. Arthritis Rheum. 54:3799–808 65. Caramaschi P, Biasi D, Tonolli E, Pieropan S, Martinelli N, et al. 2005. Antibodies against cyclic citrullinated peptides in patients affected by rheumatoid arthritis before and after infliximab treatment. Rheumatol. Int. 26:58–62 66. De Rycke L, Verhelst X, Kruithof E, Van den Bosch F, Hoffman IE, et al. 2005. Rheumatoid factor, but not anticyclic citrullinated peptide antibodies, is modulated by infliximab treatment in rheumatoid arthritis. Ann. Rheum. Dis. 64:299–302 67. Bobbio-Pallavicini F, Alpini C, Caporali R, Avalle S, Bugatti S, Montecucco C. 2004. Autoantibody profile in rheumatoid arthritis during long-term infliximab treatment. Arthritis Res. Ther. 6:R264–72 68. Alessandri C, Bombardieri M, Papa N, Cinquini M, Magrini L, et al. 2004. Decrease of anticyclic citrullinated peptide antibodies and rheumatoid factor following anti-TNFα therapy (infliximab) in rheumatoid arthritis is associated with clinical improvement. Ann. Rheum. Dis. 63:1218–21 69. Chen HA, Lin KC, Chen CH, Liao HT, Wang HP, et al. 2006. The effect of etanercept on anticyclic citrullinated peptide antibodies and rheumatoid factor in patients with rheumatoid arthritis. Ann. Rheum. Dis. 65:35–39 70. Bogliolo L, Alpini C, Caporali R, Scire CA, Moratti R, Montecucco C. 2005. Antibodies to cyclic citrullinated peptides in psoriatic arthritis. J. Rheumatol. 32:511– 15 71. Korendowych E, Owen P, Ravindran J, Carmichael C, McHugh N. 2005. The clinical and genetic associations of anticyclic citrullinated peptide antibodies in psoriatic arthritis. Rheumatology 44:1056–60 72. Vander Cruyssen B, Hoffman IE, Zmierczak H, Van den Berghe M, Kruithof E, et al. 2005. Anti-citrullinated peptide antibodies may occur in patients with psoriatic arthritis. Ann. Rheum. Dis. 64:1145–49 73. Alenius GM, Berglin E, Rantapaa Dahlqvist S. 2006. Antibodies against cyclic citrullinated peptide (CCP) in psoriatic patients with or without joint inflammation. Ann. Rheum. Dis. 65:398–400 74. Low JM, Chauhan AK, Kietz DA, Daud U, Pepmueller PH, Moore TL. 2004. Determination of anticyclic citrullinated peptide antibodies in the sera of patients with juvenile idiopathic arthritis. J. Rheumatol. 31:1829–33 75. Kasapcopur O, Altun S, Aslan M, Karaarslan S, Kamburoglu-Goksel A, et al. 2004. Diagnostic accuracy of anticyclic citrullinated peptide antibodies in juvenile idiopathic arthritis. Ann. Rheum. Dis. 63:1687–89 76. Ferucci ED, Majka DS, Parrish LA, Moroldo MB, Ryan M, et al. 2005. Antibodies against cyclic citrullinated peptide are associated with HLA-DR4 in simplex and multiplex polyarticular-onset juvenile rheumatoid arthritis. Arthritis Rheum. 52:239– 46 www.annualreviews.org • Immunity to Citrullinated Proteins in Rheumatoid Arthritis
671
ARI
16 February 2008
15:51
77. Kwok JS, Hui KH, Lee TL, Wong W, Lau YL, et al. 2005. Anti-cyclic citrullinated peptide: diagnostic and prognostic values in juvenile idiopathic arthritis and rheumatoid arthritis in a Chinese population. Scand. J. Rheumatol. 34:359–66 78. Martinez JB, Valero JS, Bautista AJ, Restrepo JF, Matteson EL, et al. 2007. Erosive arthropathy: clinical variance in lupus erythematosus and association with anti-CCP case series and review of the literature. Clin. Exp. Rheumatol. 25:47–53 79. Takasaki Y, Yamanaka K, Takasaki C, Matsushita M, Yamada H, et al. 2004. Anticyclic citrullinated peptide antibodies in patients with mixed connective tissue disease. Mod. Rheumatol. 14:367–75 80. Kroot EJ, de Jong BA, van Leeuwen MA, Swinkels H, van den Hoogen FH, et al. 2000. The prognostic value of anticyclic citrullinated peptide antibody in patients with recentonset rheumatoid arthritis. Arthritis Rheum. 43:1831–35 ¨ I, Svensson B. 2004. Prediction of radio81. Forslind K, Ahlmen M, Eberhardt K, Hafstrom logical outcome in early RA in clinical practice: role of antibodies to citrullinated peptides (anti-CCP). Ann. Rheum. Dis. 63:1090–95 82. Vencovsky J, Machacek S, Sedova L, Kafkova J, Gatterova J, et al. 2003. Autoantibodies can be prognostic markers of an erosive disease in early rheumatoid arthritis. Ann. Rheum. Dis. 62:427–30 83. Meyer O, Labarre C, Dougados M, Goupille P, Cantagrel A, et al. 2003. Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage. Ann. Rheum. Dis. 62:120–26 84. van Dongen H, van Aken J, Lard LR, Visser K, Ronday HK, et al. 2007. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 56:1424–32 85. Wordsworth BP, Lanchbury JSS, Sakkas LI, Welsh KI, Panayi GS, Bell JI. 1989. HLADR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region. Proc. Natl. Acad. Sci. USA 86:10049– 53 86. Khan MA, Mathieu A, Sorrentino R, Akkoc N. 2007. The pathogenetic role of HLA-B27 and its subtypes. Autoimmun. Rev. 6:183–89 87. Huizinga TW, Amos CI, van der Helm-van Mil AH, Chen W, van Gaalen FA, et al. 2005. Refining the complex rheumatoid arthritis phenotype based on specificity of the HLADRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum. 52:3433– 38 88. van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Huizinga TW, Toes RE, de Vries RR. 2006. The HLA-DRB1 shared epitope alleles are primarily a risk factor for anticyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. Arthritis Rheum. 54:1117–21 89. Irigoyen P, Lee AT, Wener MH, Li W, Kern M, et al. 2005. Regulation of anticyclic citrullinated peptide antibodies in rheumatoid arthritis: contrasting effects of HLA-DR3 and the shared epitope alleles. Arthritis Rheum. 52:3813–18 90. Plenge RM, Padyukov L, Remmers EF, Purcell S, Lee AT, et al. 2005. Replication of putative candidate-gene associations with rheumatoid arthritis in >4000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am. J. Hum. Genet. 77:1044–60 91. Wesoly J, van der Helm-van Mil AH, Toes RE, Chokkalingam AP, Carlton VE, et al. 2005. Association of the PTPN22 C1858T single-nucleotide polymorphism with rheumatoid arthritis phenotypes in an inception cohort. Arthritis Rheum. 52:2948–50
Annu. Rev. Immunol. 2008.26:651-675. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-21
672
Klareskog et al.
Annu. Rev. Immunol. 2008.26:651-675. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-21
ARI
16 February 2008
15:51
¨ 92. K¨allberg H, Padyukov L, Plenge RM, Ronnelid J, Gregersen PK, et al. 2007. Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am. J. Hum. Genet. 80:867–75 93. Sigurdsson S, Padyukov L, Kurreeman FA, Liljedahl U, Wiman AC, et al. 2007. Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis. Arthritis Rheum. 56:2202–10 ¨ C, B¨ackdahl L, Ribbhammar U, et al. 2007. Association 94. Lorentzen JC, Flomes L, Eklow with arthritis of a gene complex encoding C-type lectin-like receptors. Arthritis Rheum. 56:2620–32 95. Aho K, Heliovaara M, Maatela J, Tuomi T, Palosuo T. 1991. Rheumatoid factors antedating clinical rheumatoid arthritis. J. Rheumatol. 18:1282–84 96. Duplan V, Foulquier C, Clavel C, Al Badine R, Serre G, et al. 2006. In the rat, citrullinated autologous fibrinogen is immunogenic but the induced autoimmune response is not arthritogenic. Clin. Exp. Immunol. 145:502–12 97. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, et al. 2004. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75:330– 37 98. Gregersen PK. 2005. Pathways to gene identification in rheumatoid arthritis: PTPN22 and beyond. Immunol. Rev. 204:74–86 99. Johansson M, Arlestig L, Hallmans G, Rantapaa-Dahlqvist S. 2006. PTPN22 polymorphism and anticyclic citrullinated peptide antibodies in combination strongly predicts future onset of rheumatoid arthritis and has a specificity of 100% for the disease. Arthritis Res. Ther. 8:R19 100. Kokkonen H, Johansson M, Innala L, Eriksson C, Jidell E, Rantapaa Dahlqvist S. 2007. The PTPN22 1858C/T polymorphism is associated with anticyclic citrullinated peptide antibody positive early rheumatoid arthritis in northern Sweden. Arthritis Res. Ther. 9: R56 101. Pierer M, Kaltenhauser S, Arnold S, Wahle M, Baerwald C, et al. 2006. Association of PTPN22 1858 single-nucleotide polymorphism with rheumatoid arthritis in a German cohort: higher frequency of the risk allele in male compared to female patients. Arthritis Res. Ther. 8:R75 102. Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, et al. 2007. Genomewide search identifies TRAF1-C5 as rheumatoid arthritis risk locus. N. Engl. J. Med. 357:1199–209 103. Seielstad M, Padyukov L, Ding B, Plenge RM, Alfredsson L, Klareskog L. 2007. A genome-wide SNP association study identifies novel risk loci for rheumatoid arthritis in Swedish EIRA study. Ann. Rheum. Dis. 66(Suppl. II):680 104. Heliovaara M, Aho K, Aromaa A, Knekt P, Reunanen A. 1993. Smoking and risk of rheumatoid arthritis. J. Rheumatol. 20:1830–35 105. Silman AJ, Newman J, MacGregor AJ. 1996. Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins. Arthritis Rheum. 39:732–35 106. Uhlig T, Hagen KB, Kvien TK. 1999. Current tobacco smoking, formal education, and the risk of rheumatoid arthritis. J. Rheumatol. 26:47–54 107. Stolt P, Bengtsson C, Nordmark B, Lindblad S, Lundberg I, et al. 2003. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann. Rheum. Dis. 62:835–41 www.annualreviews.org • Immunity to Citrullinated Proteins in Rheumatoid Arthritis
673
ARI
16 February 2008
15:51
108. Masdottir B, Jonsson T, Manfredsdottir V, Vikingsson A, Brekkan A, Valdimarsson H. 2000. Smoking, rheumatoid factor isotypes and severity of rheumatoid arthritis. Rheumatology 39:1202–5 109. Wolfe F. 2000. The effect of smoking on clinical, laboratory, and radiographic status in rheumatoid arthritis. J. Rheumatol. 27:630–37 110. Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L. 2004. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum. 50:3085–92 111. Pedersen M, Jacobsen S, Garred P, Madsen HO, Klarlund M, et al. 2007. Strong combined gene-environment effects in anticyclic citrullinated peptide-positive rheumatoid arthritis: a nationwide case-control study in Denmark. Arthritis Rheum. 56:1446–53 ¨ 112. K¨allberg H, Padyukov L, Bengtsson C, Ronnelid J, Klareskog L, Alfredsson L. 2007. Smoking is associated with anti-CCP positive RA in a dose dependent manner, results from the Swedish EIRA study. Ann. Rheum. Dis. 66(Suppl. II):291 113. Lee HS, Irigoyen P, Kern M, Lee A, Batliwalla F, et al. 2007. Interaction between smoking, the shared epitope, and anticyclic citrullinated peptide: a mixed picture in three large North American rheumatoid arthritis cohorts. Arthritis Rheum. 56:1745–53 114. Sverdrup B, Kallberg H, Bengtsson C, Lundberg I, Padyukov L, et al. 2005. Association between occupational exposure to mineral oil and rheumatoid arthritis: results from the Swedish EIRA case-control study. Arthritis Res. Ther. 7:R1296–303 115. Hill JA, Southwood S, Sette A, Jevnikar AM, Bell DA, Cairns E. 2003. The conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1∗ 0401 MHC class II molecule. J. Immunol. 171:538– 41 116. Tsuji Y, Akiyama M, Arita K, Senshu T, Shimizu H. 2003. Changing pattern of deiminated proteins in developing human epidermis. J. Invest. Dermatol. 120:817–22 117. Casciola-Rosen LA, Anhalt G, Rosen A. 1994. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J. Exp. Med. 179:1317–30 118. Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, et al. 2003. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat. Genet. 34:395–402 119. Kang CP, Lee HS, Ju H, Cho H, Kang C, Bae SC. 2006. A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Koreans. Arthritis Rheum. 54:90–96 120. Barton A, Bowes J, Eyre S, Spreckley K, Hinks A, et al. 2004. A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population. Arthritis Rheum. 50:1117–21 121. Caponi L, Petit-Teixeira E, Sebbag M, Bongiorni F, Moscato S, et al. 2005. A family based study shows no association between rheumatoid arthritis and the PADI4 gene in a white French population. Ann. Rheum. Dis. 64:587–93 122. Harney SM, Meisel C, Sims AM, Woon PY, Wordsworth BP, Brown MA. 2005. Genetic and genomic studies of PADI4 in rheumatoid arthritis. Rheumatology 44:869–72 123. Martinez A, Valdivia A, Pascual-Salcedo D, Lamas JR, Fernandez-Arquero M, et al. 2005. PADI4 polymorphisms are not associated with rheumatoid arthritis in the Spanish population. Rheumatology 44:1263–66 124. Nissinen R, Paimela L, Julkunen H, Tienari PJ, Leirisalo-Repo M, et al. 2003. Peptidylarginine deiminase, the arginine to citrulline converting enzyme, is frequently recognized
Annu. Rev. Immunol. 2008.26:651-675. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-21
674
Klareskog et al.
ANRV338-IY26-21
125.
126. 127.
Annu. Rev. Immunol. 2008.26:651-675. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
128.
129.
130.
131.
132. 133.
134. 135.
136. 137.
ARI
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by sera of patients with rheumatoid arthritis, systemic lupus erythematosus and primary Sjogren syndrome. Scand. J. Rheumatol. 32:337–42 Roth EB, Stenberg P, Book C, Sjoberg K. 2006. Antibodies against transglutaminases, peptidylarginine deiminase and citrulline in rheumatoid arthritis—new pathways to epitope spreading. Clin. Exp. Rheumatol. 24:12–18 Caplan A. 1963. Contribution to discussion on rheumatoid pneumoconiosis. Grundfr. Silikoseforsch. 6:345–49 Pratesi F, Tommasi C, Anzilotti C, Chimenti D, Migliorini P. 2006. Deiminated EpsteinBarr virus nuclear antigen 1 is a target of anticitrullinated protein antibodies in rheumatoid arthritis. Arthritis Rheum. 54:733–41 Katz J, Goultschin J, Benoliel R, Brautbar C. 1987. Human leukocyte antigen (HLA) DR4. Positive association with rapidly progressing periodontitis. J. Periodontol. 58:607– 10 Marotte H, Farge P, Gaudin P, Alexandre C, Mougin B, Miossec P. 2006. The association between periodontal disease and joint destruction in rheumatoid arthritis extends the link between the HLA-DR shared epitope and severity of bone destruction. Ann. Rheum. Dis. 65:905–9 Heinlen LD, McClain MT, Merrill J, Akbarali YW, Edgerton CC, et al. 2007. Clinical criteria for systemic lupus erythematosus precede diagnosis, and associated autoantibodies are present before clinical symptoms. Arthritis Rheum. 56:2344–51 Jansen AL, van der Horst-Bruinsma I, van Schaardenburg D, van de Stadt RJ, de Koning MH, Dijkmans BA. 2002. Rheumatoid factor and antibodies to cyclic citrullinated peptide differentiate rheumatoid arthritis from undifferentiated polyarthritis in patients with early arthritis. J. Rheumatol. 29:2074–76 Matsumoto I, Staub A, Benoist C, Mathis D. 1999. Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. Science 286:1732–35 Binstadt BA, Patel PR, Alencar H, Nigrovic PA, Lee DM, et al. 2006. Particularities of the vasculature can promote the organ specificity of autoimmune attack. Nat. Immunol. 7:284–92 Hulsemann JL, Zeidler H. 1995. Undifferentiated arthritis in an early synovitis outpatient clinic. Clin. Exp. Rheumatol. 13:37–43 Nielen MM, van der Horst AR, van Schaardenburg D, van der Horst-Bruinsma IE, van de Stadt RJ, et al. 2005. Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis. Ann. Rheum. Dis. 64:1199–204 Wellcome Trust Case Control Consort. 2007. Genome-wide association study of 14,000 cases of seven common diseases and 3000 shared controls. Nature 447:661–78 Hueber W, Kidd BA, Tomooka BH, Lee BJ, Bruce B, et al. 2005. Antigen microarray profiling of autoantibodies in rheumatoid arthritis. Arthritis Rheum. 52:2645–55
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Annual Review of Immunology
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:651-675. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir,1 Manish J. Butte,1 Gordon J. Freeman,2 and Arlene H. Sharpe1 1
Department of Pathology, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts 02115-5727; email: arlene
[email protected] 2
Department of Medical Oncology, Dana Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115-6013
Annu. Rev. Immunol. 2008. 26:677–704
Key Words
First published online as a Review in Advance on January 2, 2008
costimulation, T cell, autoimmunity, infectious disease, tumor
The Annual Review of Immunology is online at immunol.annualreviews.org This article’s doi: 10.1146/annurev.immunol.26.021607.090331 c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0677$20.00
Abstract Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance, and immunopathology. Immune responses to foreign and self-antigens require specific and balanced responses to clear pathogens and tumors and yet maintain tolerance. Induction and maintenance of T cell tolerance requires PD-1, and its ligand PD-L1 on nonhematopoietic cells can limit effector T cell responses and protect tissues from immune-mediated tissue damage. The PD-1:PD-L pathway also has been usurped by microorganisms and tumors to attenuate antimicrobial or tumor immunity and facilitate chronic infection and tumor survival. The identification of B7-1 as an additional binding partner for PD-L1, together with the discovery of an inhibitory bidirectional interaction between PD-L1 and B7-1, reveals new ways the B7:CD28 family regulates T cell activation and tolerance. In this review, we discuss current understanding of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential.
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INTRODUCTION The concept of T cell costimulation has evolved over time. The two-signal model for T cell activation was proposed by Kevin Lafferty as a model for the activation of naive T cells (1). According to this model, T cells require two signals to become fully activated. The first signal, which gives specificity to the immune response, is provided by the interaction of antigenic peptide−MHC complex with the T cell receptor (TCR). The second, antigen-independent costimulatory signal, is delivered to T cells by antigen-presenting cells (APCs) to promote T cell clonal expansion, cytokine secretion, and effector function. In the absence of the second signal, antigen-specific lymphocytes fail to respond effectively and are functionally inactivated, or anergic, and resistant to subsequent activation by the antigen. The critical inhibitory function of cytotoxic T lymphocyte–associated antigen 4 (CTLA-4, also known as CD152) was revealed by the fatal lymphoproliferative phenotype of Ctla4−/− mice (2, 3). This function demonstrated that T cell pathways could provide negative as well as positive second signals and provided the first indication that negative second signals could regulate T cell tolerance. The discovery of more members of the B7:CD28 family has revealed additional costimulatory pathways that can provide positive and negative second signals to antigenexperienced effector T cells. The functions of these newer pathways have broadened the concept of costimulation. This review focuses on recent advances in our understanding of one of the newer pathways in the B7:CD28 family, the pathway consisting of the programmed death 1 (PD-1; also known as CD279) receptor and its ligands, PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273). The PD-1 receptor was discovered in 1992 as a gene upregulated in a T cell hybridoma undergoing cell death (4). The important negative regulatory function of PD-1 was revealed by the autoimmuneprone phenotype of Pdcd1−/− mice in 1999
ITIM: immunoreceptor tyrosine-based inhibitory motif
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ITSM: immunoreceptor tyrosine-based switch motif
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(5, 6). Since the ligands for PD-1 were identified in 2000 (7, 8) and 2001 (9, 10), there has been steady progress in understanding the functions of PD-1 and its ligands. Here, we first describe the structure and expression of PD-1, PD-L1, and PD-L2. Next, we review recent advances in understanding PD-1 and PD-L signaling. We then summarize recent studies that identify B7-1 (CD80) as a binding partner for PD-L1 and indicate that PDL1 interactions with B7-1 can lead to bidirectional inhibitory responses in T cells (11). Finally, we discuss our current understanding of the roles played by PD-1 and its ligands in regulating T cell activation and tolerance and consider the therapeutic potential of manipulation of PD-1 and its ligands.
STRUCTURE OF GENES PD-1 is a 288 amino acid (aa) type I transmembrane protein composed of one immunoglobulin (Ig) superfamily domain, a ∼20 aa stalk, a transmembrane domain, and an intracellular domain of approximately 95 residues containing an immunoreceptor tyrosine-based inhibitory motif (ITIM) as well as an immunoreceptor tyrosine-based switch motif (ITSM). PD-1 is encoded by the Pdcd1 gene on chromosome 1 in mice and chromosome 2 in humans. In both species, Pdcd1 consists of 5 exons. Exon 1 encodes a short signal sequence, whereas exon 2 encodes an Ig domain. The stalk and transmembrane domains make up exon 3, and exon 4 codes for a short 12 aa sequence that marks the beginning of the cytoplasmic domain. Exon 5 contains the C-terminal intracellular residues and a long 3 UTR. Splice variants of PD-1 have been cloned from activated human T cells (12). These transcripts lack exon 2, exon 3, exons 2 and 3, or exons 2 through 4. All these variants, except for the splice variant lacking exon 3 only (PD-1ex3), are expressed at similar levels as full-length PD-1 in resting peripheral blood mononuclear cells (PBMCs). All variants are
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significantly induced upon activation of human T cells with anti-CD3 and anti-CD28. The PD-1ex3 variant encodes an mRNA that lacks the transmembrane domain and resembles soluble CTLA-4, which plays an important role in autoimmunity (13). This variant is enriched in the synovial fluid and sera of patients with rheumatoid arthritis (14). PD-L1 is a 290 aa type I transmembrane protein encoded by the Cd274 gene on mouse chromosome 19 and human chromosome 9. Cd274 comprises seven exons, the first of which is noncoding and contains the 5 UTR. The next three exons contain the signal sequence, IgV-like domain, and IgC-like domains, respectively. The transmembrane domain and the intracellular domains are contained in the next two exons (exons 5 and 6). The last exon contains intracellular domain residues plus the 3 UTR. The intracellular domain of PD-L1 is short, only about 30 aa, and highly conserved in all reported species. There is no known function for the intracellular tail of PD-L1. There is one reported splice variant of PDL1 in humans (15) consisting of a sequence lacking the IgV-like domain encoded in exon 2. This mutant should not be able to bind PD1, although the function of this splice variant has not yet been reported. No splice variants have been identified for mouse PD-L1. PD-L2 is a type I transmembrane protein encoded by the Pdcd1lg2 gene adjacent to Cd274 and separated by only 23 kb of intervening genomic DNA in mouse and 42 kb in human. The gene comprises six exons in mouse and seven in human. Exon 1 is noncoding, whereas the second exon contains the signal sequence. The IgV-like domain is composed of exon 3, the IgC-like domain is exon 4, and exon 5 contains a short stalk, transmembrane region, and the beginning of the cytoplasmic domain. In mouse exon 5, there is a stop codon that results in a cytoplasmic domain of only 4 aa. In human, exon 6 and 7 contain an additional coding region resulting in a cytoplasmic domain of 30 aa. The longer form of the cytoplasmic domain is found in
human, macaque, chimp, dog, cow, pig, and horse but is lost in mouse and rat. The long form of the cytoplasmic domain has no appreciable signaling motifs but is conserved across diverse species, suggesting that the cytoplasmic tail of PD-L2 may have a functional role. There are three PD-L2 splice variants identified from activated human PBMCs (9, 16). Analogous to the splice variant described in PD-L1, one form drops out the IgV-like exon and presumably loses the capacity to bind PD-1 (9). A second form (called type II) drops out the IgC-like domain. Another form (called type III) loses the IgC-like domain and the transmembrane residues but preserves the intracellular residues. The type II form would be expected to bind PD-1, as most binding activity resides in the IgV-like domain (17), and the type III form might represent a soluble ligand for PD-1.
STRUCTURE OF PROTEINS The unbound three-dimensional structure of PD-1 has been obtained by X-ray crystallography and shows that the β-strands of the Ig superfamily fold are well conserved between CTLA-4 and PD-1 (root mean squared deviation of 1.5 A˚ comparing common α carbons) (18). The CDR3 loop in PD-1 is loosely ordered and does not have conserved amino acids, unlike the binding interface of CTLA4, which is centered on the MYPPPY motif of the CDR3 loop and is highly ordered owing to the consecutive prolines in this motif. None of the PD-1 CDR3 amino acids was found to be important for binding PD-L by scanning mutagenesis. Biophysical studies have addressed the question of self-association of PD-1. Fluorescence resonance energy transfer analyses of full-length PD-1 expressed in CHO cells and analytical ultracentrifugation on a soluble extracellular PD-1 IgVlike domain showed PD-1 to be monomeric. Whether PD-1 requires dimerization to transduce signals is unclear. Molecular models of PD-L1 and PD-L2 have been generated on the basis of the crystal
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structures of B7-1 and B7-2 to guide sitedirected alanine scanning mutagenesis (17). The binding interfaces of both PD-L1 and PD-L2 to PD-1 are on their IgV-like domains. Interestingly, certain mutants of PDL1 and PD-L2 that were unable to bind PD-1 could stimulate T cell proliferation in conHuman
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Figure 1 Comparison of expression of PD-1, PD-L1, PD-L2, and B7-1 on human and mouse cells. PD-1, PD-L1, PD-L2, and B7-1 are expressed on a wide range of human (7–9, 20, 23, 37, 55, 89, 143, 146–149) and mouse cells (4, 9, 24, 31, 85, 87, 113, 143, 147, 150–153). 680
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junction with anti-CD3. These non-PD-1 binding mutants were also able to stimulate Pdcd1−/− T cells, providing evidence for another receptor for PD-L1 and PD-L2.
EXPRESSION OF PD-1 AND ITS LIGANDS PD-1 can be expressed on T cells, B cells, natural killer T cells, activated monocytes, and dendritic cells (DCs) (Figure 1). PD-1 is not expressed on resting T cells but is inducibly expressed after activation (19). Although PD1 cell surface protein expression can be detected within 24 h of stimulation, functional effects of PD-1 ligation are observed within a few hours following T cell activation (20). Ligation of TCR or BCR can upregulate PD1 on lymphocytes, and the level of mRNA transcription does not strictly correlate with protein production (21). In normal human reactive lymphoid tissue, PD-1 is expressed on germinal center–associated T cells (133). PD-1 compartmentalization in intracellular stores has been described in a regulatory T cell population (22, 22a). PD-1 is inducibly expressed on APCs on myeloid CD11c+ DCs and monocytes in humans (23), but its function on these cells is not clear. There are no data to support a function for PD-1 in the absence of antigen receptor signaling. The two PD-1 ligands differ in their expression patterns. PD-L1 is constitutively expressed on mouse T and B cells, DCs, macrophages, mesenchymal stem cells, and bone marrow–derived mast cells (24). PD-L1 expression is also found on a wide range of nonhematopoietic cells (see Figure 1) and is upregulated on a number of cell types after activation. Both type I and type II interferons (IFNs) upregulate PD-L1 (25, 26). Analyses of the human PD-L1 promoter demonstrate that both constitutive and inducible PD-L1 expression are dependent on two IFN regulatory factor-1 (IRF-1) binding sites that are between 200 and 320 bp upstream of the transcriptional start site (27). These IRF-1 binding sites are also found in mouse,
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although their importance has not been directly tested. Several studies have examined which signaling pathways are required for PD-L1 expression by using pharmacological inhibitors. PD-L1 expression in cell lines is decreased when MyD88, TRAF6, and MEK are inhibited (28). JAK2 has also been implicated in PD-L1 induction (27, 28). Loss or inhibition of phosphatase and tensin homolog (PTEN), a cellular phosphatase that modifies phosphatidylinositol 3-kinase (PI3K) and Akt signaling, increases post-transcriptional PD-L1 expression in cancers (29). PD-L2 expression is much more restricted than PD-L1 expression. PD-L2 is inducibly expressed on DCs, macrophages, and bone marrow–derived mast cells. PD-L2 is also expressed on 50% to 70% of resting peritoneal B1 cells, but not on conventional B2 B cells (30). PD-L2 expression on B1 cells tracks with a restricted VH usage that is skewed toward VH 11/VH 12. PD-L2+ B1 cells bind phosphatidylcholine and may be important for innate immune responses against bacterial antigens. Less is known about transcriptional regulation of PD-L2. Its induction by IFNγ is partially dependent on NF-κB (31). PD-L2 can also be induced on monocytes and macrophages by GM-CSF, IL-4, and IFN-γ (24, 32).
Signaling Through PD-1 Signaling through costimulatory receptors primarily functions to modify antigen receptor signaling. PD-1 typically has greater effects on cytokine production than on cellular proliferation, with significant effects on IFN-γ, TNF-α, and IL-2 production. PD1-mediated inhibitory signals depend on the strength of the TCR signal, with greater inhibition delivered at low levels of TCR stimulation. This reduction can be overcome by costimulation through CD28 (8) or IL-2 (33). PD-1 may exert its effects on cell differentiation and survival directly by inhibiting early activation events that are positively regulated by CD28 or indirectly through IL-2
(33). Both CD28 and IL-2 promote cell expansion and survival through effects on antiapoptotic, cell cycle, and cytokine genes. IL2 withdrawal can lead to cell death, another process in which PD-1 has been implicated. There is strong evidence that PD-1 ligation inhibits the induction of the cell survival factor Bcl-xL (20). PD-1 inhibits the expression of transcription factors associated with effector cell function, including GATA-3, Tbet, and Eomes (34). Further studies are required to determine whether PD-1-mediated inhibition is related to its ability to counteract cell survival signals and effector differentiation mediated through CD28, IL-2, Bcl-xL, or a combination of these factors. PD-1 is phosphorylated on its two intracellular tyrosines upon ligand engagement, and then binds phosphatases that downregulate antigen receptor signaling through direct dephosphorylation of signaling intermediates. Two phosphatases, SH2-domain containing tyrosine phosphatase 1 (SHP-1) and SHP-2, can bind to the ITIM and ITSM motifs of PD-1 (35, 36). PD-1 inhibitory function is lost when the ITSM alone is mutated, demonstrating that this tyrosine plays the primary functional role of PD-1 inhibition (20, 36). The association between SHP-1 and PD1 appears to be weaker than the interaction of PD-1 with SHP-2. Together, these studies suggest that PD-1 functions by recruiting SHP-2, and possibly SHP-1, to the antigen receptor signaling complex (35). While the binding of SHP-2 to PD-1 is significantly enhanced by PD-1 ligation (20), proximity of PD-1 to the antigen receptor appears to be important for inhibition by PD-1. PD-1 ligation inhibits antigen receptor signaling only in cis and not in trans, indicating that PD-1 ligation must occur close to the site of antigen receptor engagement (37). CTLA-4 moves from an intracellular store to the immunological synapse between an APC and lymphocyte after antigen recognition, depending on the strength of signal (38). In contrast, PD-1 redistributes from uniform cell surface expression to the synapse during
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tor protein SH2 domain–containing molecule 1A (SH2D1A, also known as SAP) (41). Unlike the CD150 family of cell surface receptors, the ITIM/ITSM motifs of PD-1 do not bind SH2D1A (20). Therefore, PD-1 inhibition likely functions solely through direct interaction with SHP-2, or possibly SHP-1, to directly inhibit early events in the antigen receptor signaling cascades (Figure 2). PD-1 interaction with SHP-1 and SHP-2 is further supported by a peptide immunoprecipitation study that investigated binding partners for the PD-1 ITIM and ITSM motifs using mass spectroscopy. The PD-1 ITIM/ITSM motifs also associate with Lck and Csk (35). These findings suggest that Csk and/or Lck may
T cell–APC interactions (22a). PD-1 could exert its inhibitory effects by bringing SHP-2 into the synapse during antigen receptor signaling, and cross-linking of PD-1 and CD3 increases the amount of SHP-2, but not SHP1, associated with PD-1 (39). PD-1 ligation inhibits PI3K activity and downstream activation of Akt. In contrast, CTLA-4 inhibits Akt activation but does not alter PI3K activity, indicating that these coinhibitory receptors function through distinct mechanisms. PD-1 ligation inhibits phosphorylation of CD3ζ, ZAP70, and PKCθ (40). Other costimulatory receptors, such as CD150, bind SHP-2 through interactions of their ITIM/ITSM domains with the adap-
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Figure 2 Ligation of PD-1 dampens TCR signaling but can be overcome by CD28 costimulation. PD-1 engagement on the cell surface leads to phosphorylation of PD-1 cytoplasmic tyrosines and increases SHP-2 association with the ITSM of PD-1. Recruitment of SHP-2 dephosphorylates signaling through the PI3K pathway and downstream signals through Akt. PD-1 ultimately decreases induction of cytokines, such as IFN-γ, and cell survival proteins, such as Bcl-xL. When signaling through CD28 is delivered at the same time as PD-1 and TCR ligation, inhibitory effects can be overcome, and cytokine production and cell survival is enhanced. 682
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mediate the phosphorylation of PD-1 in T cells, similar to Lyn phosphorylation of PD-1 in a B cell line (36). PD-1 ligation also reduces Erk activation, but this effect can be overcome through cytokine receptor signaling, particularly cytokines that activate STAT5, such as IL-2, IL-7, and IL-15 (37). SHP-2 positively regulates Erk phosphorylation by interacting with Gab2 after IL-2R ligation (42). Both activation of Erk, which is specifically inhibited by PD-1 ligation, and activation of STAT5, which can overcome PD-1 inhibition, are demonstrated to be involved in the antiapoptotic and proliferative function of IL-2 (43). This suggests a model whereby the association of PD-1 with SHP-2 serves not only to dephosphorylate signaling intermediates, but also perhaps to sequester SHP-2 from its positive signaling role in Erk activation.
Reverse Signaling Through PD-L1 and PD-L2 PD-L1 and PD-L2 not only may influence responses by engaging PD-1 and modifying TCR or BCR signaling, but also may deliver signals into PD-L1- or PD-L2-expressing cells. The first indication that PD-L2 may transmit signals into DCs came from studies using a novel, naturally occurring human IgM antibody (sHIgM12), isolated from a patient with Waldenstrom’s macroglobulinemia, that binds both mouse and human PD-L2 (44). Although DCs treated with sHIgM12 do not upregulate MHC II or B7 costimulatory molecules, they produce greater amounts of proinflammatory cytokines, particularly TNF-α and IL-6, and stimulate naive T cell proliferation. Treatment of mice with the sHIgM12 enhances resistance to transplanted B16 melanoma and rapidly induces potent tumor-specific CTL (45–47). sHIgM12 also completely blocked the development of airway inflammatory disease in a mouse model of allergic asthma (48, 49). A recombinantly expressed IgM antibody was generated from sHIgM12 that recapitulates observations with
the patient-derived antibody, arguing for a specific effect through PD-L2 ligation (50). Further studies are needed to determine how PD-L2 signals into the DC and how these signals influence immunity or tolerance. Additional evidence for reverse signaling through PD-L1 or PD-L2 on DCs comes from studies of bone marrow–derived DCs cultured with soluble PD-1-Ig fusion protein containing the extracellular domain of mouse PD-1 fused to the constant region of human IgG (51). This soluble PD-1 (sPD-1) inhibited DC activation and increased IL-10 production independent of 2,3-dioxygenase (IDO). These effects could be prevented by preneutralization of sPD-1 with anti-PD-1, suggesting that the acquisition of this suppressive DC phenotype is PD-1-specific and occurs via PD-L1 or PD-L2. These findings are consistent with previous studies in which sPD-1 induced IL-10 production by CD4 T cells (52). Bidirectional signaling of PD-1 and PDL may help clarify some of the contradictory results of studies analyzing the PD-1:PD-L pathway. As is discussed in the next section, the discovery of B7-1 as an additional ligand for PD-L1 also may help explain differences observed in functional studies of PD-1 and PD-L1. The identification of bidirectional interactions between B7-1 and PD-L1 that inhibit T cell responses further underscores the importance of reverse signaling through PDL1 and demonstrates that PD-L1 can signal into T cells.
sHIgM12: naturally occurring human anti-PD-L2 IgM antibody derived from a patient with Waldenstrom’s macroglobulinemia
B7-1:PD-L1 Interactions Inhibit T Cell Responses A number of lines of evidence have suggested a receptor for PD-L1 or PD-L2, aside from PD-1. B7-1 has recently been identified as a binding partner for PD-L1 (11). Surface plasmon resonance studies demonstrate specific and unique interaction between PD-L1 and B7-1, with an affinity (∼1.7 μM) intermediate between the affinities of B7-1 for CD28 (4 μM) and CTLA-4 (0.2 μM), and PD-L1 for
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Table 1 Commonly used mAbs that display neutralizing activity against PD-L1:B7-1, PD-L1:PD-1, or B7-1:CTLA-4 Blocking capacity of mAbs PD-1:PD-L1
B7-1:PD-L1
++
+
−
+
αPD-L1 10F.9G2 10F.2H11
CD28, CTLA-4:B7-1
B7-1:PD-L1
αB7-1 1G10
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16–10A1
+
+
++
−
PD-1 (0.5 μM). B7-2 does not bind to PD-L1 or PD-L2, and PD-L2 does not bind to B7-1. Chemical cross-linking studies indicate that PD-L1 and B7-1 can interact through their IgV-like domains. These domains are known to be important for interactions of B7-1 and PD-L1 with their previously known receptors. On B7-1, there is a partial overlap between the B7-1:PD-L1 interface and that of B7-1:CTLA-4. Likewise, on PD-L1, the PDL1:B7-1 interface overlaps at least partially with the putative PD-L1:PD-1 interface (17). The substantial overlap of B7-1:PD-L1 regions of interaction with those of their previously identified binding partners suggests that blocking antibodies might interrupt B7-1:PD-L1 binding as well as B7-1:CTLA-4 or PD-L1:PD-1 binding interactions. Adhesion assays tested the capacity of anti-B7-1 and anti-PD-L1 monoclonal antibodies (mAbs) to interfere with PD-L1 and B7-1 binding to B7-1 or PD-L1 300.19 transfectants, respectively. Two classes of B7-1 antibodies could be identified: one that blocks both B7-1:PDL1 and B7-1:CTLA-4 binding and another that only blocks the B7-1:CTLA-4 interaction (Table 1). Four categories of PD-L1 antibodies have been identified: those that block only PD-1, those that block only B7-1, those that block both, and those that block neither PD-1 nor B7-1 interactions. B7-1:PD-L1 interactions can induce an inhibitory signal into T cells. Ligation of PD-L1 on CD4 T cells by B7-1, or ligation of B7-1 on 684
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CD4 T cells by PD-L1, delivers a functionally significant, inhibitory signal. T cells lacking the previously known receptors for B71 (i.e., T cells lacking CD28 and CTLA-4) showed decreased proliferation and cytokine production when stimulated by anti-CD3 plus B7-1-coated beads. When T cells lacking all the receptors for B7-1 (i.e., T cells lacking CD28, CTLA-4, and PD-L1) were employed, T cell proliferation and cytokine production were no longer inhibited by anti-CD3 plus B7-1-coated beads, indicating that B7-1 acts specifically through PD-L1 on the T cell in the absence of CD28 and CTLA-4. Similarly, T cells lacking the previously known receptor for PD-L1 (PD-1) showed decreased proliferation and cytokine production when stimulated in the presence of anti-CD3 plus PD-L1-coated beads, demonstrating the inhibitory effect of PD-L1 ligation of B7-1 on T cells. When T cells lacking all known receptors for PD-L1 (i.e., T cells lacking PD-1 and B7-1) were used, T cell proliferation was no longer impaired by anti-CD3 plus PD-L1coated beads. Thus, PD-L1 can exert an inhibitory effect on T cells either through B7-1 or PD-1. Taken together, these results demonstrate a specific and significant bidirectional interaction between B7-1 and PD-L1 that inhibits T cell responses (Figure 3). The identification of the PD-L1:B7-1 interaction necessitates a reassessment of the roles of B7-1 and PD-L1 in regulating the activation and inhibition of immune responses, as well as their therapeutic manipulation. Differences in antiPD-L1-blocking antibody specificities may help explain distinct functional outcomes of blockade of PD-1, PD-L1, and PD-L2 in disease models in vivo. For example, many in vivo studies (discussed below) have found a greater effect of anti-PD-L1 blockade compared with anti-PD-1 or anti-PD-L2 blockade, and this has been attributed to differences in the expression of PD-L1 and PD-L2 or to the half-life or affinities of the antibodies. The 10F.9G2 anti-PD-L1 mAb that has been used in many in vivo studies blocks PD-L1:B7-1
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B7-2 (CD86)
YYYY
MYPPPY
B7-1 (CD80)
MYPPPY
YY CTLA-4 (CD152)
PD-L1
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Antigenpresenting cell
MHC
CD28
YY
PD-L2 (B7-DC)
B7-1
Inhibition
Inhibition
T cell
TCR
PD-L1 (B7-H1)
Activation
PD-1
Inhibition
Inhibition
Figure 3 B7-1:PD-L1 interaction expands pathways in the B7:CD28 family. Recent data demonstrate that PD-L1 and B7-1 productively interact on T cells and can deliver bidirectional inhibitory signals. The identification of these costimulatory molecules as binding partners increases our understanding of the interactions that can occur on T cells and APCs and raises the possibility that PD-L1:B7-1 binding may not only deliver signals when ligated, but may also serve to segregate binding away from previously identified receptors (PD-1, CD28, CTLA-4). IgV-like regions are depicted in blue and IgC-like regions in green, while tyrosine-containing signaling motifs are depicted by Ys.
as well as PD-L1:B7-1 interactions (Table 1). Anti-PD-L1 antibodies that block solely PDL1:PD-1 or PD-L1:B7-1 interactions should have reduced effects on T cell activation as compared with the dual-specific anti-PD-L1 mAb. Further studies are needed to compare the functional effects of anti-PD-L1 mAb that block solely PD-L1:PD-1 or PD-L1:B7-1 interactions with mAbs that block both interactions. The direct interaction between B7-1 and PD-L1 also compels a revised view of the interactions among molecules within the B7:CD28 family in regulating T cell activation and tolerance and gives increased significance to B7-1 and PD-L1 on T cells. There are limited studies of PD-L1 function on T
cells, but studies of PD-L1−/− T cells indicate that PD-L1 on T cells can downregulate T cell cytokine production (53). Because both PD-L1 and B7-1 are expressed on T cells, B cells, DCs, and macrophages, there is the potential for bidirectional interactions between B7-1 and PD-L1 on these cell types. In addition, PD-L1 on nonhematopoietic cells may interact with B7-1 as well as PD-1 on T cells to regulate cells. In the sections below, we summarize our current understanding of the roles of PD-1 and its ligands in disease models and discuss the outcomes of PD-L1 manipulation in light of the new PD-L1:B7-1 interaction. We also consider the therapeutic potential of manipulation of PD-1 and its ligands.
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AUTOIMMUNITY AND PERIPHERAL TOLERANCE
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The first indication that the PD-1 pathway plays a critical role in autoimmunity came from the phenotype of Pdcd1−/− mice. Aged Pdcd1−/− C57BL/6 mice develop a mild glomerulonephritis with low frequency (5). Pdcd1−/− Balb/c mice develop a dilated cardiomyopathy owing to the production of an autoantibody against cardiac troponin (6, 54). Autoimmunity is accelerated by PD-1 deficiency on autoimmune-prone backgrounds. These findings broadly support a role for PD1 in the induction and/or maintenance of tolerance. Subsequent work has examined the mechanisms by which PD-1 and its ligands can control self-reactive T cell responses. PD-1 and PD-L1 provide inhibitory signals that regulate both central and peripheral tolerance in multiple ways. PD-1 is expressed on maturing thymocytes in the course of central tolerance induction. PD-L1 is expressed broadly on the thymic cortex and on thymocytes themselves, whereas PD-L2 expression is limited to the thymic medulla (31, 55). CD4− CD8− (DN) thymocytes start to express PD-1 as they undergo TCRβ rearrangement and begin to display functional preTCRs on the cell surface (19). PD-1:PD-L1 interactions inhibit positive selection during the DN to CD4+ CD8+ (DP) maturational stage (56). PD-1 signaling modifies positive selection signaling thresholds, and loss of either PD-1 or PD-L1 increases DP thymocyte cell numbers (57). PD-1 also can contribute to negative selection (58) and has been identified as a candidate gene in a microarray analysis of aberrant central tolerance in nonobese diabetic (NOD) mice (59). Together, these findings point to a role for PD-1 and PD-L1 in central tolerance induction. Self-reactive T cells that escape negative selection are controlled in the periphery by mechanisms of peripheral tolerance. Initial interactions between T cells and APCs, such as DCs, can modify potentially self-reactive responses by the display of self-antigen on
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resting DCs. PD-1 has an important role in controlling the outcome of initial encounters between naive self-reactive T cells and DCs by inhibiting responses of self-reactive T cells. Emerging evidence suggests that immature DCs tolerize T cells, and loss of PD-1 on antigen-specific T cells increases CD8 T cell responses to antigen-bearing resting DCs (60). Studies in mouse models of autoimmunity and tolerance have revealed that PD-1:PDL interactions not only are important in the initial phase of activation and expansion of self-reactive T cells, but also influence selfreactive T cell effector function upon antigen reencounter. In the NOD mouse model of autoimmune T cell–mediated diabetes, PDL1 is upregulated in the pancreas on islet cells (31), and loss or blockade of PD-1 or PD-L1 leads to rapid and exacerbated diabetes with accelerated insulitis and proinflammatory cytokine production by T cells (61– 63). In a model of antigen-specific therapy in which administration of antigen-coupled fixed splenocytes induces tolerance and reverses diabetes in NOD mice, PD-1:PD-L1 interactions were required for both the induction and maintenance of CD4 T cell tolerance (64). Notably, blockade of PD-1 or PDL1 reversed anergy in islet-antigen-specific T cells, whereas CTLA-4 blockade did not break tolerance, indicating a unique function for PD-1:PD-L1 interactions in maintaining T cell anergy. Bone marrow chimera experiments have demonstrated that PD-L1 expression on non–bone marrow–derived cells, including islet cells, inhibits T cell effector function in tissues (63, 65, 66). These studies also suggest a key role for the PD-1:PD-L1 pathway in limiting immune-mediated tissue damage caused by pathogenic T cells upon antigen reencounter in the periphery. Collectively, these findings demonstrate that PD-1: PD-L1 interactions regulate both the initiation and progression of autoimmune diabetes in NOD mice and identify PD-1:PD-L1 interactions as key mediators of T cell tolerance in tissues.
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In the experimental autoimmune encephalomyelitis (EAE) model of human multiple sclerosis (MS), PD-1 and its ligands also control self-reactive T cells. PD-1, PD-L1, and PD-L2 are all expressed on cellular infiltrates within the meninges during active EAE disease in C57BL/6 mice (31). PD-L1 is expressed in the CNS on inflammatory cells as well as on astrocytes and vascular endothelial cells. PD-L1 is specifically induced on CD11b+ APCs by IL-12 (67) and on microglial cells by IFN-γ (68). Initial studies described a role for PD-1 and PD-L2 using neutralizing antibody treatment (69). Anti-PD-1 or anti-PD-L2 mAb administration during the induction of EAE accelerated disease onset and severity, increased CNS inflammatory infiltrates, and led to increased myelin oligodendrocyte glycoprotein (MOG)-reactive T cells and antibodies. Subsequent studies (70) using blocking antibodies in different mouse strains, such as Balb/c, or gene-deficient animals (53, 71) suggest that PD-1 and PD-L1, but not PD-L2, are predominantly responsible for regulating the severity of disease in most mouse strains. The strain-dependent effects of PD-1 and its ligands in influencing disease severity in EAE cannot be explained by expression of PDL1 or PD-L2 on APCs or inflammatory cells (70). Cytokine production is important in the pathogenesis of EAE, and Pdcd1−/− and Cd274−/− T cells secrete increased amounts of inflammatory cytokines, including IL-17 and IFN-γ, in recall responses to myelin antigen (71). Adoptive transfer studies emphasize the critical function for PD-L1 in limiting myelin-reactive pathogenic effector T cells and show that PD-L1 both on the transferred T cell and in the recipient restrains encephalitogenic T cell responses (53). Another important mechanism of peripheral tolerance involves regulatory T cells, which can suppress activated T cell proliferation and cytokine production. Both PD-1 and PD-L1 are highly expressed on these populations and may play a role in regulatory T cell function (72). A number of studies suggest
that PD-L1 may be important for inducing regulatory T cell populations, although the mechanism is not yet clear (73). Experiments in colitis models support the argument for a role of PD-1:PD-L1 on a regulatory cell population and identified a regulatory subpopulation of CD4+ CD25− PD-1+ T cells that can inhibit the development of colitis (74). PD-L1 is important for in vitro inhibition by another suppressive population of CD4+ DX5+ T cells (75). A role for PD-1:PD-L in humans is suggested by polymorphisms in PDCD1 that have been associated with human autoimmune diseases, including systemic lupus erythematosus (SLE), type 1 diabetes, rheumatoid arthritis, Grave’s disease, and MS (76). Most of these polymorphisms are found in conserved regions in intronic sequences. One intronic single nucleotide polymorphism (G7146A) in PDCD1 is located in a binding site for Runx1 (AML-1), a transcription factor with an important regulatory role in hematopoiesis (77). This polymorphism may alter PD-1 mRNA stability or expression level and is associated with reduced PD-1mediated inhibition of IFN-γ production in German patients with MS (78). A recent study suggests that PDCD1 genetic variation may influence the risk and expression of SLE, and effects of PD-1 polymorphisms vary according to ethnic background, similar to the effects of mouse PD-1 deficiency in different genetic backgrounds (79). A polymorphism in PDCD1LG2 has been described that correlates with SLE (80), but no polymorphisms in CD274 have been linked to human autoimmune diseases. In addition, autoantibodies to PD-L1 that correlate with active disease have been found in rheumatoid arthritis patients and may contribute to disease progression by dysregulating T cell responses (52). It remains to be determined if the signals that hold autoimmunity in check are generated through interactions between PD1 and PD-L1 or between PD-L1 and B7-1. In the NOD mouse model, Cd80−/− NOD mice develop autoimmunity more rapidly
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and with higher incidence than NOD mice (81), although less quickly than Pdcd1−/− and Cd274−/− NOD mice. B7-1-blocking antibodies significantly accelerate diabetes onset in NOD mice and induce diabetes in normally resistant male NOD mice, but the two antiB7-1 mAbs appear to differ in their functional effects. The 16–10A1 mAb (which blocks B71:CTLA-4 but not B7-1:PD-L1 interactions) caused more rapid diabetes onset than did the 1G10 mAb (which blocks both B7-1:CTLA4 and B7-1:PD-L1 interactions) (82). Further studies are needed to test the role of PDL1:B7-1 interactions and to understand the mechanisms by which PD-L1 promotes peripheral tolerance. In view of its important role in autoimmune disease, the PD-1:PD-L pathway has become a new therapeutic target. Therapies that increase the expression of PD-L and trigger PD-1 may ameloriate autoimmune diseases. These approaches are only beginning to be evaluated in animal models, but the results appear promising. DCs genetically modified to overexpress PD-L1 and MOG in the context of MHC II dramatically ameliorate clinical EAE and reduce severity of CNS inflammation (83). A recombinant adenovirus expressing full-length mouse PD-L1 partially protects against the development of nephritis in lupus-prone mice (84). IFN-β, an immunemodulatory treatment for MS, can upregulate PD-L1 on APC in vitro and in MS patients in vivo, suggesting that IFN-β may exert its antiinflammatory effects in part via upregulation of PD-L1 expression (26).
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INFECTIOUS DISEASE AND MICROBIAL PATHOGENESIS PD-1 and its ligands have important roles in regulating immune defenses against microbes that cause acute and chronic infections. The PD-1:PD-L pathway appears to be a key determinant of the outcome of infection, regulating the delicate balance between effective antimicrobial immune defenses and immunemediated tissue damage. For example, 688
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Pdcd1−/− mice clear an adenovirus infection more rapidly but develop more severe hepatocellular injury than WT mice (85). In a mouse model of herpes stromal keratitis, a blocking anti-PD-L1 mAb exacerbated keratitis, increasing HSV-1-specific effector CD4 T cell expansion and IFN-γ production and survival (86). These studies suggest that the PD-1:PD-L pathway limits the potentially detrimental consequences of vigorous antipathogen effector T cells. A number of microorganisms that cause chronic infection appear to have exploited the PD-1:PD-L pathway to evade the immune responses and establish persistent infection. Studies in the lymphocytic choriomeningitis virus (LCMV) model of chronic viral infection were the first to show a role for the PD-1:PD-L pathway during chronic infection (87). Viruses that cause chronic infections can render virus-specific T cells nonfunctional and thereby silence the antiviral T cell response (88). Functional dysregulation, or exhaustion, of CD8 T cells is an important reason for ineffective viral control during chronic infections and is characteristic of chronic LCMV infection in mice, as well as of HIV, HBV, HCV, and HTLV infection in humans and SIV infection in primates. There appears to be a hierarchical, progressive loss of function within the phenotype of exhausted virus-specific CD8 T cells, with cytotoxicity and IL-2 production lost first, followed by effector cytokine production (88). PD-1 is upregulated upon activation, and a functionally significant high level of expression is maintained by exhausted CD8 T cells in mice chronically infected with LCMV (87). In vivo administration of antibodies that blocked PD-1:PD-L1 interactions enhanced T cell responses. Most importantly, PD-1 and PD-L1 blockade led to a substantial reduction in viral burden. In persistently infected mice that lack CD4 T cell help, blockaded of this pathway restored and maintained the ability of “helpless” CD8 T cells to proliferate, secrete cytokines, kill infected cells, and decrease viral load. Taken together, these studies
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demonstrate that the PD-1:PD-L pathway contributes to T cell dysfunction and lack of viral control in chronic LCMV infection, and they suggest a novel strategy for treating chronic viral infections. Because of the critical role of PD-1:PD-L1 interactions in LCMV, there has been interest in extending this work to chronic viral infection in humans. Several groups have shown that PD-1 expression is high on HIV-specific (23, 89, 90), HBV-specific (91, 92), and HCVspecific T cells (93). PD-L1 is also upregulated on peripheral blood CD14+ monocytes and myeloid DCs in patients with chronic HBV infection (94, 95), and on CD14+ cells and T cells in HIV patients (96). Blocking PD1:PD-L interactions in vitro reverses the exhaustion of HIV-specific, HBV-specific (92), HCV-specific, and SIV-specific (97) CD8 and CD4 T cells and restores proliferation and cytokine production (23, 89, 90, 93). A mechanistic understanding of PD-1 upregulation during chronic viral infection is at an early stage. Recent work shows that the HCV core, a nucleocapsid protein, can upregulate PD1 and PD-L1 expression on healthy donor T cells and that upregulation of PD-1 is mediated by interaction of the HCV core with the complement receptor C1QBP (98). PD-1 also may serve as a useful marker on virus-specific CD8 T cells to indicate the degree of T cell exhaustion and disease severity. The level of PD-1 protein per cell is important in regulating T cell dysfunction. For example, the level and percentage of PD-1 expression on HIV-specific CD8 T cells correlates with viral load, declining CD4 counts, and decreased capacity of CD8 T cells to proliferate in response to HIV antigen in vitro. Similarly, there was a direct correlation between PD-1 expression on HIV-specific CD4 T cells and viral load (99). Long-term nonprogressors have functional HIV-specific memory CD8 T cells with markedly lower PD-1 expression, in contrast to typical progressors who express significantly upregulated PD-1, which correlates with reduced CD4 T cell number, decreased HIV-specific effector memory CD8
T cell function, and elevated plasma viral load (100). The PD-1:PD-L pathway also may play a key role in the chronicity of bacterial infections. Helicobacter pylori causes chronic gastritis and gastroduodenal ulcers and is a risk factor for development of gastric cancer. During H. pylori infection, T cell responses are insufficient to clear infection, leading to persistent infection. Gastric epithelial cells express MHC class II molecules and are thought to have important APC function during H. pylori infection. Following exposure to H. pylori in vitro or in vivo, PD-L1 also is upregulated on human gastric epithelial cells. Anti-PD-L1 blocking antibodies enhance T cell proliferation and IL-2 production in cultures of gastric epithelial cells exposed to H. pylori and CD4 T cells, suggesting that PD-L1 may play an important role in inhibiting T cell responses during H. pylori infection (101). PD-L1 is upregulated in gastric mucosal biopsies from H. pylori–infected individuals, who show a marked increase in the CD4+ CD25hi FoxP3+ cell population. Naive T cells cultured with H. pylori–exposed gastric epithelial cells can develop into functional CD4+ CD25hi FoxP3+ regulatory T cells (102). Blocking PD-L1 on in gastric epithelial cells with anti-PDL1 mAb or specific small interfering RNA (siRNA) prevented generation of the regulatory T cells, suggesting that PD-L1 may promote T cell suppression and persistent infection by controlling the dynamic between regulatory and effector T cells during H. pylori infection. Parasitic worms also have exploited the PD-1:PD-L pathway to induce macrophages with strong suppressive function. During Taenia crassiceps infection in mice, PD-L1 and PD-L2 are upregulated on activated macrophages, and a high percentage of CD4 T cells express PD-1. Blockade of PDL1, PD-L2, or PD-1 significantly decreased suppression of in vitro T cell proliferation by macrophages from Taenia-infected mice (103). Similarly, during Schistosoma mansoni infection in mice, macrophages express high
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levels of PD-L1 and more modest levels of PD-L2. Anti-PD-L1 completely abrogated the ability of these macrophages to suppress T cell proliferation in vitro, whereas antiPD-L2 had no effect. PD-L1 expression on macrophages from infected mice declines after 12 weeks of infection, correlating with a break in T cell anergy (104). Thus, an emerging theme is that PD-L1 and PDL2 can mediate the suppressive functions of macrophages during parasite infections. PD-L1 and PD-L2 have distinct roles in the immune response to the protozoan parasite Leishmania mexicana. Cd274−/− 129Sv mice showed resistance to L. mexicana, whereas Pdcd1lg2−/− mice developed exacerbated disease with increased parasite burdens. Cd274−/− mice exhibited a diminished Th2 response, which may explain the increased resistance of Cd274−/− mice. Pdcd1lg2−/− mice exhibited a marked increase in L. mexicana–specific IgM and IgG2a, which may contribute to the exacerbated disease observed in Pdcd1lg2−/− mice. Increased parasite-specific IgG production may suppress the healing response through FcγR ligation on macrophages. Further studies are needed to determine whether these distinct outcomes of infection reflect impaired PD1 signaling into T cells, B cells, and/or macrophages (105). The key roles of the PD-1:PD-L pathway in reducing T cell responses during chronic viral infections propel development of strategies to manipulate the interaction of PD-1 and its ligands to restore antiviral T cell responses during chronic viral infections. This pathway may have evolved to limit immunemediated damage to the host during infection by turning off pathogen-specific T cells. We must better understand the immunoregulatory roles of this pathway to determine how to modulate it to activate effective pathogenspecific T cells while minimizing the risk of autoimmunity and immunopathology. Notably, anti-PD-L1 mAb had greater effects than anti-PD-1 mAb in the chronic LCMV model; the anti-PD-L1 mAb used in these
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studies blocks both PD-L1:PD-1 and PDL1:B7-1 interactions. The therapeutic potential of manipulating PD-1 and PD-L1 to enhance immune responses during chronic infection gives impetus to analyzing the relative effects of blocking PD-1:PD-L1 interactions versus B7-1:PD-L1 interactions during chronic infection.
THE ROLE OF PD-1:PD-L IN TRANSPLANTATION Negative costimulatory pathways play a key role in regulating rejection of transplanted allogeneic tissues (106–108), and several important lines of evidence demonstrate that PD1:PD-L1 interactions control engraftment of solid organs and graft-versus-host disease (GVHD). Redundancy among negative costimulatory pathways is clearly important for controlling alloreactive T cells, and several studies have demonstrated unique roles for the PD-1:PD-L and CTLA-4:B7 pathways. Both PD-1 and PD-L1 are significantly upregulated on alloreactive T cells in transplant recipients (109, 110). The inducible expression of PD-L1 in tissues, such as the heart and pancreatic islets, as well as constitutive expression on other tissues such as the cornea, also may control alloreactive immune responses. Studies in heart transplant models have demonstrated that PD-L1 is upregulated on cardiac allografts as early as one day after heart transplant (111). PD-1 and PD-L2 are induced much later in the response, presumably because they are expressed primarily by infiltrating cells. PD-1 upregulation occurs after the onset of GVHD, and PD-L1 is extensively expressed on most cells in GVHD target organs. In heart (112), corneal (113), and skin transplant models (109), administration of PD-L1, but not PD-L2, blocking antibodies accelerated transplant rejection. The absence of a significant effect of PD-L2 blocking antibody in transplant models suggests several possibilities. First, PD-L1 and PD-L2 may play different roles in tolerance induction by
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tolerogenic DCs. In support of this view, there is evidence of differential expression of these molecules on tolerogenic DCs in a transplant setting, but there has been no direct test of their respective roles on DCs during rejection (114, 115). In addition, the importance of PD-L1 as a ligand, either on tissues or on lymphocytes themselves, may be central to graft tolerance (63). Recent studies have investigated the role of the PD-1:PD-L pathway in acquired transplantation tolerance using a fully MHC mismatch cardiac transplant model, in which tolerance can be induced by CTLA-4-Ig (116). To examine the role of PD-L1 on the donor versus the recipient in the acquired tolerance model of CTLA-4-Ig, Cd274−/− mice were used as graft donors or recipients of cardiac allografts and given CTLA-4-Ig treatment. Cd274−/− recipients of WT cardiac allografts had accelerated graft rejection compared with WT recipients given CTLA4-Ig therapy. Cd274−/− cardiac allografts were accepted by WT recipients treated with CTLA-4-Ig, yet histologic examination showed evidence of severe chronic rejection and vasculopathy. These data indicate that PD-L1 in the graft protects from local pathology and chronic rejection, whereas PD-L1 expression in the recipient immune system is required for induction and/or maintenance of transplantation tolerance after CTLA-4-Ig therapy. These findings suggest that PD-1 agonists may be useful for promoting transplant tolerance and preventing local inflammation that leads to graft arterial disease (GAD) and chronic rejection. In fully MHC class I and II mismatched allografts, acute rejection occurs within days, and there is a strong induction of PD-1 expression on T cells. Administration of PDL1 blocking antibodies significantly hastens rejection in the full mismatch cardiac transplant model (112). The role of PD-1 in regulating alloresponses also appears to depend on the strength of TCR signaling. In heart transplant models in which only MHC class I or II are mismatched, chronic rejection in the
form of GAD is induced. GAD is accompanied by mild PD-1 and PD-L1 upregulation (117), and blockade in the setting of MHC class I or II mismatch does not hasten rejection (110). PD-1 can exert its negative regulatory effect in the presence or absence of positive CD28 costimulation. When fully MHC class I and II mismatched hearts are transplanted into Cd28−/− recipients, positive signals transduced through CD28 are eliminated, which doubles the time to rejection. When PD-1 or PD-L1 blocking antibodies are used in Cd28−/− recipients, rejection is accelerated, indicating that PD-1:PD-L1 interactions are important in acute rejection in the absence of CD28 stimulation. Additionally, PD-1 and CTLA-4 effects are not redundant, as evidenced by findings in GVHD, where blocking antibodies to PD-1 augment disease induction and coadministration with anti-CTLA-4 substantially accelerates GVHD (118). One mechanism by which PD-L1 blockade may accelerate graft rejection is through prevention of T cell apoptosis. PD-L1, but not PD-1 or PD-L2, blocking antibodies induce accelerated rejection in a skin transplant model using allospecific TCR transgenic T cells (109). PD-L1 blocking antibody inhibited in vivo apoptosis of alloreactive TCR transgenic T cells, whereas a PD-1 blocking antibody did not. Similar results were obtained in a corneal transplant mode, where only PD-L1, but not PD-1 or PD-L2, blocking antibodies induced rapid rejection (113). This suggests a PD-1-independent role for PD-L1 in promoting tolerance through inducing apoptosis of alloreactive T cells. The mechanism of apoptosis induction, whether it is TCR-dependent or -independent, and whether B7-1 is involved have yet to be determined. Induction of allograft tolerance is dependent on the balance of regulatory and effector T cells, and PD-1 and PD-L1 have been implicated in controlling both regulatory T cell induction as well as increased effector T cell generation in transplant models. PD-L1
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blockade can inhibit allospecific effector responses in vitro (119), as well as inhibit the induction of allogeneic regulatory T cells by vascular endothelium (73). The acceleration of graft rejection observed after PD-L1 neutralizing antibody administration may depend on regulatory T cells. Administration of anti-PD-L1 on the day of transplantation or on day 60 after transplantation led to cardiac graft rejection in CTLA-4-Ig-treated recipients, with an increase in lymphocyte production of inflammatory cytokines and significant decreases in regulatory T cell numbers within the allograft. Similar studies in both a skin allograft and a GVHD model have also suggested that PD-1:PD-L1 interactions on regulatory and effector T cells may be important (109, 119). No acceleration of rejection was observed when anti-PD-L1 treatment was given in the absence of CD25+ T cells. The loss of PD-1 and PD-L1 through genetic deletion or antibody blockade also has been demonstrated to increase effector cell generation and cytokine production (110, 118, 119). These studies suggest that PDL1 may regulate transplantation tolerance by controlling the balance between regulatory and pathogenic effector cells, limiting the expansion of alloreactive effector cells in the periphery.
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ALLERGY AND ASTHMA Asthma and allergic responses constitute inappropriately vigorous immune responses to innocuous stimuli. B7 family members are implicated in the regulation of allergy and asthma and are involved in the priming events, helper T cell differentiation, and effector function that underlie the pathology of these diseases. Although a picture of the definitive role of PD-1 and its ligands in asthma and allergy has yet to emerge, most data point to PD-L2 as a critical molecule in these diseases. PD-L2 is abundantly expressed in DCs in the lung in a mouse model of asthma. In a mouse ovalbumin-induced allergic asthma model, PD-L2 treatment during challenge 692
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but not sensitization resulted in an increase in airway hyperresponsiveness and in Th2 cytokine production (120). There was no effect of either PD-1 or PD-L1 mAbs in either the priming or effector phase. These results suggest that the effector responses of T cells in asthma may be influenced by PD-L2, but not PD-1. Use of sHIgM12 mAb, which was previously described as inducing reverse signaling through PD-L2, in a mouse model of allergic asthma completely blocked the development of airway inflammatory disease, and sHIgM12-treated DCs could mediate these same protective effects when transferred into hyperimmune mice (48, 49). Finally, treatment with PD-L2-Fc prior to sensitization and challenge exacerbated T cell proliferation and cytokine production and increased eosinophilia in vivo but had the opposite effect in vitro, where it inhibited T cell proliferation and cytokine production (121). PDL2 blockade, but not PD-1 or PD-L1 blockade, diminished eosinophil migration to the conjunctiva in a mouse model of allergic conjunctivitis (122). Among the studies that have tested the function of PD-1 and its ligands in allergy and asthma, most have utilized different reagents. Further work is required to understand the role of PD-1 and its ligands in allergic diseases, yet a consistent finding has been the implication of PD-L2 in these processes.
TUMOR IMMUNITY Tumors express antigens that can be recognized by host T cells, but immunologic clearance of tumors is rare. Part of this failure is due to immune suppression by the tumor microenvironment. PD-L1 expression on many tumors is a component of this suppressive milieu and may act in concert with other immunosuppressive signals. PDL1 expression has been shown in situ on a wide variety of solid tumors including breast, lung, colon, ovarian, melanoma, bladder, liver, salivary, stomach, gliomas, thyroid, thymic epithelial, head, and neck (55, 123–131).
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Immunohistochemical staining of normal and malignant breast tissue is contrasted in Figure 4. In addition, PD-1 expression is upregulated on tumor infiltrating lymphocytes, and this may also contribute to tumor immunosuppression (58). In ovarian cancer, PD-L1 expression is inversely correlated with intraepithelial, but not stromal, infiltrating CD8 T cells, suggesting that PD-L1 inhibits the intratumor migration of CD8 T cells (124). Expression on tumor cell lines is generally lower in vitro, and expression is increased upon adoptive transfer into animals. Translation of PD-L1 mRNA is enhanced by loss of PTEN and the ensuing activation of Akt, a common event in tumorigenesis (29). Most importantly, studies relating PD-L1 expression on tumors to disease outcome show that PDL1 expression strongly correlates with unfavorable prognosis in kidney, ovarian, bladder, breast, gastric, and pancreatic cancer but not small cell lung cancer (124, 126–131). In addition, these studies suggest that higher levels of PD-L1 expression on tumors may facilitate advancement of tumor stage and invasion into deeper tissue structures. The PD-1 pathway may also play a role in hematologic malignancies. PD-1 or PDL1 are rarely expressed on B cell malignancies (55), but PD-L2 has been identified by microarray analysis as being highly expressed in mantle cell lymphomas (132). PDL1 is expressed on multiple myeloma cells but not on normal plasma cells. T cell expansion in response to myeloma cells is enhanced in vitro by PD-L1 blockade (28). PD-L1 is expressed on some primary T cell lymphomas, particularly anaplastic large cell T lymphomas (55). PD-1 is highly expressed on the T cells of angioimmunoblastic lymphomas, and PD-L1 is expressed on the associated follicular dendritic cell network (133). In nodular lymphocyte-predominant Hodgkin lymphoma, the T cells associated with lymphocytic and/or histiocytic (L&H) cells express PD-1. Microarray analysis using a readout of genes induced by PD-1 ligation suggests that tumor-associated T cells are re-
Figure 4 PD-L1 is upregulated on breast tumor, but not normal, cells Immunohistochemical staining (brown) of a breast ductal carcinoma showing high expression of PD-L1 on neoplastic tissue (thick arrow) and low expression on adjacent normal tissue (thin arrow) (figure kindly provided by David Dorfman, Brigham and Women’s Hospital). Note that lymphocytes are more abundant in normal tissue areas than in cancer cell nests.
sponding to PD-1 signals in situ in Hodgkin lymphoma (134). PD-1 and PD-L1 are expressed on CD4 T cells in HTLV-1-mediated adult T cell leukemia and lymphoma (135). These tumor cells are hyporesponsive to TCR signals, and PD-1 blockade increased their expression of TNF-α, but not IFN-γ. Studies in animal models demonstrate that PD-L1 on tumors inhibits T cell activation and lysis of tumor cells and in some cases leads to increased tumor-specific T cell death (123, 136). Treatment with anti-PD-L1 or injection of tumor cells into Pdcd1−/− mice augments antitumor responses, as measured by cytotoxicity and cytokine production (136– 138). Treatment with anti-PD-L1 in vivo delays, but does not halt, tumorigenesis of PDL1-expressing mouse myeloma cell lines (137) PD-L1 blockade can improve the outcome of immunotherapy. PD-L1 expression on the immunogenic tumor P815 causes resistance to immunotherapy, but blockade with antiPD-L1 restores the response to anti-CD137 therapeutic mAb (136). Treatment with antiPD-L1 mAb enhances T cell immunotherapy, and administration of anti-PD-L1 with activated T cells augments rejection of a
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PD-L1-expressing squamous cell carcinoma (125). Tumor-associated APCs can also utilize the PD-1:PD-L pathway to control antitumor T cell responses. PD-L1 expression on a population of tumor-associated myeloid DCs is upregulated by tumor environmental factors, and PD-L1 mAb blockade enhanced DC-mediated T cell activation (139). Plasmacytoid DCs in the tumor-draining lymph node of B16 melanoma express IDO, which strongly activates the suppressive activity of regulatory T cells. The suppressive activity of IDO-treated regulatory T cells required cell contact with IDO-expressing DCs and was abrogated by PD-L blockade (140). A fully human PD-1 mAb has been developed and is in Phase 1 clinical trials for cancer. Preclinical studies show that PD-1 is expressed on tumor-specific human T cells following vaccination with tumor peptide antigen. Blockade of PD-1 with this mAb during in vitro stimulation with melanoma peptide increased the numbers and effector activity of tumor-specific human T cells (141). Both Th1 and Th2 cytokine production were increased. PD-1 blockade did not change the percentage of apoptotic antigen-specific human T cells, indicating that the increase in number was due to increased proliferation, not decreased death. In mice, a triple treatment therapy of anti-PD-L1 blockade, depletion of CD4 T cells (primarily regulatory T cells), and irradiated tumor cell vaccination induced complete elimination of large established renal cancer cell (RENCA) tumors with long-lasting tumor-specific immunity (142), further suggesting that this pathway is a promising target for therapeutic intervention.
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PD-1 AND IMMUNOPATHOLOGY A number of studies point to an important role for PD-L1 in limiting immunopathology. Following infection with LCMV clone 13, WT mice develop a chronic infection, whereas Cd274−/− mice die (87). Blockade or elimination of PD-L1 in mouse models of 694
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autoimmunity leads to exacerbated autoimmunity associated with severe inflammation and tissue damage (61, 63–66, 69). Bone marrow chimera studies point to an important role for PD-L1 on non–bone marrow–derived cells in limiting effector T cell responses and immunopathology. The expression of PD-L1 on vascular endothelial cells has led to the hypothesis that PD-L1 on endothelial cells may regulate the activation of T cells that contact the vessel wall, the extravasation of T cells into tissue, and/or limit detrimental consequences of immunopathology. Blockade of PD-L1 on vascular endothelial cells enhances IFN-γ production and cytolytic activity of CD8 T cells in vitro (143). Cd274−/− Pdcd1lg2−/− mice developed severely increased atherosclerotic lesion burden, suggesting that PD-L1 also may play a significant role in inflammatory diseases in which vascular endothelium and T cells are important for pathogenesis (144). Fibroblastic reticular cells (FRC) express high levels of PD-L1, which can be upregulated during LCMV clone 13 infection (145). Elegant confocal, electron, and intravital microscopy studies demonstrate that the FRC network can regulate T cell access to the paracortex within the lymph node and regulate movement within the LN. In vivo administration of blocking PD-L1 mAb during LCMV clone 13 infection induced significant CD8 T cell–mediated damage to the splenic stroma, demonstrating an essential role for this pathway in minimizing virus-induced immunopathology. These studies suggest that PD-L1 on FRC may contribute to viral persistence during chronic infection. Further studies are needed to test whether expression of PD-L1 by FRC may contribute to the influence of FRC on T cell trafficking.
CONCLUDING REMARKS PD-1:PD-L interactions exert a vital and diverse range of immunoregulatory roles in T cell activation, tolerance, and immune-mediated tissue damage. How do
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PD-1 and its ligands exert their inhibitory effects? One of their most significant functions is controlling potentially pathogenic effector T cells, yet PD-1:PD-L can also dampen early activation events when naive T cells encounter antigen in lymph nodes. PD-1 and PD-L1 are also expressed on regulatory T cells and may control their suppression of effector T cells. Recent studies indicate that PD-L1 and PD-L2 can signal bidirectionally by engaging PD-1 on T cells and by delivering signals into PD-L-expressing cells. These bidirectional interactions between PD-1 and its ligands, along with the identification of B7-1 as an additional binding partner for PD-L1, may help explain the seemingly contradictory results seen with reagents developed to manipulate this pathway. The discovery of B7-1:PD-L1 interactions also reveals additional ways by which PD-L1 exerts its inhibitory functions.
Because both PD-L1 and B7-1 are expressed on T cells, B cells, DCs, and macrophages, there is the potential for bidirectional interactions between B7-1 and PDL1 on these cell types. Emerging evidence demonstrates a unique and critical role for PD-L1 on nonhematopoetic cells for mediating tissue tolerance as well as protecting tissues from the detrimental consequences of overaggressive effector responses. Microbes and tumors appear to have exploited this pathway to evade eradication by the immune system. These distinctive functions provide therapeutic opportunities for developing PD1/PD-L antagonists to boost antimicrobial and antitumor immunity as well as agonists to control pathogenic T cells in autoimmune diseases and graft rejection. The fundamental and therapeutic importance of the PD-1:PDL pathway gives impetus to further investigation of its functions.
DISCLOSURE STATEMENT A.H.S. and G.J.F. have patents on PD-1 ligands and grants on PD-1 and PD-1 ligands.
ACKNOWLEDGMENTS This work was supported by grants from National Institutes of Health and the Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative (to A.H.S. and G.J.F.) and the National Multiple Sclerosis Society (to A.H.S.). Because of space restrictions, we were able to cite only a fraction of the relevant literature and apologize to colleagues whose contributions may not be appropriately acknowledged in this review.
LITERATURE CITED 1. Lafferty KJ, Cunningham AJ. 1975. A new analysis of allogeneic interactions. Aust. J. Exp. Biol. Med. Sci. 53:27–42 2. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. 1995. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541–47 3. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, et al. 1995. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985–88 4. Ishida Y, Agata Y, Shibahara K, Honjo T. 1992. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11:3887–95 www.annualreviews.org • PD-1 and Its Ligands in Tolerance and Immunity
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ARI
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5. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. 1999. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141–51 6. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, et al. 2001. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:319–22 7. Dong H, Zhu G, Tamada K, Chen L. 1999. B7-H1, a third member of the B7 family, costimulates T-cell proliferation and interleukin-10 secretion. Nat. Med. 5:1365–69 8. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, et al. 2000. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192:1027–34 9. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, et al. 2001. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2:261–68 10. Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, et al. 2001. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J. Exp. Med. 193:839–46 11. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. 2007. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27:111–22 12. Nielsen C, Ohm-Laursen L, Barington T, Husby S, Lillevang ST. 2005. Alternative splice variants of the human PD-1 gene. Cell. Immunol. 235:109–16 13. Ueda H, Howson JM, Esposito L, Heward J, Snook H, et al. 2003. Association of the Tcell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506– 11 14. Wan B, Nie H, Liu A, Feng G, He D, et al. 2006. Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis. J. Immunol. 177:8844–50 15. He XH, Xu LH, Liu Y. 2005. Identification of a novel splice variant of human PD-L1 mRNA encoding an isoform-lacking Igv-like domain. Acta Pharmacol. Sin. 26:462–68 16. He XH, Liu Y, Xu LH, Zeng YY. 2004. Cloning and identification of two novel splice variants of human PD-L2. Acta Biochim. Biophys. Sin. 36:284–89 17. Wang S, Bajorath J, Flies DB, Dong H, Honjo T, Chen L. 2003. Molecular modeling and functional mapping of B7-H1 and B7-DC uncouple costimulatory function from PD-1 interaction. J. Exp. Med. 197:1083–91 18. Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, et al. 2004. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity 20:337–47 19. Nishimura H, Agata Y, Kawasaki A, Sato M, Imamura S, et al. 1996. Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4− CD8− ) thymocytes. Int. Immunol. 8:773–80 20. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. 2004. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J. Immunol. 173:945–54 21. Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, et al. 1996. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8:765–72 22. Raimondi G, Shufesky WJ, Tokita D, Morelli AE, Thomson AW. 2006. Regulated compartmentalization of programmed cell death-1 discriminates CD4+ CD25+ resting regulatory T cells from activated T cells. J. Immunol. 176:2808–16
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22a. Pentcheva-Hoang T, Chen L, Pardoll DM, Allison JP. 2007. Programmed death-1 concentration at the immunological synapse is determined by ligand affinity and availability. Proc. Natl. Acad. Sci. USA 104:17765–70 23. Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E, et al. 2006. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J. Exp. Med. 203:2281– 92 24. Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, et al. 2002. Expression of programmed death 1 ligands by murine T cells and APC. J. Immunol. 169:5538–45 25. Eppihimer MJ, Gunn J, Freeman GJ, Greenfield EA, Chernova T, et al. 2002. Expression and regulation of the PD-L1 immunoinhibitory molecule on microvascular endothelial cells. Microcirculation 9:133–45 26. Schreiner B, Mitsdoerffer M, Kieseier BC, Chen L, Hartung HP, et al. 2004. Interferonβ enhances monocyte and dendritic cell expression of B7-H1 (PD-L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis. J. Neuroimmunol. 155:172–82 27. Lee SJ, Jang BC, Lee SW, Yang YI, Suh SI, et al. 2006. Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-γ-induced upregulation of B7-H1 (CD274). FEBS Lett. 580:755–62 28. Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, et al. 2007. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-γ and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood 110:296–304 29. Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, et al. 2007. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat. Med. 13:84–88 30. Zhong X, Tumang JR, Gao W, Bai C, Rothstein TL. 2007. PD-L2 expression extends beyond dendritic cells/macrophages to B1 cells enriched for VH 11/VH 12 and phosphatidylcholine binding. Eur. J. Immunol. 37:2405–10 31. Liang SC, Latchman YE, Buhlmann JE, Tomczak MF, Horwitz BH, et al. 2003. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur. J. Immunol. 33:2706–16 32. Loke P, Allison JP. 2003. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc. Natl. Acad. Sci. USA 100:5336–41 33. Carter L, Fouser LA, Jussif J, Fitz L, Deng B, et al. 2002. PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2. Eur. J. Immunol. 32:634–43 34. Nurieva R, Thomas S, Nguyen T, Martin-Orozco N, Wang Y, et al. 2006. T-cell tolerance or function is determined by combinatorial costimulatory signals. EMBO J. 25:2623–33 35. Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, et al. 2004. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ. FEBS Lett. 574:37–41 36. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. 2001. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domaincontaining tyrosine phosphatase 2 to phosphotyrosine. Proc. Natl. Acad. Sci. USA 98:13866–71 37. Bennett F, Luxenberg D, Ling V, Wang IM, Marquette K, et al. 2003. Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokinedriven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses. J. Immunol. 170:711–18 www.annualreviews.org • PD-1 and Its Ligands in Tolerance and Immunity
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38. Egen JG, Allison JP. 2002. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 16:23–35 39. Saunders PA, Hendrycks VR, Lidinsky WA, Woods ML. 2005. PD-L2:PD-1 involvement in T cell proliferation, cytokine production, and integrin-mediated adhesion. Eur. J. Immunol. 35:3561–69 40. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, et al. 2005. CTLA4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell. Biol. 25:9543–53 41. Shlapatska LM, Mikhalap SV, Berdova AG, Zelensky OM, Yun TJ, et al. 2001. CD150 association with either the SH2-containing inositol phosphatase or the SH2-containing protein tyrosine phosphatase is regulated by the adaptor protein SH2D1A. J. Immunol. 166:5480–87 42. Arnaud M, Crouin C, Deon C, Loyaux D, Bertoglio J. 2004. Phosphorylation of Grb2associated binder 2 on serine 623 by ERK MAPK regulates its association with the phosphatase SHP-2 and decreases STAT5 activation. J. Immunol. 173:3962–71 43. Van Parijs L, Refaeli Y, Lord JD, Nelson BH, Abbas AK, Baltimore D. 1999. Uncoupling IL-2 signals that regulate T cell proliferation, survival, and Fas-mediated activationinduced cell death. Immunity 11:281–88 44. Nguyen LT, Radhakrishnan S, Ciric B, Tamada K, Shin T, et al. 2002. Cross-linking the B7 family molecule B7-DC directly activates immune functions of dendritic cells. J. Exp. Med. 196:1393–98 45. Radhakrishnan S, Nguyen LT, Ciric B, Ure DR, Zhou B, et al. 2003. Naturally occurring human IgM antibody that binds B7-DC and potentiates T cell stimulation by dendritic cells. J. Immunol. 170:1830–38 46. Radhakrishnan S, Nguyen LT, Ciric B, Flies D, Van Keulen VP, et al. 2004. Immunotherapeutic potential of B7-DC (PD-L2) cross-linking antibody in conferring antitumor immunity. Cancer Res. 64:4965–72 47. Heckman KL, Schenk EL, Radhakrishnan S, Pavelko KD, Hansen MJ, Pease LR. 2007. Fast-tracked CTL: rapid induction of potent antitumor killer T cells in situ. Eur. J. Immunol. 37:1827–35 48. Radhakrishnan S, Iijima K, Kobayashi T, Rodriguez M, Kita H, Pease LR. 2004. Blockade of allergic airway inflammation following systemic treatment with a B7-dendritic cell (PD-L2) cross-linking human antibody. J. Immunol. 173:1360–65 49. Radhakrishnan S, Iijima K, Kobayashi T, Kita H, Pease LR. 2005. Dendritic cells activated by cross-linking B7-DC (PD-L2) block inflammatory airway disease. J. Allergy Clin. Immunol. 116:668–74 50. Van Keulen VP, Ciric B, Radhakrishnan S, Heckman KL, Mitsunaga Y, et al. 2006. Immunomodulation using the recombinant monoclonal human B7-DC cross-linking antibody rHIgM12. Clin. Exp. Immunol. 143:314–21 51. Kuipers H, Muskens F, Willart M, Hijdra D, van Assema FB, et al. 2006. Contribution of the PD-1 ligands/PD-1 signaling pathway to dendritic cell-mediated CD4+ T cell activation. Eur. J. Immunol. 36:2472–82 52. Dong H, Strome SE, Matteson EL, Moder KG, Flies DB, et al. 2003. Costimulating aberrant T cell responses by B7-H1 autoantibodies in rheumatoid arthritis. J. Clin. Invest. 111:363–70 53. Latchman YE, Liang SC, Wu Y, Chernova T, Sobel RA, et al. 2004. PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. Proc. Natl. Acad. Sci. USA 101:10691–96
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54. Okazaki T, Tanaka Y, Nishio R, Mitsuiye T, Mizoguchi A, et al. 2003. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat. Med. 9:1477–83 55. Brown JA, Dorfman DM, Ma FR, Sullivan EL, Munoz O, et al. 2003. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J. Immunol. 170:1257–66 56. Nishimura H, Honjo T, Minato N. 2000. Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. J. Exp. Med. 191:891–98 57. Keir ME, Latchman YE, Freeman GJ, Sharpe AH. 2005. Programmed death-1 (PD-1): PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes. J. Immunol. 175:7372–79 58. Blank C, Brown I, Marks R, Nishimura H, Honjo T, Gajewski TF. 2003. Absence of programmed death receptor 1 alters thymic development and enhances generation of CD4/CD8 double-negative TCR-transgenic T cells. J. Immunol. 171:4574–81 59. Zucchelli S, Holler P, Yamagata T, Roy M, Benoist C, Mathis D. 2005. Defective central tolerance induction in NOD mice: genomics and genetics. Immunity 22:385–96 60. Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M. 2005. Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat. Immunol. 6:280–86 61. Ansari MJ, Salama AD, Chitnis T, Smith RN, Yagita H, et al. 2003. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J. Exp. Med. 198:63–69 62. Wang J, Yoshida T, Nakaki F, Hiai H, Okazaki T, Honjo T. 2005. Establishment of NOD-Pdcd1−/− mice as an efficient animal model of type I diabetes. Proc. Natl. Acad. Sci. USA 102:11823–28 63. Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, et al. 2006. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J. Exp. Med. 203:883–95 64. Fife BT, Guleria I, Gubbels Bupp M, Eagar TN, Tang Q, et al. 2006. Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. J. Exp. Med. 203:2737–47 65. Grabie N, Gotsman I, Dacosta R, Pang H, Stravrakis G, et al. 2007. Endothelial PD-L1 regulates CD8+ T cell mediated injury in the heart. Circulation 116:2062–71 66. Keir ME, Freeman GJ, Sharpe AH. 2007. PD-1 regulates self-antigen specific responses in lymph nodes and tissues. J. Immunol. 179:5064–70 67. Cheng X, Zhao Z, Ventura E, Gran B, Shindler KS, Rostami A. 2007. The PD-1/PD-L pathway is up-regulated during IL-12-induced suppression of EAE mediated by IFN-γ. J. Neuroimmunol. 185:75–86 68. Magnus T, Schreiner B, Korn T, Jack C, Guo H, et al. 2005. Microglial expression of the B7 family member B7 homolog 1 confers strong immune inhibition: implications for immune responses and autoimmunity in the CNS. J. Neurosci. 25:2537–46 69. Salama AD, Chitnis T, Imitola J, Ansari MJ, Akiba H, et al. 2003. Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis. J. Exp. Med. 198:71–78 70. Zhu B, Guleria I, Khosroshahi A, Chitnis T, Imitola J, et al. 2006. Differential role of programmed death-ligand 1 and programmed death-ligand 2 in regulating the susceptibility and chronic progression of experimental autoimmune encephalomyelitis. J. Immunol. 176:3480–89 www.annualreviews.org • PD-1 and Its Ligands in Tolerance and Immunity
699
ARI
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71. Carter LL, Leach MW, Azoitei ML, Cui J, Pelker JW, et al. 2007. PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 182:124–34 72. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. 2003. CD4+ CD25+ regulatory cells from human peripheral blood express very high levels of CD25 ex vivo. Novartis Found. Symp. 252:67–88 73. Krupnick AS, Gelman AE, Barchet W, Richardson S, Kreisel FH, et al. 2005. Murine vascular endothelium activates and induces the generation of allogeneic CD4+ 25+ Foxp3+ regulatory T cells. J. Immunol. 175:6265–70 74. Totsuka T, Kanai T, Makita S, Fujii R, Nemoto Y, et al. 2005. Regulation of murine chronic colitis by CD4+ CD25− programmed death-1+ T cells. Eur. J. Immunol. 35:1773– 85 75. Hornung M, Farkas SA, Sattler C, Schlitt HJ, Geissler EK. 2006. DX5+ NKT cells induce the death of colitis-associated cells: involvement of programmed death ligand-1. Eur. J. Immunol. 36:1210–21 76. Okazaki T, Honjo T. 2007. PD-1 and PD-1 ligands: from discovery to clinical application. Int. Immunol. 19:813–24 77. Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, et al. 2002. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat. Genet 32:666–69 78. Kroner A, Mehling M, Hemmer B, Rieckmann P, Toyka KV, et al. 2005. A PD-1 polymorphism is associated with disease progression in multiple sclerosis. Ann. Neurol. 58:50–57 79. Thorburn CM, Prokunina-Olsson L, Sterba KA, Lum RF, Seldin MF, et al. 2007. Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort. Genes Immun. 8:279–87 80. Wang SC, Lin CH, Ou TT, Wu CC, Tsai WC, et al. 2007. Ligands for programmed cell death 1 gene in patients with systemic lupus erythematosus. J. Rheumatol. 34:721–25 81. Yadav D, Fine C, Azuma M, Sarvetnick N. 2007. B7-1 mediated costimulation regulates pancreatic autoimmunity. Mol. Immunol. 44:2616–24 82. Lenschow DJ, Ho SC, Sattar H, Rhee L, Gray G, et al. 1995. Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse. J. Exp. Med. 181:1145–55 83. Hirata S, Senju S, Matsuyoshi H, Fukuma D, Uemura Y, Nishimura Y. 2005. Prevention of experimental autoimmune encephalomyelitis by transfer of embryonic stem cellderived dendritic cells expressing myelin oligodendrocyte glycoprotein peptide along with TRAIL or programmed death-1 ligand. J. Immunol. 174:1888–97 84. Ding H, Wu X, Wu J, Yagita H, He Y, et al. 2006. Delivering PD-1 inhibitory signal concomitant with blocking ICOS costimulation suppresses lupus-like syndrome in autoimmune BXSB mice. Clin. Immunol. 118:258–67 85. Iwai Y, Terawaki S, Ikegawa M, Okazaki T, Honjo T. 2003. PD-1 inhibits antiviral immunity at the effector phase in the liver. J. Exp. Med. 198:39–50 86. Jun H, Seo SK, Jeong HY, Seo HM, Zhu G, et al. 2005. B7-H1 (CD274) inhibits the development of herpetic stromal keratitis (HSK). FEBS Lett. 579:6259–64 87. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, et al. 2006. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–87 88. Wherry EJ, Ahmed R. 2004. Memory CD8 T-cell differentiation during viral infection. J. Virol. 78:5535–45
Annu. Rev. Immunol. 2008.26:677-704. Downloaded from www.annualreviews.org by Harvard University on 08/23/11. For personal use only.
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89. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, et al. 2006. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443:350–54 90. Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, et al. 2006. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat. Med. 12:1198–202 91. Boettler T, Panther E, Bengsch B, Nazarova N, Spangenberg HC, et al. 2006. Expression of the interleukin-7 receptor α chain (CD127) on virus-specific CD8+ T cells identifies functionally and phenotypically defined memory T cells during acute resolving hepatitis B virus infection. J. Virol. 80:3532–40 92. Boni C, Fisicaro P, Valdatta C, Amadei B, Di Vincenzo P, et al. 2007. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J. Virol. 81:4215–25 93. Urbani S, Amadei B, Tola D, Massari M, Schivazappa S, et al. 2006. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J. Virol. 80:11398–403 94. Chen L, Zhang Z, Chen W, Zhang Z, Li Y, et al. 2007. B7-H1 up-regulation on myeloid dendritic cells significantly suppresses T cell immune function in patients with chronic hepatitis B. J. Immunol. 178:6634–41 95. Geng L, Jiang G, Fang Y, Dong S, Xie H, et al. 2006. B7-H1 expression is upregulated in peripheral blood CD14+ monocytes of patients with chronic hepatitis B virus infection, which correlates with higher serum IL-10 levels. J. Viral Hepat. 13:725–33 96. Trabattoni D, Saresella M, Biasin M, Boasso A, Piacentini L, et al. 2003. B7-H1 is upregulated in HIV infection and is a novel surrogate marker of disease progression. Blood 101:2514–20 97. Velu V, Kannanganat S, Ibegbu C, Chennareddi L, Villinger F, et al. 2007. Elevated expression levels of inhibitory receptor programmed death 1 on simian immunodeficiency virus-specific CD8 T cells during chronic infection but not after vaccination. J. Virol. 81:5819–28 98. Yao ZQ, King E, Prayther D, Yin D, Moorman J. 2007. T cell dysfunction by hepatitis C virus core protein involves PD-1/PDL-1 signaling. Viral Immunol. 20:276– 87 99. D’Souza M, Fontenot AP, Mack DG, Lozupone C, Dillon S, et al. 2007. Programmed death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and associated with T cell dysfunction. J. Immunol. 179:1979–87 100. Zhang JY, Zhang Z, Wang X, Fu JL, Yao J, et al. 2007. PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors. Blood 109:4671–78 101. Das S, Suarez G, Beswick EJ, Sierra JC, Graham DY, Reyes VE. 2006. Expression of B7-H1 on gastric epithelial cells: its potential role in regulating T cells during Helicobacter pylori infection. J. Immunol. 176:3000–9 102. Beswick EJ, Pinchuk IV, Das S, Powell DW, Reyes VE. 2007. Expression of the programmed death ligand 1, B7-H1, on gastric epithelial cells after Helicobacter pylori exposure promotes development of CD4+ CD25+ FoxP3+ regulatory T cells. Infect. Immun. 75:4334–41 103. Terrazas LI, Montero D, Terrazas CA, Reyes JL, Rodriguez-Sosa M. 2005. Role of the programmed Death-1 pathway in the suppressive activity of alternatively activated macrophages in experimental cysticercosis. Int. J. Parasitol. 35:1349–58 www.annualreviews.org • PD-1 and Its Ligands in Tolerance and Immunity
701
ARI
16 February 2008
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104. Smith P, Walsh CM, Mangan NE, Fallon RE, Sayers JR, et al. 2004. Schistosoma mansoni worms induce anergy of T cells via selective up-regulation of programmed death ligand 1 on macrophages. J. Immunol. 173:1240–48 105. Liang SC, Greenwald RJ, Latchman YE, Rosas L, Satoskar A, et al. 2006. PD-L1 and PD-L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis. Eur. J. Immunol. 36:58–64 106. Clarkson MR, Sayegh MH. 2005. T-cell costimulatory pathways in allograft rejection and tolerance. Transplantation 80:555–63 107. Vadivel N, Trikudanathan S, Chandraker A. 2007. Transplant tolerance through costimulation blockade—are we there yet? Front. Biosci. 12:2935–46 108. Kean LS, Gangappa S, Pearson TC, Larsen CP. 2006. Transplant tolerance in nonhuman primates: progress, current challenges and unmet needs. Am. J. Transplant. 6:884–93 109. Sandner SE, Clarkson MR, Salama AD, Sanchez-Fueyo A, Domenig C, et al. 2005. Role of the programmed death-1 pathway in regulation of alloimmune responses in vivo. J. Immunol. 174:3408–15 110. Tao R, Wang L, Han R, Wang T, Ye Q, et al. 2005. Differential effects of B and T lymphocyte attenuator and programmed death-1 on acceptance of partially versus fully MHC-mismatched cardiac allografts. J. Immunol. 175:5774–82 111. Ozkaynak E, Wang L, Goodearl A, McDonald K, Qin S, et al. 2002. Programmed death-1 targeting can promote allograft survival. J. Immunol. 169:6546–53 112. Ito T, Ueno T, Clarkson MR, Yuan X, Jurewicz MM, et al. 2005. Analysis of the role of negative T cell costimulatory pathways in CD4 and CD8 T cell-mediated alloimmune responses in vivo. J. Immunol. 174:6648–56 113. Hori J, Wang M, Miyashita M, Tanemoto K, Takahashi H, et al. 2006. B7-H1-induced apoptosis as a mechanism of immune privilege of corneal allografts. J. Immunol. 177:5928– 35 114. Selenko-Gebauer N, Majdic O, Szekeres A, Hofler G, Guthann E, et al. 2003. B7H1 (programmed death-1 ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy. J. Immunol. 170:3637–44 115. Abe M, Wang Z, de Creus A, Thomson AW. 2005. Plasmacytoid dendritic cell precursors induce allogeneic T-cell hyporesponsiveness and prolong heart graft survival. Am. J. Transplant. 5:1808–19 116. Tanaka K, Albin MJ, Yuan X, Yamaura K, Habicht A, et al. 2007. PD-L1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection. J. Immunol. 179:5204–10 117. Koga N, Suzuki J, Kosuge H, Haraguchi G, Onai Y, et al. 2004. Blockade of the interaction between PD-1 and PD-L1 accelerates graft arterial disease in cardiac allografts. Arterioscler. Thromb. Vasc. Biol. 24:2057–62 118. Blazar BR, Carreno BM, Panoskaltsis-Mortari A, Carter L, Iwai Y, et al. 2003. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-γ-dependent mechanism. J. Immunol. 171:1272–77 119. Kitazawa Y, Fujino M, Wang Q, Kimura H, Azuma M, et al. 2007. Involvement of the programmed death-1/programmed death-1 ligand pathway in CD4+ CD25+ regulatory T-cell activity to suppress alloimmune responses. Transplantation 83:774–82 120. Matsumoto K, Inoue H, Nakano T, Tsuda M, Yoshiura Y, et al. 2004. B7-DC regulates asthmatic response by an IFN-γ-dependent mechanism. J. Immunol. 172:2530–41 121. Oflazoglu E, Swart DA, Anders-Bartholo P, Jessup HK, Norment AM, et al. 2004. Paradoxical role of programmed death-1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo. Eur. J. Immunol. 34:3326–36
Annu. Rev. Immunol. 2008.26:677-704. Downloaded from www.annualreviews.org by Harvard University on 08/23/11. For personal use only.
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122. Fukushima A, Yamaguchi T, Azuma M, Yagita H, Ueno H. 2006. Involvement of programmed death-ligand 2 (PD-L2) in the development of experimental allergic conjunctivitis in mice. Br. J. Ophthalmol. 90:1040–45 123. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, et al. 2002. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8:793–800 124. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, et al. 2007. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc. Natl. Acad. Sci. USA 104:3360–65 125. Strome SE, Dong H, Tamura H, Voss SG, Flies DB, et al. 2003. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 63:6501– 5 126. Inman BA, Sebo TJ, Frigola X, Dong H, Bergstralh EJ, et al. 2007. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer 109:1499–505 127. Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. 2004. B7-H1 expression on nonsmall cell lung cancer cells and its relationship with tumorinfiltrating lymphocytes and their PD-1 expression. Clin. Cancer Res. 10:5094–100 128. Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S. 2007. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol. Immunother. 56:1173–82 129. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, et al. 2007. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin. Cancer Res. 13:2151–57 130. Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, et al. 2004. Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc. Natl. Acad. Sci. USA 101:17174–79 131. Wu C, Zhu Y, Jiang J, Zhao J, Zhang XG, Xu N. 2006. Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem. 108:19–24 132. Rosenwald A, Wright G, Leroy K, Yu X, Gaulard RD, et al. 2003. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J. Exp. Med. 198:851–62 133. Dorfman DM, Brown JA, Shahsafaei A, Freeman GJ. 2006. Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am. J. Surg. Pathol. 30:802–10 134. Chemnitz JM, Eggle D, Driesen J, Classen S, Riley JL, et al. 2007. RNA-fingerprints provide direct evidence for the inhibitory role of TGFβ and PD-1 on CD4+ T cells in Hodgkin’s lymphoma. Blood 110:3226–33 135. Shimauchi T, Kabashima K, Nakashima D, Sugita K, Yamada Y, et al. 2007. Augmented expression of programmed death-1 in both neoplastic and non-neoplastic CD4+ T-cells in adult T-cell leukemia/lymphoma. Int. J. Cancer 121:2585–90 136. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, et al. 2005. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 65:1089–96 137. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. 2002. Involvement of PDL1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl. Acad. Sci. USA 99:12293–97 www.annualreviews.org • PD-1 and Its Ligands in Tolerance and Immunity
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138. Iwai Y, Terawaki S, Honjo T. 2005. PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int. Immunol. 17:133–44 139. Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, et al. 2003. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat. Med. 9:562–67 140. Sharma MD, Baban B, Chandler P, Hou DY, Singh N, et al. 2007. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J. Clin. Invest. 117:2570–82 141. Wong RM, Scotland RR, Lau RL, Wang C, Korman AJ, et al. 2007. Programmed death1 blockade enhances expansion and functional capacity of human melanoma antigenspecific CTLs. Int. Immunol. 19:1223–34 142. Webster WS, Thompson RH, Harris KJ, Frigola X, Kuntz S, et al. 2007. Targeting molecular and cellular inhibitory mechanisms for improvement of antitumor memory responses reactivated by tumor cell vaccine. J. Immunol. 179:2860–69 143. Rodig N, Ryan T, Allen JA, Pang H, Grabie N, et al. 2003. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur. J. Immunol. 33:3117–26 144. Gotsman I, Grabie N, Dacosta R, Sukhova G, Sharpe A, Lichtman AH. 2007. Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice. J. Clin. Invest. 117:2974–82 145. Mueller SN, Matloubian M, Clemens DM, Sharpe AH, Freeman GJ, et al. 2007. Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection. Proc. Natl. Acad. Sci. USA 104:15430–35 146. Iwai Y, Okazaki T, Nishimura H, Kawasaki A, Yagita H, Honjo T. 2002. Microanatomical localization of PD-1 in human tonsils. Immunol. Lett. 83:215–20 147. Tsuda M, Matsumoto K, Inoue H, Matsumura M, Nakano T, et al. 2005. Expression of B7-H1 and B7-DC on the airway epithelium is enhanced by double-stranded RNA. Biochem. Biophys. Res. Commun. 330:263–70 148. Mataki N, Kikuchi K, Kawai T, Higashiyama M, Okada Y, et al. 2007. Expression of PD-1, PD-L1, and PD-L2 in the liver in autoimmune liver diseases. Am. J. Gastroenterol. 102:302–12 149. Mazanet MM, Hughes CC. 2002. B7-H1 is expressed by human endothelial cells and suppresses T cell cytokine synthesis. J. Immunol. 169:3581–88 150. Nakae S, Suto H, Iikura M, Kakurai M, Sedgwick JD, et al. 2006. Mast cells enhance T cell activation: importance of mast cell costimulatory molecules and secreted TNF. J. Immunol. 176:2238–48 151. Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, et al. 2005. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur. J. Immunol. 35:1482–90 152. English K, Barry FP, Field-Corbett CP, Mahon BP. 2007. IFN-γ and TNF-α differentially regulate immunomodulation by murine mesenchymal stem cells. Immunol. Lett. 110:91–100 153. Genomics Institute of the Novartis Research Foundation. Online database. GNF SymAtlas v1.2.4. http://expression.gnf.org
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389
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Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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Contents
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The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; email:
[email protected],
[email protected],
[email protected],
[email protected] Annu. Rev. Immunol. 2008. 26:705–39
Key Words
The Annual Review of Immunology is online at immunol.annualreviews.org
mast cells, hypersensitivity responses, adaptive immunity, EAE, MS
This article’s doi: 10.1146/annurev.immunol.26.021607.090320 c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0705$20.00
Abstract There are many parallels between allergic and autoimmune responses. Both are considered hypersensitivity responses: pathologies that are elicited by an exuberant reaction to antigens that do not pose any inherent danger to the organism. Although mast cells have long been recognized as central players in allergy, only recently has their role in autoimmunity become apparent. Because of the commonalities of these responses, much of what we have learned about the underlying mast cell–dependent mechanisms of inflammatory damage in allergy and asthma can be used to understand autoimmunity. Here we review mast cell biology in the context of autoimmune disease. We discuss the huge diversity in mast cell responses that can exert either proinflammatory or antiinflammatory activity. We also consider the myriad factors that cause one response to predominate over another in a particular immune setting.
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INTRODUCTION
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Hypersensitivity reactions are a diverse group of pathologic immune responses. The eliciting antigens are not inherently harmful; rather, it is the overzealous immune response that causes the pathology (reviewed in 1). These reactions are classified into Types I– IV on the basis of the major effector mechanism employed. The term hypersensitivity typically brings to mind the immediate-type allergic reactions (Type I) that include hay fever, atopic dermatitis, venom sensitivity, and systemic anaphylaxis. The mast cell is a central figure in these responses. When activated by cross-linking of the high-affinity IgE receptor upon allergen encounter, these cells release a plethora of preformed mediators present in granules (hence an immediate-type response) and initiate new production of molecules that can act later to sustain inflammation. Other classes of hypersensitivity responses have been considered mast cell independent and result either from the direct interaction of IgG or IgM antibody with a cellular antigen or hapten (Type II) or from immune complex deposition (Type III) or involve CD4+ and CD8+ T cells (Type IV, delayed-type hypersensitivity). However, the recent evidence that mast cells are activated by complement and can modulate both B and T cell responses suggests that Types II, III, and IV hypersensitivities also have mast cell–dependent components. The location of mast cells, the numerous FcεRI-independent activation pathways, and the impressive numbers of cell surface and secreted immunomodulatory molecules expressed by mast cells poise these cells to exert an influence in most, if not all, immune responses (Figure 1). Indeed, mast cells are implicated in several of the pathologic responses to self-derived antigens associated with autoimmune diseases, many of which fall under the umbrella of hypersensitivity reactions. Our understanding of mast cell biology has undergone a revolution in recent years, and several excellent reviews have covered the newly discovered roles of these cells in innate
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and adaptive responses to infection and allergic disease (2–4). In this review, we focus on what is known about mast cells in hypersensitive autoimmune responses, with an emphasis on how mast cells can affect the adaptive immune system. In the first part of this discussion, we review key features of mast cells and describe the range of autoimmune diseases in which mast cells have been implicated. The defined and hypothesized mechanisms of mast cell action are then discussed, including the seemingly paradoxical antiinflammatory role of these cells in promoting tolerance. We finish with a discussion of the genetically determined heterogeneity of mast cells and the implications for disease susceptibility.
WHAT ARE MAST CELLS? Mast cells are members of the innate immune system and are often considered first-line responders to immunological insults because of their prevalence in areas highly exposed to the external environment (4). Mature mast cells can be identified in most tissues as relatively large cells that express high levels of c-kit, the receptor for stem cell factor (SCF), and FcεRI, the high-affinity IgE receptor. Microscopically, these cells are easy to identify with toluidine blue or alcian blue dyes. Despite their relatively immobile nature (mast cells are generally found “fixed” in tissues and do not circulate through the blood), mast cells exert profound and far-reaching effects. They are normally found throughout the skin, mucosa of the genitourinary, respiratory, and gastrointestinal tracts, as well as in most other vascularized tissues of adult mammals, including the lymphoid organs (5). Mast cells are also present in sites directly adjacent to blood vessels and peripheral nerves, as well as in the central nervous system (CNS) where they are most numerous in the leptomeninges, thalamus, and hypothalamus and along nerves in the dura mater of the spinal cord (6). Although some pathologic conditions are associated with increased numbers of mast cells,
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Newly synthesized mediators IL-1, 2, 3, 4, 5, 6, 7, 8, 10 12, 13, 15, 18, 21, 23 Prostaglandins Leukotrienes VEGF, NGF, FGF PAF TGF-β CCL3 CCL2 IFN-α, -β, -γ CRH TSLP CXCL10 TNF
Preformed mediators
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Histamine Proteases Peroxidase Serotonin Heparin IL-4 TNF GM-CSF
T and B cell ligands Receptor-binding agonists IgE + Ag Monomeric IgE IgG + Ag lg light chain Complement hormones Neuropeptides Cytokines Microbial products
Physical activators Heat Cold Pressure
B7 PD-L1 OX40L CD30L CD40L CCL19 4-1BB
Figure 1 Activators and potential responses of mast cells. The versatility of the mast cell lies in its ability to be activated by a variety of stimuli, both receptor-mediated and physical, and produce specific responses, ranging from the immediate release of preformed mediators to the increased expression of co-stimulatory molecules to the de novo production of cytokines and chemokines.
this expansion might appear minimal when compared to clonally expanding T and B effector cells. Yet, collectively, mast cells comprise a substantial population. It has been estimated that if all human tissue mast cells were amassed together in a single organ, it would equal the size of a normal spleen (D. Metcalfe, personal communication).
tile and act both as effector cells that amplify inflammation, as well as regulatory cells that suppress responses. This versatility is reflected in the numerous IgE-independent activation pathways that intersect to modulate the quality and magnitude of the mast cell response.
IgE-Dependent Mast Cell Activation MAST CELL ACTIVATION The widely held idea that mast cells evolved primarily to respond vigorously to certain parasites and allergens is a somewhat simplistic notion. Mast cells are extremely versa-
FcεRI-mediated signaling pathways are among the best characterized in mast cells (for review, see 4, 5). Recent studies have also demonstrated the ability of monomeric IgE to activate mast cells (7). Akin to the
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two-signal model of T cell activation, antigen signaling through the FcεRI is often modified by co-inhibitory or co-stimulatory signals in mast cells (reviewed in 8). For example, concurrent administration of αCD28 enhances TNF (tumor necrosis factor) secretion by bone marrow–derived mast cells (BMMC) activated by IgE + Ag (9). Similarly, simultaneous ligation of the IgE-FcεRI complex and 4-1BB (CD137), a co-stimulatory molecule and member of the TNFR family, induces increased BMMC cytokine production and secretion (10). Some Toll-like receptor (TLR) ligands also synergize with antigen to potentiate cytokine secretion by IgE-FcεRI activation in mast cells (11). Conversely, the IgG receptor FcγRIIB (12), leukocyte immunoglobulin (Ig)-like receptor B4 (LILRB4) (formerly gp49B1) (13) and platelet endothelial cell adhesion molecule-1 (PECAM-1) (14) all utilize the Ig-immunoreceptor tyrosine-based inhibitory motif (ITIM) and suppress FcεRIIgE-mediated activation. Mice with targeted disruptions in genes encoding these receptors demonstrate enhanced cytokine release and hyper-responsiveness in IgE-dependent reactions. Given the paradigm of accessory signals in T cell activation and the fact that mast cells express other inhibitory signaling molecules such as B7-H1 (PD-L1) (15) and coactivating molecules such as CD80, CD86, and CD40L (16, 17), we are probably only beginning to understand a more complicated but extremely important picture.
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IgE-Independent Modes of Mast Cell Activation There are limited examples of IgE-dependent mechanisms of mast cell activation that are important in autoimmunity. These include bullous pemphigoid (BP) and Graves’ ophthalmology (18, 19). Of more relevance to this discussion are the IgE-independent modes of activation that include other immunoglobulins, microbial antigens, complement, hormones, peptides, and cytokines. 708
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Both murine and human mast cells express the low-affinity IgG receptors FcγRII and FcγRIII (5) that when cross-linked by IgGantigen complexes are potent inducers of degranulation. Human mast cells also express the high-affinity IgG receptor FcγRI, which is induced after culture with IFN-γ (20). The expression of IgG receptors on mast cells is of particular importance when we consider that autoimmune diseases classified as Type II and III hypersensitivity reactions are IgGmediated. Ig-free light chains (IgLCs) can also function to elicit antigen-specific mast cell– dependent hypersensitivity reactions in mice. Cross-linking of mast cell surface proteins with IgLC results in degranulation and mediator release in vitro and in vivo and induces vascular permeability and plasma extravasation into tissue (21). Mast cells express several complement receptors including C3aR, C5aR CR2, CR4, and the recently described collectin/C1qR (2, 22). The importance of some of these receptors was shown in a cecal ligation and puncture model of septic peritonitis in which complement-mediated mast cell activation is necessary for bacterial clearance (23, 24). There is significant heterogeneity in the expression of receptors on distinct mast cell subsets as well as differences in the outcome of complement receptor engagement (reviewed in 25). Activated complement contributes to the tissue injury associated with many autoimmune diseases, especially those classified as Type II and Type III hypersensitivities. It has also been implicated in Type IV autoimmune diseases such as the murine model of multiple sclerosis (26, 27). Pattern recognition receptors (PRRs) are a class of receptors that recognize broad pathogen-specific motifs, the best studied of which are the TLRs (28). Mast cells from a variety of sources express TLRs 1–4, 6, 7, and 9, the ligands for which include doublestranded viral RNA, peptidoglycan (PGN) from Gram+ bacteria, and lipopolysaccharide (LPS) from Gram− bacteria (2, 29). Mast cell participation in the earliest events in
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immune responses is elicited through these receptors via expression of mediators and costimulatory molecules. Mast cells also express at least one isoform of the nucleotide-binding oligomerization domain proteins, a family of intracellular receptors that recognize bacterial components or their degradation products; a recent study demonstrates that nucleotidebinding oligomerization domain-1 mediates PGN activation of mast cells (30). Other FcεRI-independent entities can influence mast cell activation outcomes. These include hormones and cytokines, as well as a variety of peptides (5). For example, estrogens, including environmental estrogenic pollutants, can induce mast cell degranulation in vitro (31), whereas progesterone appears to inhibit histamine secretion (32). Neuropeptides, such as substance P (SP), calcitonin gene-related peptide (CGRP), somatostatin, vasoactive intestinal peptide (VIP), and neurotensin, can also induce degranulation of mast cells (33).
Mediator Release from Mast Cells: Degranulation versus New Synthesis Mast cell mediator release is phasic in nature (reviewed in 34). Immediate (early phase) release of preformed mediators during degranulation regulates initial events in an immune response including those exhibited in Type I hypersensitivity reactions. This same signal also generates delayed mediator production. The late-phase response involves the de novo synthesis and release of other mediators including cytokines, lipid mediators, and growth factors (1) (Figure 1). Mast cells can also engage in piecemeal degranulation (or intragranular activation), which involves vesicular transport of the contents of selective secretory granules to the cellular surface (4). For instance, serotonin, rather than histamine, is released in response to IgE-Ag or Compound 48/80 when mast cells are stimulated in the presence of amitriptyline, an inhibitor of serotonin and noradrenaline reuptake (35). Mast cells
MAST CELLS AND B CELLS Little is known about mast cell–B cell interactions in vivo. A major pathway of mast cell activation is through antibody receptors, and mast cells express a number of B cell–modulating molecules. Thus, a functional connection between these cell types is highly likely and important to study in the context of autoimmunity. There are some in vitro data to support this idea. Co-culture with even a small number of unstimulated BMMCs has been shown to activate B cells, an effect that is blocked by treatment with mast cell stabilizers (191, 192). Mast cells also induce synthesis of IgE from B cells through expression of CD40L in the presence of exogenous IL-4 (17). B cells express histamine receptors (H1), and in the presence of histamine demonstrate an increased proliferative response to B cell receptor cross-linking (193), although H1 receptor–deficient B cells appear functional and can produce immunoglobulins IgM, IgE, IgG1, IgG3, and IgG2b (158).
can also selectively release mediators without degranulation (36).
HOW MAST CELLS ARE IMPLICATED IN DISEASE Several indices have been used to implicate mast cells in autoimmune diseases. Obviously, in human disease one must rely largely on correlative evidence. The presence of increased numbers of mast cells, mast cell degranulation, or mast cell expression of implicated molecules at local affected sites in diseased versus normal individuals is supportive, but not definitive, evidence of mast cell influence. Among many similar correlative findings in murine models of autoimmunity, perhaps the most definitive proof derives from a comparison of disease incidence and severity in mast cell–deficient mice versus their wild-type counterparts. The two most common strains of mast cell–deficient mice currently in use are the (WB X C57BL/6)F1-KitW /KitWv (termed W/Wv ) and KitWsh /KitWsh mice (termed W-sash, C57BL/6 background) (37–39). Both strains carry mutations in the c-kit receptor,
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+/+ 104
IL-3 SCF
c-kit
Bone marrow stem cells
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103 102
3
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Analyze by flow cytometry
100 0 10
101
102
103
104
FCεRI
Local or IV reconstitution
W/W V
Confirm reconstitution Evaluate disease
Figure 2 Mast cell reconstitution. Mast cell “knock-in” experiments can establish if mast cells contribute to disease. Mast cell populations are typically derived from bone marrow cultured with IL-3+/− SCF. Reconstitution occurs within 4–8 weeks via intravenous or local transfer of these bone marrow–derived mast cells (BMMCs). There are limitations to this approach owing to the inability to efficiently reconstitute all tissues in which mast cells normally reside. The CNS and skin are two organs in which mast cells are not typically restored within this time frame (104). To determine whether a specific mast cell–expressed mediator is essential for a disease phenotype, BMMCs lacking the ability to express the molecule in question can be transferred, and their ability to restore wild-type disease can be measured.
which results in profound deficits in their mast cell populations and can be locally or systemically reconstituted with BMMC (Figure 2). Although the mice, particularly the W/Wv mice, have other mild phenotypic abnormalities, they remain the gold standard for demonstrating mast cell involvement in disease.
MAST CELLS AND THE AUTOIMMUNE HYPERSENSITIVITY RESPONSE Autoimmune diseases result from the coincident loss of tolerance to self in the face of an 710
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unregulated proinflammatory response (40). It is our contention that mast cells play a role in both these processes. However, much of the evidence to support this idea is merely correlative and is based, for example, on the presence of activated mast cells in regions of inflammation or autoimmune destruction or on the actions of mast cells in other disease processes. To understand fully the extent of mast cell involvement in autoimmunity will require suitable animal models for evaluating the role of mast cells in vivo. Indeed, until such models were available to study multiple sclerosis and rheumatoid arthritis, a role for mast
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cells was considered to be unlikely. In the following sections, we review those autoimmune diseases for which there are considerable and convincing data supporting a role for mast cell involvement. These and other examples of autoimmune diseases in which mast cells are weakly implicated are included in Table 1.
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Mast Cells in Type I Hypersensitivities Much of what we know about mast cells comes from studies of their role in Type I immediate hypersensitivity reactions. As other reviews cover this topic in depth (55), we deal with it only briefly here. The manifestations of Type I reactions are evident within minutes and are dependent on IgE interaction with mast cells. During initial antigen (allergen) sensitization, certain individuals develop an IgE-dominated antibody response for reasons not yet fully understood. Subsequent re-exposure leads to immediate mast cell degranulation and release of mediators that contribute to the early symptoms in allergic and anaphylactic responses including excessive vascular permeability, local swelling, and itch. Late-phase responses can be elicited hours to days later at the site of antigen challenge and are characterized by the influx of inflammatory cells to the affected site, tissue remodeling, bronchial hyperreactivity and mucus overproduction in the airways, and local cutaneous swelling.
Mast Cells and Type II Hypersensitivities Type II hypersensitivities are elicited by the interaction of IgG or IgM antibody with a cell surface antigen, followed by the binding of complement and, often, complementmediated cell lysis. Mast cells are well equipped to participate in Type II reactions both directly and indirectly. As described, mast cell activation through IgG or complement receptors causes inflammatory mediator release. Mast cells also influence T cell responses and may be necessary for full T cell
activation that generates T cell help for B cell isotype switching. Among the Type II diseases in which mast cells have a demonstrated role is bullous pemphigoid (BP), a chronic subepidermal blistering skin disease characterized by the presence of IgG autoantibodies to hemidesmosomal antigens BP20 and BP180. Passive transfer of BP20- or BP180-specific IgG leads to disease in neonatal BALB/c mice and reproduces the key clinical features of human BP, including complement deposition at the junction of the dermis and epidermis, dermal inflammation, and subepidermal blistering (56). Mast cell degranulation occurs within 60 min of antibody transfer and elicits neutrophilic infiltration and subsequent blistering of the skin in this mouse model (57). Mast cell–deficient or wild-type mice treated with an inhibitor of mast cell degranulation fail to develop disease, but local engraftment of W/Wv mice with BMMCs restores the BP phenotype. Mice deficient for C4 are also resistant to BP but develop disease when pretreated with the mast cell degranulating agent 48/80 (41). In BP, mast cells triggered by complement activation appear to be a crucial source of the potent neutrophil chemoattractant CXCL8 (41, 57). The implication of mast cell–produced CXCL8 is particularly interesting, as BP lesions are often precipitated by exposure to UV light (58), and UV-B irradiation has been shown to selectively and specifically increase CXCL8 release from mast cells in vitro (59). Human BP is associated with elevated serum levels of IgE autoantibodies and the presence of eosinophils in blisters (which are also recruited in latephase Type I responses) (60, 61). In addition, passive transfer of IgE from BP patients into athymic mice elicits the development of erythematous plaques similar to those observed in BP (18). Taken together, these data support a role for IgE acting through mast cells in human BP. In Graves’ disease (GD), also considered a Type II disease, autoantibodies function in a distinctive manner. In GD, binding of autoantibodies to the thyroid-stimulating hormone
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Disease (type of HS)
Proposed self targets
Major animal models
Strongest evidence for mast cell (MC) involvement
References
Graves’ ophthalmology (II or I)
TSH receptor (TSHR)
Transfer of TSHRprimed splenocytes
MC infiltrates in orbital tissues in humans and mice
19
Bullous pemphigoid (II or I)
Hemi-desmosomal antigens BP20 and BP180
Transfer of anti-BP20 and -BP180 IgG
MC-deficient mice do not develop disease
41
Pemphigus vulgaris (II)
Desmogleins and desmoplakins
—
Increased MC numbers in human lesions
42
Rheumatoid arthritis (III)
Fc portion of IgG (rheumatoid factor)
Transfer of K/BxN serum
MC blockers used to treat human disease
43
MC-deficient mice not susceptible to disease
44
SLE (III)
Nuclear proteins
Pristane injection
Correlative evidence in human disease
Multiple sclerosis (IV)
CNS myelin proteins
EAE
Correlative evidence in human disease
45
MC-deficient mice have delayed onset and reduced EAE severity Insulin-dependent diabetes mellitus (IV)
Pancreatic β cell-derived Ag (IGRP)
NOD mouse and BB rat
Correlative evidence in human disease and animal models
46
MC-targeted therapy delays disease onset in BB rat Guillain-Barr´e syndrome (IV)
PNS myelin proteins
EAN
Increase in degranulated MC around peripheral nerves in EAN
47
MC-targeted therapy decreases EAN incidence and severity
48
Sjogren’s syndrome (N/A)
RNA-protein complexes, nuclear proteins
NOD and Id3 mice
In human disease, MC found in salivary glands
49
Systemic sclerosis (N/A)
Unclear; nuclear proteins?
“Tight-skin” (TSK) mouse
In human disease, activated MC found in skin
50
MC-targeted therapies improve disease in TSK mice
51–53
Autoimmune vasculitides (II, III, IV)
Unclear; nuclear proteins?
HgCl2 in BN rat
MC-targeted therapies reduce disease in rat model
54
Abbreviations: EAE, encephalomyelitis; EAN, experimental autoimmune neuritis; IGRP, islet-specific glucose-6-phosphatase catalytic subunit; NON, nonobese diabetic; PNS, peripheral nervous system; SLE, systemic lupus erythematosus.
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(TSH) receptor causes thyrocyte growth and increased thyroid hormone secretion, thus causing clinical symptoms of hyperthyroidism (62). In addition to the lymphocytic infiltration of the thyroid, a large number of GD patients have localized connective tissue inflammation, which is thought to result from the underlying autoimmune process rather than from thyroid dysfunction. One of the most common forms of this connective tissue inflammation is Graves’ ophthalmology, in which inflammation in the periorbital space leads to edema, extraocular muscle dysfunction, swelling and redness of the conjunctiva, double vision, and corneal ulceration (63). In Graves’ ophthalmology, mast cells have been found to infiltrate the orbital tissue of the eye, and increased circulating levels of IgE (some TSHR-specific) (19) and SCF are observed in some patients (64). A murine adoptive transfer model of Graves’ ophthalmology also displays mast cell orbital infiltration, which precedes the appearance of lymphocytes (65). Mast cells are theorized to function in Graves’ ophthalmology as important sources of chemoattractants (e.g., IL-16 and CCL2), cytokines (e.g., IL-4, IL-5, IL-13), and B cell co-stimulatory signals (e.g., CD154) (19).
Mast Cells and Type III Hypersensitivities Antigen-antibody complexes mediate the major immune destruction in Type III hypersensitivities by depositing in organs and tissues, binding complement, and attracting macrophages and neutrophils. This immune complex formation and deposition can occur during prolonged infection, acute exposure to antigen, or autoimmunity. As in Type II hypersensitivity reactions, there are many reasons to suggest mast cells play a central role in these diseases. These include the ability of both antibodies and complement to activate mast cells resulting in the production of chemoattractant molecules that recruit the pathology-inducing effector cells. In addition, mast cells play an essential role in experi-
mental Arthus reactions. Although not autoimmune in nature, the study of these reactions has provided information on the mechanisms that underlie the common pathology of Type III hypersensitivity diseases. Arthus reactions occur when Ag-Ab complexes deposit in the skin, vasculature, serosa of organs, and the kidney glomeruli (66). They are rare occurrences during vaccination or other instances in which antigen is injected into a sensitized individual. The animal model most often used is the reverse Arthus reaction, in which a dose of antigen is given, followed by passive transfer of antigen-specific antibody (67). An inflammatory response quickly ensues and is characterized by edema, hemorrhage, and neutrophil infiltration. Mast cells were first implicated in a cutaneous Arthus response using W/Wv mice (68). When compared to wild-type controls, mast cell– deficient mice have decreased edema, neutrophil infiltration, and hemorrhage. Mast cell activation through FcγRIII is important for this response (69), as is mast cell activation by complement, which releases neutrophilattracting leukotrienes and TNF (70, 71). Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial membranes and articular structures of the joints. Rheumatoid factor, an autoantibody against the Fc portion of IgG, is considered an instigating factor in RA and a good marker for disease, although it is neither unique to RA nor present in all patients (72). Both Th1 and Th17 cells exert a major influence in this disease by helping generate a B cell antibody response and recruiting neutrophils, respectively (73). A commonly used murine model of RA, among several different ones (reviewed in 74), is induced by the injection of immune complex–rich serum from spontaneously arthritic K/BxN mice. This complement- and autoantibody-mediated disease is characterized by synovial inflammation and erosion of the joints. Mast cell–deficient mice do not develop disease in this model, although arthritis can be elicited after reconstitution of
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the mast cell compartment (44). Mast cell– derived TNF is implicated in disease pathogenesis, and anti-TNF therapies have been successful in humans (75). However, the ability of some TNF-null mice to develop arthritis after serum transfer suggests that other mediators are required and act in concert with TNF (76). The administration of IL-1 completely restores arthritic disease in W/Wv mice, despite an absence of mast cells (77). Mast cell IL-1 production in this serum transfer model is dependent on activation through the IgG receptor FcγRIII. Mast cells are normally present in the synovial compartments of healthy individuals as well as in RA patients, and in arthritic synovial tissue the mast cells increase in number and appear degranulated (reviewed in 78). High levels of tryptase and histamine have been detected in the synovial fluid of some RA patients. Newer treatments for RA aim to decrease inflammation by reducing mast cell numbers and activation. In mice, treatment with the mast cell–inhibiting drugs cromolyn or salbutamol decreases disease severity in susceptible animals (79). Imatinib mesylate, a tyrosine kinase inhibitor developed for the treatment of Bcr/Abl-positive cancers, acts on the c-kit tyrosine kinase receptor and induces apoptosis both in cultured mast cells and in those present in explant cultures of synovial tissue obtained from patients with RA (43). Imatinib prevents disease development and effectively treats established disease in a collagen-induced model of disease (80). Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease characterized by the production of a variety of antinuclear autoantibodies (reviewed in 81). Symptoms range from rash and arthritis to neuropathies and severe renal disease. Mast cell infiltrates are present in affected tissue from patients with SLE-mediated glomerulonephritis, which strongly suggests mast cell influence (82). Despite this correlative evidence in human disease, results in a pristane-induced model of disease do not support a pathologic role
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for mast cells. Upon intraperitoneal injection of pristane, an isoprenoid alkane, mice develop lupus autoantibodies, including antinRNP/Sm, anti-ribosomal P, anti-Su, antichromatin, anti-single-stranded DNA, and anti-double-stranded DNA (83–85). This is accompanied by the characteristic SLE symptoms including severe glomerulonephritis with immune complex deposition, mesangial proliferation, and proteinuria. In a small-scale study, W/Wv mice develop SLE symptoms that are of equal or greater magnitude to those of their wild-type counterparts (86), suggesting that mast cells have no role in disease or may actually exert a protective influence. However, pristane induction of disease may bypass the early mast cell–dependent events that initiate SLE in humans. Other models, including those utilizing the lupus-prone NZM or MRL mice, may provide a better system to evaluate disease development (81).
Mast Cells in Type IV Hypersensitivities Type IV hypersensitivity diseases, also called delayed-type hypersensitivities (DTH), are mediated by antigen-specific CD4+ T cells and generally occur several days following the initial exposure to antigen. Activated T cells migrate to the target tissue site, where they release cytokines and chemokines that recruit other inflammatory cells. Contact dermatitis (e.g., a poison ivy response) and the clinical tuberculin test are common examples of DTH, as are some classic T cell–dependent autoimmune disorders. Murine models have shown that mast cells can make important contributions to cutaneous DTH (87, 88), suggesting they may play a role in other T cell–dependent diseases. Multiple sclerosis (MS), a CNS demyelinating disease, is among the most common of the autoimmune diseases (reviewed in 89). MS patients exhibit multicentric CNS lesions that correspond to destruction of the myelin sheaths surrounding nerve axons. These myelin sheaths insulate nerve axons,
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facilitating the saltatory conduction necessary for transmitting nerve impulses over long distances. This loss of nerve impulse transmission accounts for the clinical problems defining MS including loss of visual acuity and other sensory disturbances, weakness, difficulty with fine and gross motor movements, as well as bowel and bladder incontinence. MS and the prototypic murine model of the disease, experimental autoimmune (also termed allergic) encephalomyelitis (EAE), are both CD4+ T cell–mediated diseases that demonstrate MHC-linked and gender-linked susceptibility (89). Although the eliciting agent is not known in MS, immunization with a myelin peptide (MBP, myelin basic protein; PLP, proteolipid protein; or MOG, myelin oligodendrocyte glycoprotein) in complete Freund’s adjuvant (CFA) generates EAE in genetically susceptible rodents. Activation of naive myelin-specific T cells occurs primarily in peripheral lymphoid organs in humans as well as mice, and the accompanying increase in blood-brain barrier (BBB) permeability allows a massive influx of inflammatory cells, including both antigen-specific and naive T cells, macrophages, and dendritic cells (DCs), into the CNS (90). Stimulation of autoreactive T cells by myelin epitopes in the brain and spinal cord initiates a local inflammatory response, profoundly damaging CNS tissues. The clinical disease phenotype varies from a chronic progressive to relapsing-remitting course. In mice this is dependent on the genetic strain and the peptide used to induce disease (91). There are several differences between the rodent model of disease and its human counterpart, including unique sites of demyelination and a different composition of the cellular infiltrate present in pathological plaques (92). Still, EAE is considered by most immunologists to be a useful model of MS pathology and has allowed identification of several therapeutic targets (93). Adoptive transfer of IFN-γ-producing autoreactive CD4+ T cells into naive mice causes disease and has been cited repeatedly as proof of the dogma that Th1 (IFN-γ-
producing) cells are the major effector cells in EAE (and presumably MS). However, that IFN-γ−/− mice paradoxically develop worse disease complicates this paradigm (94). Recently, Th17 cells were shown to orchestrate the inflammatory cascade in the CNS in EAE, presumably by recruiting monocytes and other innate immune cells to the site of inflammation (95). Th17 cells originate from the same naive precursors as Th1 and Th2 cells, but differentiate under the influence of TGF-β and IL-6, rather than IL-12 and IL-4, respectively (96–98). The Th17 pathway appears to be exclusive; addition of IFN-γ or IL4 to the culture medium inhibits production of IL-17 (97, 98). Although IFN-γ-producing cells may contribute to established inflammation, loss of potential for Th1 differentiation that occurs in IFN-γ−/− mice may “shunt” T cells toward the Th17 pathway and thus worsen disease. The data supporting a role for mast cells in the pathogenesis of MS and EAE are compelling. In both the murine and human disease, mast cells accumulate at sites of inflammatory demyelination in the brain and spinal cord and are often found degranulated (99). High levels of tryptase, a mast cell–specific proteolytic enzyme, and histamine are found in the cerebrospinal fluid of MS patients, suggesting mast cell activation (100, 101). Gene-expression profiling demonstrates that transcripts encoding the histamine 1 (H1) receptor, as well as the mast cell–specific genes tryptase and FcεRI, are highly expressed in CNS plaques of patients with chronic MS (102). The most direct evidence that mast cells are involved in this disease syndrome comes from studies using mast cell–deficient mice. Under defined disease induction conditions, W/Wv mice display a very mild disease and delayed onset when compared to their wildtype littermates (Figure 3) (45). The entry of CD4+ and CD8+ T cells into the CNS also appears compromised in W/Wv mice (103). Selective mast cell reconstitution of W/Wv mice through intravenous transfer of BMMCs
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Figure 3 Mast cell–deficient mice exhibit reduced EAE disease severity. EAE was induced by immunization with MOG35−55 in CFA (complete Freund’s adjuvant). Wild-type, W/Wv , and W/Wv mice reconstituted with BMMCs were scored daily according to the following clinical scoring system: 0, no clinical disease; 1, tail flaccidity; 2, hind limb weakness; 3, hind limb paralysis; 4, fore limb paralysis or loss of ability to right from supine; 5, death (45). (Figure reproduced from J. Exp. Med. 2000, 191:813–22, with permission.)
restores severe disease susceptibility. This occurs despite the inability of intravenous mast cell reconstitution to appreciably repopulate CNS mast cells, indicating that mast cells can exert effects at other sites outside the target tissue in this experimental model (104). Indeed, as discussed below, mast cells exert profound effects on the initiation of peripheral T cell responses as well as on their effector function. Insulin-dependent diabetes mellitus (IDDM), also called type 1 diabetes, is a chronic metabolic disorder that develops in two discrete phases and is mediated in part by CD8+ T cells (reviewed in 105). Prior to clinical signs of disease, a mixed population of leukocytes invades the pancreatic islets resulting in insulitis. The consequent destruction of the insulin-producing β cells of the pancreas leads to hyperglycemia. There are several rodent models of IDDM (106). In experimental chemical diabetes, toxins such as alloxan or streptozotocin are injected into an animal, selectively killing 716
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insulin-producing pancreatic β cells. Both the nonobese diabetic (NOD) mouse and the BioBreeding (BB) rat spontaneously develop insulitis that ultimately progresses to IDDM at a high frequency. There are several reasons to suspect that mast cells are implicated in IDDM. Mast cells are normal residents within the pancreatic ducts, placing them in close proximity to the pancreatic islets (107). There is a striking increase in the frequency of mast cells in the acinar parenchyma in inflammatory diseases of the pancreas such as chronic pancreatitis and pancreatic cancer, and this cellular increase correlates positively with the extent of inflammation (107–109). Mast cells produce several mediators that could affect the development of diabetes, including oxygen intermediates and proteases, which may have direct actions on the destruction of the β islet cells. Release of leukotriene B4 (LTB4), a mast cell–derived chemoattractant that may be essential for efficient recruitment and/or retention of autoreactive T cells in the target organ, is increased in type 1 diabetes (110). The ability of mast cells to regulate the development of CD8+ T cell responses in other disease models suggests another possible mode of action in diabetes (103). Of most significance is the finding that more mast cells are present in the pancreatic lymph nodes of lymphopenic diabetic BB rats prior to disease onset (compared to lymphosufficient littermates). This correlates with overexpression of mast cell transcripts in these mice (46). In addition, treatment of spontaneously diabetic BB rats with cromolyn delays disease onset. The influence of mast cells in IDDM may be more complicated than simply increasing inflammation or enhancing CTL function. Mast cells produce TNF and TGF-β, cytokines that can be proinflammatory but also regulate T cell tolerance to autoantigens in some models of diabetes (111, 112). Mast cells also express PD-L1 (15), an inhibitory molecule implicated in protection from disease (113).
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Guillain-Barr´e syndrome (GBS), a T celldependent demyelinating autoimmune disease of the peripheral nervous system (PNS), is usually preceded by illness, most commonly infection with Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, or Mycoplasma pneumoniae (114). All of these pathogens possess lipo-oligosaccharides in their bacterial walls that resemble gangliosides found in peripheral nervous tissue, indicating that molecular mimicry is important in the initiation of this disease (115). As a result, innate immune cells are activated and B and T cells respond to both the microorganism and its conjugate gangliosides in the host tissue, leading to eventual peripheral nerve myelin destruction. Experimental autoimmune neuritis, the rodent model of GBS, is generated through immunization with a PNS myelin peptide in CFA (116). After immunization, inflammatory cells infiltrate the PNS, leading to demyelination of axons, weakness, and, occasionally, paralysis. Directly preceding onset of symptoms, there is a marked increase in the number of degranulated mast cells around the affected peripheral nerves (47). The activation and proliferation of nerve-associated mast cells are also observed after adoptive transfer of a neuritogenic P2 protein-specific T cell line into Lewis rats (117), and treatment with a mast cell–stabilizing drug decreases the incidence and severity of disease (48).
MAST CELLS IN OTHER AUTOIMMUNE DISORDERS There is evidence for mast cell involvement in a variety of other diseases with autoimmune components that do not fit neatly into the Type I–IV hypersensitivity classification. Systemic sclerosis (SSc), or scleroderma, is characterized by symptoms that include excessive collagen accumulation and vascular lesions in the skin and the internal organs, causing thick, indurated skin and often progressing to pulmonary hypertension or renal crisis (118). Antinuclear and antinucleo-
lar autoantibodies, along with putative new pathogenic autoantibodies, including antiendothelial cell antibodies and antiplateletderived growth factor receptor antibodies, are present in a high percentage of SSc patients (119). Activated tryptase-producing mast cells have been found in the skin of human patients with SSc (50) and have been implicated as a source of fibrogenic cytokines, including TGF-β, and fibroblast-attracting proteases (120). Increased mast cell density and degranulation are observed in the “tight skin” mouse model of SSc (121), and dermal fibrosis is reduced after treatment with mast cell stabilizers (52, 53) or a mast cell chymase inhibitor (51). The latter acts to prevent the cleavage of TGF-β into its active form. Mast cells also appear to play important roles in inflammatory bowel disease, namely ulcerative colitis (UC) and Crohn’s disease (CD). Although there is some debate on whether these diseases are “true” autoimmune diseases, as the eliciting antigens are hypothesized to be part of the normal gut flora, these diseases clearly result from exaggerated immune responses to nonpathogenic antigens in genetically susceptible individuals (reviewed in 122). Tissue from UC patients shows mast cell aggregation along the line of demarcation dividing inflamed from healthy tissue (123). An increase in mast cell density in involved tissue of CD patients has been well documented (124), and mast cells are thought to modify the inflammatory CD process through release of histamine (125), TNF (126), and the T cell chemoattractants XCL-1 (127) and IL-16 (128).
HOW DO MAST CELLS INFLUENCE AUTOIMMUNE DISEASE? Despite substantial evidence that mast cells are critical players in the pathogenesis of autoimmunity, their precise mode of action is, for the most part, still a subject of speculation. We know a great deal about how mast cells influence innate and adaptive immunity in
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MAST CELLS, STRESS, AND AUTOIMMUNITY Another link between autoimmunity and mast cells lies in the tendency for many of these diseases to flare during times of stress. Corticotropin-releasing hormone (CRH) is produced by the paraventricular nucleus of the hypothalamus in response to stress and initiates a hormonal cascade that results in activation of the sympathetic system and release of epinephrine and norepinephrine. CRH is localized in inflamed tissues, and mast cells possess both receptors for CRH (194) and the ability to release CRH de novo (195). CRH causes release of VEGF (vascular endothelial growth factor) from mast cells in vitro (196). The promotion of angiogenesis and subsequent regional inflammation is another way by which mast cells can contribute to disease pathology.
infection and allergy. Assuming that there are commonalities in all immune responses, much of this information can be applied to understanding the role of these cells in autoimmunity. Although not required for all responses, mast cells are perfectly situated to directly affect many cell types and play a responseamplifying role. Of importance, mast cells are not just proinflammatory but can also dampen an immune response directly through expression of certain cytokines such as IL-10 or TGF-β or indirectly by facilitating T regulatory cell (Treg) activity.
Overview of a Prototypic Adaptive Immune Response During an infection, immature DCs residing in peripheral tissues such as the skin, airways, and gastrointestinal tract capture and process microbial antigens during routine sampling of the environment. Pathogens also activate DCs via cell surface or intracellular PRRs, triggering DC maturation and migration to the secondary lymphoid organs. Here DCs present microbial-derived peptides in the context of the class II MHC to naive T cells initiating T cell activation, clonal expansion, and dif718
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ferentiation (Figure 4) (129). DCs are also crucial for priming cytotoxic CD8+ T cells through the presentation of exogenous Ag by class I MHC. Mature DCs secrete cytokines such as IL-12, IL-23, TGF-β, and IL-6, providing CD4+ T cells with differentiation signals for at least four alternative pathways: Th1 (IL-2- and IFN-γ-producing), Th2 (IL-4-, IL-5-, and IL-13-producing), Th17 (IL-17producing), or Treg (Foxp3-expressing) cells. The differentiation process gives rise to effector T cells that have acquired the ability to leave the lymph nodes and, informed by cellderived mediators in the tissue, home to sites of inflammation. Similar events generate the antigenspecific T and B cells that mediate autoimmune responses. However, beyond the distinct target antigens in such responses, it is not clear what distinguishes pathologic from protective responses. Self-proteins are not normally immunogenic because of multiple mechanisms that act to maintain tolerance. In addition, how the DC co-stimulatory signals required for generating fully activated T cells are elicited is unclear, although there is evidence that infection may be involved and can initiate or exacerbate both allergic and autoimmune responses (130).
Mast Cells Exert Influence at Multiple Disease Checkpoints in EAE The study of mast cell influence on EAE disease course provides an excellent framework for dissecting mast cell actions on adaptive immune responses. It is postulated that mast cells act at several checkpoints in disease development. These include events at the peripheral sites of antigen exposure that regulate DC function, in secondary lymphoid organs where T cells are primed and differentiated, at the BBB where inflammatory cell efflux into the CNS is controlled, and within the CNS where myelin and nerve damage occurs (131). Several aspects of the T cell response to myelin peptide in MOG35−55 –induced EAE
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Ag capture Migration and maturation
Ag:MHC presentation with CD80/86
Clonal expansion and acquisition of T cell effector function
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TLR activation
DC release of IL-12, IL-23, IL-6, or TGF-β regulates Th cell fate decision
Figure 4 A prototypic adaptive T cell immune response. At the onset of a typical infection, dendritic cells (DCs) in peripheral tissues capture and process antigens before migrating to local secondary lymphoid organs where they present antigen to T cells and elicit T cell differentiation and proliferation. The effector T cells then leave the lymph node and home to areas of inflammation. Mast cells have the potential to affect all of these events.
appear to be defective in W/Wv mice and can be corrected by mast cell reconstitution (103). First, there is a marked absence of normal lymph node hypertrophy after immunization, due in part to reduced numbers of T cells that enter and undergo clonal expansion. There is a reproducible though not statistically significant defect in the induction of MOG-specific IFN-γ and IL-17 production by CD4+ T cells postimmunization in the lymph node and spleen of W/Wv mice (103; B.A. Sayed & M.A. Brown, unpublished observation). Ex vivo analysis of whole spleen cultures reveals that both IL-4 and IFN-γ levels are significantly diminished in W/Wv mice compared to their wild-type littermates. The normal activation-induced increases in CD11a, CD44, and CD54 are also reduced. Most striking are the differences in antigen-specific T cell influx into the CNS beginning as early as day 8 post disease induction (B.A. Sayed & M.A. Brown, unpublished observation). W/Wv mice exhibit five- to seven fold decreases in the numbers of CD4+ and CD8+ T cells that enter the CNS, an observation that corresponds to reduced inflammation and
demyelination in the brain and spinal cord (45, 103). It has been definitively established that these differences in T cell response are not due to an inherent defect in W/Wv T cell function: W/Wv mice display normal T cell development in the thymus and numbers of peripheral CD4+ and CD8+ T cells (103) that are comparable to those of wild-type littermates. Furthermore, in vitro differentiation of W/Wv - or wild-type-derived T cells shows that similar Th1 and Th17 cytokine production and transfer of self-reactive encephalitogenic CD4+ T cells from W/Wv or wild-type mice cause equivalent disease in naive T cell–deficient hosts (103; B.A. Sayed & M.A. Brown, unpublished observation).
DC–Mast Cell Interactions in the Initiation of an Immune Response DCs are likely to be one of the earliest target cells of mast cell influence. Mast cells are found in close apposition to DCs in all tissues except blood and are thus subject to the same microbial activation signals as DCs during infection. The induction of EAE depends on the
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concurrent administration of myelin peptide and CFA. Heat-killed Mycobacterium tuberculosis, a component of CFA, serves as an initial DC- and mast cell–activating stimulus in the periphery. LPS, PGN, zymosan, and dsRNA are among the microbial-related agonists that may be relevant in other infection-associated autoimmune responses. A large body of evidence documents the effects of mast cells on DCs in infection and contact hypersensitivity settings, where mast cell activation through PRRs affects DC migration, maturation, and function. This is a probable mechanism whereby mast cells exert a major effect on T cell responses in EAE and other autoimmune diseases (Figure 5). Like mast cells, DCs are quite heterogeneous (reviewed in 132). Thus the responses of DCs to mast cell interaction are likely to be variable as well. They are broadly classified into either myeloid (mDCs) or lymphoid (lDCs) based on the precursor cell from which they are derived. DCs present in the thymus are thought to develop from both myeloid and lymphoid precursors, whereas peripheral DCs arise almost solely from myeloid precursors. mDCs are considered most important for both T cell priming and tolerance; however, there appears to be some plasticity between the phenotype and function of the two subsets. The myeloid subset of DCs can be further classified into Langerhans cells (LCs), found in skin and other stratified epithelia, and interstitial DCs (iDCs), found in most other organs. A third DC subset, plasmacytoid DCs (pDCs), may originate from either lymphoid or myeloid precursors and are located with iDCs in blood and peripheral tissues. Upon activation, there are impressive changes in the expression of co-stimulatory markers and mediators in mast cells (see Table 2) that are particularly relevant to DC function. For example, mast cells can release relatively large amounts of both PGE2 and TNF within minutes of activation. Both of these mediators have the ability to alter DC cell migration and lymph node hypertrophy (133, 134). The importance of mast cell–
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derived TNF was shown in a footpad infection model in Escherichia coli, in which mast cell–deficient mice fail to exhibit the characteristic hypertrophy of draining lymph nodes (135). Reconstitution with wild-type but not TNF-deficient mast cells restores the wildtype phenotype. Similarly, following subcutaneous injection of PGN, lymph node hypertrophy and DC mobilization in vivo are mast cell–dependent phenomena, although this response appears to be TNF-independent (136). Contact hypersensitivity (CHS) responses to chemical haptens are highly dependent on the local density and migratory properties of epidermal LCs. In these responses, the mast cell can be activated through FcεRI crosslinking or via monomeric IgE binding to this receptor (158, 159). Following sensitization and challenge with the hapten FITC, both W/Wv and TNF−/− mice exhibit deficits in the CHS response and show significant delays in the migration of haptenated DCs into draining lymph nodes (133). Engraftment of mast cell–deficient mice with wild-type but not TNF−/− BMMCs repairs the DC migration defect. Histamine released from mast cells may also contribute to LC migration from the skin to draining lymph nodes. After passive sensitization with IgE, mast cell– deficient mice challenged with antigen show significant defects in LC activation and trafficking to draining lymph nodes, which are repaired by mast cell reconstitution (160). Treatment of wild-type mice with cimetidine, an H2 (histamine 2) receptor antagonist, inhibits the observed IgE/Ag-induced LC migration, implicating mast cell–released histamine. DC migration goes hand in hand with maturation, defined as inducible changes in cytokine, chemokine, or cell surface marker expression. Mast cells also affect DC maturation and ultimately influence the ability of DCs to direct the quality of Th cell differentiation through the expression of inducible mediators. Histamine, perhaps the best-known mast cell mediator (although other cells can make it), has profound effects on DCs and Th
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a
Mast cell
TLR activation
(–)
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Ag:MHC II
(+) Histamine IL-10 TGF-β PGD2, PGE2
TNF IL-4 IL-12 TSLP
CD40L CD40
Maturation
No maturation Dendritic cell (immature)
b
CD80/86 Ag:MHC II
PD-L2 OX40L
Th1-inducing IL-4, IL-12, IL-25, TSLP Th2-inducing Histamine, PGD2, PGE2, IL-18
Mast cell
DC
Naive CD4+ T cell
Regulatory T-inducing TGF-β, IL-10 Th17-inducing ? Figure 5 (a) A model for mast cell influence on DC responses I. Both mast cells and DCs are activated by microbial antigens through TLRs. The outcome of the response, DC maturation or suppression of the maturation process, is regulated by the predominant mediators and cell surface molecules expressed by locally activated mast cells. (b) Mast cell influence on DC responses II. Mast cells express mediators that act to “polarize” the DC and therefore ultimately influence naive CD4+ T cell fate decisions.
cell fate decisions. Immature and mature DCs (from human blood) express all four histamine receptors (H1–H4) (161). Histamine as well as PGD2 , PDE2 , and leukotrienes suppress DC IL-12 production in vitro (134, 140, 144, 145). Histamine also inhibits TLR-mediated
induction of other DC-produced cytokines, including IFN-α, IL-1α, IL-1β, IL-18, IL-6, CXCL10, CCL20, CCL5, and TNF and increases the expression of CXCL8 and IL-10 (140, 162). Antigen uptake and presentation by DCs (163) and DC chemotaxis (137)
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Mast cell-derived factors and their effects on DCs
Mast cell-derived factor
Effect on DCs
Leukotrienes Prostaglandins
IL-4
137
Promotes Th2 skewing of T cellsa
138–140
Enhances migrationa,b,c
141–143
Increases IL-10 and decreases IL-12c
144
PGD2 : decreases IL-12 and promotes Th2 skewingc
145
PGE2 : increases IL-10c
134
migrationa
146
Essential for
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References
Decreases IL-12a
Histamine
Increases production of Th2-attracting chemokinesa
147
Inhibits maturation of DC during infectionb
148
Decreases IL-10 leading to increased IL-12c
149
Decreases prostaglandin E productiona
150
Enhances DC migrationb
TNF
133, 136
Produces tolerogenic DC that induce Tregsc TGF-β
Promotes DC generation of
CD4+ CD25+
Tregsc
151 152
Increases expression of chemokine receptorsa
153
Essential for generation of LCsb
154
TSLP
Promotes inflammatory Th2-skewing of T cells by ex vivo human DC
155
Serotonin
Differentiates DC with reduced stimulatory capacity but increased cytokine productiona
156
Heparin
Differentiates CD1a+ DCa
157
a
Human monocyte-derived DC, in vitro. Murine DC, in vivo. c Murine DC, in vitro. b
are enhanced by histamine as well. In vivo, protocols that induce mast cell degranulation (and elicit histamine release) coincident with immunization result in a polarized Th2 response (164). In contrast, mast cell– derived IL-4 is necessary for severe disease and an optimal Th1 response in MOG35−55 –induced EAE (165). The finding that IL-4 promotes IL-12 expression by inhibiting IL-10 transcription in DCs (149) may explain this seemingly paradoxical observation. Activated mast cells release many cytokines that alter the expression of DC activation markers as well. For example, TNF induces increases in IFN-γR, CD40, ICAM1 (CD54), MHC class II, and CD86 in vivo, a finding that corresponds to accelerated autoimmune disease in NOD mice (166). Thymic stromal lymphopoietin (TSLP), an 722
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epithelial-derived cytokine, is also expressed by mast cells and has potent effects on DCs. These effects include ability to induce OX40 ligand expression resulting in a DC population that preferentially converts DCs to a Th2-polarizing antigen-presenting cell (167). Although a mast cell source for these cytokines has not been confirmed in vivo, the coculture of activated mast cells and human DCs in vitro results in impressive increases in CD80, CD86, CD83, CCR7, and MHC class I and class II expression on DCs (139).
Direct Mast Cell Effects on Initiating the T Cell Response Mast cells may directly regulate T cell priming in a number of ways (Figure 6). Peripheral mast cells in the skin and mucosa and secondary lymphoid system are the most
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Ag presentation? Co-stimulation
Naive CD4+ T cell TGF-β IL-6 IL-21 IL-23 IL-12 IL-4
TGF-β IL-10, IL-2 IL-12, IL-4 IL-6, IFN-γ
IL-4 IL-12
IFN-γ IL-12 Histamine IL-4
Th17
Th1
Regulatory T cell
Th2
Figure 6 Direct mast cell–T cell interactions. MHC class II and T cell co-stimulatory molecule expression by mast cells provides potential antigen-presenting cell capability. Mast cells also express most cytokines that control T cell differentiation pathways and directly regulate T cell fate decisions.
likely orchestrators of these early effects. Some mast cell lines can be induced to express MHC class II molecules and have been shown to have antigen-presenting capability in in vitro settings (168, 169). Mast cells could also provide direct costimulation to T cells within the secondary lymphoid organs via their expression of CD80, CD86, CD153, ICOSL, 41BB, CD40L, and OX40L or enhance T cell proliferation and expression of activation markers through elaboration of cytokines such as IL-2, IL-4, IL-7, and IL-15 (15). Mast cells express all of the cytokines (IL-12, IL-6, IL-4, IL-1, IL-21, IL-23, IL25, and TGF-β) implicated in Th polariza-
tion and may augment DC-derived cytokine contributions to Th differentiation decisions. Furthermore, histamine has been shown to have direct effects on T cell differentiation (170). CD8+ T cells have been implicated in both the exacerbation and suppression of EAE and MS in a number of studies (171, 172), and the effects of mast cells are not limited to CD4+ T cell responses in EAE. W/Wv mice also generate a diminished primary CD8+ T cell response. CD8+ T cell cells primed in mast cell– deficient mice express significantly decreased amounts of IFN-γ and CD44 post-MOG immunization (103). The requirement of mast
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cells for the initiation of strong CD8+ T cell responses has implications not only for EAE but also for diseases such as type I diabetes, where CD8+ T cells are among the major effector cells and play a role in the direct cytotoxic destruction of insulin-producing pancreatic β cells.
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In addition to influencing migration to lymph nodes, mast cells can recruit DCs to sites of tissue inflammation. Cross-linking of FcεRI on mast cells induces the release of the CCL1 chemokine, which acts to recruit LCs bearing the CCL1 receptor, CCR8, to sites of allergic inflammation (173). Mast cells also express CCL19 (174), the ligand for CCR7, a chemokine receptor required for DC migration (175) and highly expressed by myeloid DC present in inflamed CNS lesions in MS (176). These findings may have relevance to relapsing-remitting models of EAE, including Theiler’s murine encephalitis virus– and PLP-induced disease in SJL mice. In these models, the activation of naive myelin-specific T cells in the CNS is dependent on the directed migration of peripheral myeloid DCs to the CNS (177). Here the DCs present new myelin epitopes distinct from those used to induce disease. This directed migration and subsequent activation of T cells with new antigen specificities are thought to make a major contribution to epitope spreading. Mast cells also appear to orchestrate the migration of T cells (Figure 7). Entry of autoreactive T cells into the CNS is a checkpoint in disease development. The ability of both antigen-specific and bystander CD4+ and CD8+ T cell populations to migrate to the CNS is compromised in W/Wv mice (103; B.A. Sayed & M.A. Brown, unpublished observation). This defect correlates with decreased peripheral T cell expression of early activation/homing markers including CD44, CD11a, and CD54, molecules that
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regulate leukocyte adhesion and are implicated in EAE, in W/Wv mice. Mast cells could influence T cell migration into the CNS in several ways: (a) During the initiation of the response, mast cells may affect DC maturation and indirectly regulate the activation state of T cells. In the absence of mast cells, DCs may not effectively prime T cells, resulting in defects in T cell homing potential and cytokine production. (b) Resident mast cells in the target organ (in the case of EAE, the CNS) may become activated and release chemoattractants such as LTB4, CCL3, CCL2, CCXCL10, CCL19, and CCL21, all of which have been implicated in T cell recruitment in EAE and MS (178). Mast cell– derived LTB4 is essential for the recruitment of both CD4+ and CD8+ effector cells to sites of inflammation through interaction with BLT1 expressed on T cells in an in vivo model of airway hyperresponsiveness (179). In vitro T cell migration studies support this finding (180). (c) Local perivascular mast cells may release vasoactive amines including histamine and serotonin that increase the BBB permeability, allowing the more efficient influx of T (and other) cells to the CNS. (d ) Mast cells express matrix metalloproteinases (MMPs) and, via chymase and tryptase, convert them to active forms that promote collagen breakdown at the underlying basement membrane, allowing transendothelial passage (181). It is postulated that upon disease induction in W/Wv mice, T cells do not acquire adequate expression of relevant homing molecules, and we speculate that the lack of chemotactic factors and factors regulating endothelial permeability normally produced by resident CNS mast cells leads to inefficient breach of the BBB. Thus, the infiltration of the CNS by inflammatory cells is compromised. Because IL-17 acts as a chemotactic factor for many innate inflammatory cells, inefficient migration of Th17 cells into the CNS may limit the extent of inflammation, myelin degradation, and disease pathology.
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CNS
Basement membrane degradation (proteases)
Vascular permeabilization (histamine, serotonin)
New myelin epitope release
Reactivation of effector T cells
Chemotaxis (CCL3, CCL2, CXCL8, LTB4) Myelin repair (NGF)
Figure 7 Model for mast cell influence on inflammatory events in the target tissues in autoimmunity. Mast cell mediators produced at the site of inflammation regulate immune cell effector function subsequent to initial T cell activation events. Proteases (chymase and tryptase) facilitate the degradation of endothelial cell basement membranes by cleaving MMPs to active forms. Together with histamine and serotonin, which increase vascular permeability, and chemotactic factors, these mediators regulate entry of immune cells into the target tissue (in this case the CNS). Mast cell proteases can act to promote epitope spreading by directly degrading the myelin sheath, resulting in tissue damage and release of new myelin epitopes that are presented by resident or infiltrating DCs to naive or effector T cells. Paradoxically, mast cells also release nerve growth factor (NGF), which could play a role in nerve axon remyelination.
Direct and Indirect Influence of Mast Cells on T Cell Tolerance In autoimmunity, there is a breakdown in one or both of the two major systems that operate to prevent large-scale self-reactive T cell– mediated responses. The first occurs during T cell development when mechanisms exist to delete such T cells in the thymus, collectively referred to as central tolerance or negative selection (182). This process is imperfect, as self-reactive T cells often escape deletion in healthy individuals. Central tolerance is augmented by peripheral tolerance mechanisms that either induce anergy (nonresponsiveness) in relevant T cells or utilize specialized populations of Tregs that inhibit effector T cell function (reviewed in 183). Virtually nothing is known about mast cells in central tolerance, though they populate the
thymus and could conceivably play a role in negative selection. However, recent work has clearly implicated mast cells in peripheral tolerance through their effects on a subset of Tregs. The Tregs encompasses a variety of cellular entities. Tregs can be divided into two general classes: naturally occurring thymic– derived Tregs and inducible or adaptive Tregs (183). The suppressor phenotype of naturally occurring Tregs and some inducible Tregs is controlled by the expression of the forkhead/winged-helix transcription factor, Foxp3. Mutations in the Foxp3 gene lead to hyperactivation of the immune system and multiorgan autoimmune disease in humans (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: IPEX) and in mice (scurfy) (184, 185).
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The best evidence for mast cell–dependent Treg-mediated suppression comes from studies in a murine skin transplant model in which mast cells are crucial intermediaries in maintaining CD4+ CD25+ Foxp3+ Treg– dependent tolerance (186). In this model, mice receive an intravenous injection of allogeneic donor lymphocytes together with anti-CD154, followed by a skin transplant from the allogeneic donor. Serial analyses of gene expression experiments demonstrated that genes encoding several mast cell products including IL-10, FcεRI, CCL2, and CCL12 are highly expressed in cultures of tolerant allografts, a finding that coincides with an influx of mast cells to the graft. Mast cell–deficient mice cannot be rendered tolerant and are unable to sustain allografts. Graft tolerance coincides with cross-talk between Tregs and mast cells; Treg secretion of IL-9, a mast cell growth factor, promotes mast cell recruitment to and activation in tolerant grafts. How mast cells then promote Treg expansion and/or survival is not yet clear.
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Other Antiinflammatory Roles of Mast Cells Mast cells can also directly suppress inflammation through the expression of IL-10. Mast cell–deficient mice (both W/Wv and W-sash) exhibit stronger CHS responses to urushiol, the allergen-bearing sap derived from poison oak (Toxicodendron diversilobum) and poison ivy (Trichomanes radicans), than their wild-type counterparts (187). At days 5 and 10 post challenge, untreated mast cell–deficient mice and those reconstituted with IL-10−/− BMMCs showed increased epidermal ulceration and necrosis and dermal leukocytic infiltration as compared to controls, revealing that mast cell production of IL-10 is required for limiting inflammation and decreasing the swelling associated with urushiol. Engraftment of mast cell–deficient mice with FcRγ−/− BMMCs, which lack expression of both FcεRI and FcγRIII, fails to reconstitute the suppressive effect, indicating 726
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that mast cells are activated through Fc receptors in this model. Dermal mast cells and mast cell–produced IL-10 plays a similar suppressive role in reducing inflammation in response to chronic UV-B irradiation.
Mast Cells at Sites of Tissue Destruction Among the several ways that mast cells can act directly within target tissue to regulate autoimmune disease severity is the ability to bestow direct damage on local tissue structures. Mast cells are the sole source of several proteolytic enzymes such as tryptase and chymase. Microarray analysis revealed that there is a substantial increase in expression of the gene encoding tryptase in plaques of MS patients when compared to nondiseased areas, suggesting that this enzyme has a critical role in local pathology (102). Mast cell proteases can degrade myelin in vitro, which leads us to speculate that mast cell activation in the CNS during the effector phase of disease (through peptides, cytokines, antibody, or complement, for example) contributes to the release of new myelin epitopes and epitope spreading (188) (Figure 4). Tryptase may also act through PAR2, a protease-activated receptor. PAR2 is expressed on several types of immune cells as well as on dorsal root ganglion neurons and spinal afferent nerve fibers (189). In neurons, tryptase elicits release of neuropeptides such as SP and CGRP. These in turn have the potential to promote activation of many other immune cells, resulting in the initiation or exacerbation of the inflammatory cascade. As in the periphery, when naive cells activated within the CNS come under the influence of specific cytokines, they undergo differentiation.
Variable Mast Cell Responses: Can This Explain Diversity in Mast Cell Influence? The major themes in this review encompass the idea that mast cells are multifunctional
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cells, are widely distributed in many tissues, and express a large array of mediators and costimulatory molecules. Most important, mast cells are tuneable; that is, depending on the physiologic setting, mast cells will respond variably (4). These differences in responsiveness translate to the distinct effects mast cells exert in specific disease conditions. For example, most features of mast cells are consistent with their primary role as proinflammatory cells and players in the breakdown of peripheral tolerance, yet two models of “tolerogenic” mast cells provide convincing evidence otherwise. There are many examples of this variability, but because most mast cell responses are assessed in vitro or ex vivo, the picture we have now is probably still very simplistic. At least four key factors influence the heterogeneous responses of mast cells: (a) The anatomic sites of specific mast cell populations confer a unique tissue-specific phenotype. A well-known illustration of this is the classification of connective tissue versus mucosal mast cells that differ not only in their preferred sites of residence but also in the expression of granule proteases and relative life span. (b) Related to the distinct locations of mast cells are the unique subsets of target cells in different tissues adding to response variability. Distinct populations of DCs could have unique phenotypic responses to the same mast cell products. (c) A vast number of agonists are able to activate mast cells, and these can elicit distinct responses. It is the convergence of multiple signals that dictates the final response of a single mast cell. For example, the classical FcεR-mediated response activation can be modified by co-stimulatory pathways, such as those triggered by 4-1BB agonists (10). In vivo, the tolerogenic response of mast cells in the skin transplant model occurs in the absence of discernible infection, unlike most proinflammatory responses. In this setting, Tregs may “educate” and expand pop-
NERVE GROWTH FACTOR: A MECHANISM OF MAST CELL PROTECTION? Nerve growth factor (NGF) is a cytokine produced by several cell types, including mast cells, that has protective effects in EAE and MS (197, 198). Administration of NGF systemically or locally within the CNS reduces EAE disease severity (199). It is highly expressed in cerebral spinal fluid during acute EAE and MS and levels decrease coincident with remitting episodes. NGF is involved in the survival and differentiation of both CNS and peripheral neurons (200) and has been implicated in myelin repair and regulating Th1 and Th2 balance within the CNS in EAE and MS (201). Thus, in contrast to their many proinflammatory effects, mast cells may act to negate the immune-mediated damage under certain circumstances through expression of nerve growth factor. ulations of tolerogenic mast cells by secretion of IL-9 and other factors. Conversely, pathogen-derived stimulatory signals, as in EAE, may push mast cells toward generating predominately proinflammatory signals. (d ) Genetically determined variability in mast cell numbers and responses may confer strikingly distinct response outcomes. SJL mice are estimated to have 4–5 times more mast cells than C57BL/6 mice have (190). A study of Th2 cytokine expression in C57BL/6, Balb/c, and SJL mice showed striking differences in the ability of BMMCs to express IL-4 and IL-5 (165). Although all these variables can explain the unique responses mast cells exert in different settings, there is still much to learn. It is worth reiterating that animal studies provide imperfect models of human disease. If the heterogeneity in mast cell populations between various murine strains affects disease susceptibility, this effect is likely amplified in mast cell populations from unique outbred humans. Thus, caution must be exercised when developing paradigms of mast cell function.
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SUMMARY POINTS 1. Mast cells are present in many tissues and collectively constitute a significant cell population. They are activated by a multitude of IgE-independent agonists including antigen-IgG complexes, complement, and microorganisms and are a rich source of many secreted and cell surface–expressed immune-modulating molecules. 2. Mast cells have been extensively studied in the context of Type I (immediate-type) hypersensitivities but also have a significant role in Types II–IV hypersensitivity responses that are associated with many autoimmune diseases. Annu. Rev. Immunol. 2008.26:705-739. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
3. Several sites of mast cell influence likely affect both the initiation and effector phase of autoimmune disease. These range from promoting DC maturation and migration to secondary lymphoid organs to directing T cell differentiation to orchestrating the migration of T cells and other immune cells to the sites of tissue inflammation. 4. In addition to proinflammatory actions, mast cells have suppressive effects on some immune responses. 5. The variable effects of mast cells are related to the activating stimulus, the tissue site of the mast cell, and the proximal target cells as well as to the genetically determined variability in mast cell mediator production.
FUTURE ISSUES 1. Mast cell–deficient mice need to be developed on diverse genetic backgrounds to expand the range of diseases that can be studied in vivo. 2. Relevant mast cell activators and mediators in autoimmune diseases must be determined. 3. Investigators must determine the molecular basis for proinflammatory and tolerogenic actions of mast cells in disease. 4. Investigators must examine the extent of mast cell response heterogeneity in disease.
DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENT The authors thank Dr. Kavitha Rao for the critical reading of this manuscript.
LITERATURE CITED 1. Galli SJ, Lantz CS. 1999. Allergy. In Fundamental Immunology, ed. WE Paul, pp. 1137–84. Philadelphia: Lippincott-Raven. 4th ed. 2. Marshall JS. 2004. Mast-cell responses to pathogens. Nat. Rev. Immunol. 4:787–99 728
Sayed et al.
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3. Galli SJ, Nakae S, Tsai M. 2005. Mast cells in the development of adaptive immune responses. Nat. Immunol. 6:135–42 4. Galli SJ, Kalesnikoff J, Grimbaldeston MA, Piliponsky AM, Williams CM, Tsai M. 2005. Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu. Rev. Immunol. 23:749–86 5. Metcalfe DD, Baram D, Mekori YA. 1997. Mast cells. Physiol. Rev. 77:1033–79 6. Johnson D, Krenger W. 1992. Interactions of mast cells with the nervous system—recent advances. Neurochem. Res. 17:939–51 7. Kalesnikoff J, Huber M, Lam V, Damen JE, Zhang J, et al. 2001. Monomeric IgE stimulates signaling pathways in mast cells that lead to cytokine production and cell survival. Immunity 14:801–11 8. Bachelet I, Levi-Schaffer F. 2007. Mast cells as effector cells: a costimulating question. Trends Immunol. 28:360–65 9. Tashiro M, Kawakami Y, Abe R, Han W, Hata D, et al. 1997. Increased secretion of TNF-alpha by costimulation of mast cells via CD28 and Fcε RI. J. Immunol. 158:2382– 89 10. Nishimoto H, Lee SW, Hong H, Potter KG, Maeda-Yamamoto M, et al. 2005. Costimulation of mast cells by 4-1BB, a member of the tumor necrosis factor receptor superfamily, with the high-affinity IgE receptor. Blood 106:4241–48 11. Qiao H, Andrade MV, Lisboa FA, Morgan K, Beaven MA. 2006. FcεR1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells. Blood 107:610–18 12. Malbec O, Daeron M. 2007. The mast cell IgG receptors and their roles in tissue inflammation. Immunol. Rev. 217:206–21 13. Katz HR. 2007. Inhibition of pathologic inflammation by leukocyte Ig-like receptor B4 and related inhibitory receptors. Immunol. Rev. 217:222–30 14. Wong MX, Roberts D, Bartley PA, Jackson DE. 2002. Absence of platelet endothelial cell adhesion molecule-1 (CD31) leads to increased severity of local and systemic IgEmediated anaphylaxis and modulation of mast cell activation. J. Immunol. 168:6455–62 15. Nakae S, Suto H, Iikura M, Kakurai M, Sedgwick JD, et al. 2006. Mast cells enhance T cell activation: importance of mast cell costimulatory molecules and secreted TNF. J. Immunol. 176:2238–48 16. Frandji P, Tkaczyk C, Oskeritzian C, David B, Desaymard C, Mecheri S. 1996. Exogenous and endogenous antigens are differentially presented by mast cells to CD4+ T lymphocytes. Eur. J. Immunol. 26:2517–28 17. Gauchat JF, Henchoz S, Mazzei G, Aubry JP, Brunner T, et al. 1993. Induction of human IgE synthesis in B cells by mast cells and basophils. Nature 365:340–43 18. Fairley JA, Burnett CT, Fu CL, Larson DL, Fleming MG, Giudice GJ. 2007. A pathogenic role for IgE in autoimmunity: bullous pemphigoid IgE reproduces the early phase of lesion development in human skin grafted to nu/nu mice. J. Invest. Dermatol. 127:2605–11 19. Ludgate M, Baker G. 2002. Unlocking the immunological mechanisms of orbital inflammation in thyroid eye disease. Clin. Exp. Immunol. 127:193–98 20. Okayama Y, Kirshenbaum AS, Metcalfe DD. 2000. Expression of a functional highaffinity IgG receptor, FcγRI, on human mast cells: up-regulation by IFN-γ. J. Immunol. 164:4332–39 21. Redegeld FA, van der Heijden MW, Kool M, Heijdra BM, Garssen J, et al. 2002. Immunoglobulin-free light chains elicit immediate hypersensitivity-like responses. Nat. Med. 8:694–701 www.annualreviews.org • Mast Cells in Autoimmunity and Tolerance
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ARI
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22. Edelson BT, Stricker TP, Li Z, Dickeson SK, Shepherd VL, et al. 2006. Novel collectin/C1q receptor mediates mast cell activation and innate immunity. Blood 107:143–50 23. Echtenacher B, Mannel DN, Hultner L. 1996. Critical protective role of mast cells in a model of acute septic peritonitis. Nature 381:75–77 24. Prodeus AP, Zhou X, Maurer M, Galli SJ, Carroll MC. 1997. Impaired mast celldependent natural immunity in complement C3-deficient mice. Nature 390:172–75 25. Marshall JS, King CA, McCurdy JD. 2003. Mast cell cytokine and chemokine responses to bacterial and viral infection. Curr. Pharm. Des. 9:11–24 26. Szalai AJ, Hu X, Adams JE, Barnum SR. 2007. Complement in experimental autoimmune encephalomyelitis revisited: C3 is required for development of maximal disease. Mol. Immunol. 44:3132–36 27. Urich E, Gutcher I, Prinz M, Becher B. 2006. Autoantibody-mediated demyelination depends on complement activation but not activatory Fc-receptors. Proc. Natl. Acad. Sci. USA 103:18697–702 28. Akira S, Takeda K, Kaisho T. 2001. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat. Immunol. 2:675–80 29. Matsushima H, Yamada N, Matsue H, Shimada S. 2004. TLR3-, TLR7-, and TLR9mediated production of proinflammatory cytokines and chemokines from murine connective tissue type skin-derived mast cells but not from bone marrow-derived mast cells. J. Immunol. 173:531–41 30. Feng BS, He SH, Zheng PY, Wu L, Yang PC. 2007. Mast cells play a crucial role in Staphylococcus aureus peptidoglycan-induced diarrhea. Am. J. Pathol. 171:537–47 31. Narita S, Goldblum RM, Watson CS, Brooks EG, Estes DM, et al. 2007. Environmental estrogens induce mast cell degranulation and enhance IgE-mediated release of allergic mediators. Environ. Health Perspect. 115:48–52 32. Vasiadi M, Kempuraj D, Boucher W, Kalogeromitros D, Theoharides TC. 2006. Progesterone inhibits mast cell secretion. Int. J. Immunopathol. Pharmacol. 19:787–94 33. Theoharides TC, Kalogeromitros D. 2006. The critical role of mast cells in allergy and inflammation. Ann. NY Acad. Sci. 1088:78–99 34. Theoharides TC, Kempuraj D, Tagen M, Conti P, Kalogeromitros D. 2007. Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol. Rev. 217:65–78 35. Theoharides TC, Bondy PK, Tsakalos ND, Askenase PW. 1982. Differential release of serotonin and histamine from mast cells. Nature 297:229–31 36. Kandere-Grzybowska K, Letourneau R, Kempuraj D, Donelan J, Poplawski S, et al. 2003. IL-1 induces vesicular secretion of IL-6 without degranulation from human mast cells. J. Immunol. 171:4830–36 37. Grimbaldeston MA, Chen CC, Piliponsky AM, Tsai M, Tam SY, Galli SJ. 2005. Mast cell–deficient W-sash c-kit mutant Kit W−sh /W−sh mice as a model for investigating mast cell biology in vivo. Am. J. Pathol. 167:835–48 38. Kitamura Y, Go S, Hatanaka K. 1978. Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation. Blood 52:447–52 39. Nakano T, Sonoda T, Hayashi C, Yamatodani A, Kanayama Y, et al. 1985. Fate of bone marrow-derived cultured mast cells after intracutaneous, intraperitoneal, and intravenous transfer into genetically mast cell–deficient W/Wv mice. J. Exp. Med. 162:1025–43 40. Marrack P, Kappler J, Kotzin BL. 2001. Autoimmune disease: Why and where it occurs. Nat. Med. 7:899–905
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41. Nelson KC, Zhao M, Schroeder PR, Li N, Wetsel RA, et al. 2006. Role of different pathways of the complement cascade in experimental bullous pemphigoid. J. Clin. Invest. 116:2892–900 42. Levi-Schaffer F, Klapholz L, Kupietzky A, Weinrauch L, Shalit M, Okon E. 1991. Increased numbers of mast cells in pemphigus vulgaris skin lesions. A histochemical study. Acta Derm.-Venereol. 71:269–71 43. Juurikivi A, Sandler C, Lindstedt KA, Kovanen PT, Juutilainen T, et al. 2005. Inhibition of c-kit tyrosine kinase by imatinib mesylate induces apoptosis in mast cells in rheumatoid synovia: a potential approach to the treatment of arthritis. Ann. Rheum. Dis. 64:1126–31 44. Lee DM, Friend DS, Gurish MF, Benoist C, Mathis D, Brenner MB. 2002. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 297:1689–92 45. Secor VH, Secor WE, Gutekunst CA, Brown MA. 2000. Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J. Exp. Med. 191:813–22 46. Geoffrey R, Jia S, Kwitek AE, Woodliff J, Ghosh S, et al. 2006. Evidence of a functional role for mast cells in the development of type 1 diabetes mellitus in the BioBreeding rat. J. Immunol. 177:7275–86 47. Brosman CF, Lyman WD, Tansey FA, Carter TH. 1985. Quantitation of mast cells in experimental allergic neuritis. J. Neuropathol. Exp. Neurol. 44:196–203 48. Seeldrayers PA, Yasui D, Weiner HL, Johnson D. 1989. Treatment of experimental allergic neuritis with nedocromil sodium. J. Neuroimmunol. 25:221–26 49. Konttinen YT, Hietanen J, Virtanen I, Ma J, Sorsa T, et al. 2000. Mast cell derangement in salivary glands in patients with Sjogren’s syndrome. Rheumatol. Int. 19:141–47 50. Akimoto S, Ishikawa O, Igarashi Y, Kurosawa M, Miyachi Y. 1998. Dermal mast cells in scleroderma: their skin density, tryptase/chymase phenotypes and degranulation. Br. J. Dermatol. 138:399–406 51. Shiota N, Kakizoe E, Shimoura K, Tanaka T, Okunishi H. 2005. Effect of mast cell chymase inhibitor on the development of scleroderma in tight-skin mice. Br. J. Pharmacol. 145:424–31 52. Walker M, Harley R, LeRoy EC. 1990. Ketotifen prevents skin fibrosis in the tight skin mouse. J. Rheumatol. 17:57–59 53. Walker MA, Harley RA, LeRoy EC. 1987. Inhibition of fibrosis in TSK mice by blocking mast cell degranulation. J. Rheumatol. 14:299–301 54. Kiely PD, Pecht I, Oliveira DB. 1997. Mercuric chloride-induced vasculitis in the Brown Norway rat: αβ T cell-dependent and -independent phases: role of the mast cell. J. Immunol. 159:5100–6 55. Grimbaldeston MA, Metz M, Yu M, Tsai M, Galli SJ. 2006. Effector and potential immunoregulatory roles of mast cells in IgE-associated acquired immune responses. Curr. Opin. Immunol. 18:751–60 56. Leighty L, Li N, Diaz LA, Liu Z. 2007. Experimental models for the autoimmune and inflammatory blistering disease, bullous pemphigoid. Arch. Dermatol. Res. 299:417–22 57. Chen R, Ning G, Zhao ML, Fleming MG, Diaz LA, et al. 2001. Mast cells play a key role in neutrophil recruitment in experimental bullous pemphigoid. J. Clin. Invest. 108:1151– 58 58. Kayashima K, Koji T, Nozawa M, Ono T, Nakane PK. 1998. Activation of bullous pemphigoid antigen gene in mouse ear epidermis by UV radiation. Cell Biochem. Funct. 16:107–16 59. Endoh I, Di Girolamo N, Hampartzoumian T, Cameron B, Geczy CL, Tedla N. 2007. Ultraviolet B irradiation selectively increases the production of interleukin-8 in human cord blood-derived mast cells. Clin. Exp. Immunol. 148:161–67 www.annualreviews.org • Mast Cells in Autoimmunity and Tolerance
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16 February 2008
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60. Dimson OG, Giudice GJ, Fu CL, Van den Bergh F, Warren SJ, et al. 2003. Identification of a potential effector function for IgE autoantibodies in the organ-specific autoimmune disease bullous pemphigoid. J. Invest. Dermatol. 120:784–88 61. Borrego L, Maynard B, Peterson EA, George T, Iglesias L, et al. 1996. Deposition of eosinophil granule proteins precedes blister formation in bullous pemphigoid. Comparison with neutrophil and mast cell granule proteins. Am. J. Pathol. 148:897–909 62. Stassi G, De Maria R. 2002. Autoimmune thyroid disease: new models of cell death in autoimmunity. Nat. Rev. Immunol. 2:195–204 63. Prabhakar BS, Bahn RS, Smith TJ. 2003. Current perspective on the pathogenesis of Graves’ disease and ophthalmopathy. Endocr. Rev. 24:802–35 64. Yamada T, Sato A, Aizawa T, Ootsuka H, Miyahara Y, et al. 1998. An elevation of stem cell factor in patients with hyperthyroid Graves’ disease. Thyroid 8:499–504 65. Many MC, Costagliola S, Detrait M, Denef F, Vassart G, Ludgate MC. 1999. Development of an animal model of autoimmune thyroid eye disease. J. Immunol. 162:4966–74 66. Arthus M. 1903. Injections repet´ees de serum de cheval cuez le lapin. C. R. Soc. Biol. 55:817–20 67. Ravetch JV, Bolland S. 2001. IgG Fc receptors. Annu. Rev. Immunol. 19:275–90 68. Zhang Y, Ramos BF, Jakschik BA. 1991. Augmentation of reverse Arthus reaction by mast cells in mice. J. Clin. Invest. 88:841–46 69. Sylvestre DL, Ravetch JV. 1996. A dominant role for mast cell Fc receptors in the Arthus reaction. Immunity 5:387–90 70. Ramos BF, Zhang Y, Qureshi R, Jakschik BA. 1991. Mast cells are critical for the production of leukotrienes responsible for neutrophil recruitment in immune complex-induced peritonitis in mice. J. Immunol. 147:1636–41 71. Zhang Y, Ramos F, Jakschik B. 1992. Neutrophil recruitment by tumor necrosis factor from mast cells in immune complex peritonitis. Science 258:1957–59 72. Feldmann M, Brennan FM, Maini RN. 1996. Rheumatoid arthritis. Cell 85:307–10 73. Dorner T, Egerer K, Feist E, Burmester GR. 2004. Rheumatoid factor revisited. Curr. Opin. Rheumatol. 16:246–53 74. Sakaguchi S, Sakaguchi N. 2005. Animal models of arthritis caused by systemic alteration of the immune system. Curr. Opin. Immunol. 17:589–94 75. Ecklund K. 2007. Mast cells in the pathogenesis of rheumatic diseases and as potential targets for antirheumatic therapy. Immunol. Rev. 217:38–52 76. Ji H, Pettit A, Ohmura K, Ortiz-Lopez A, Duchatelle V, et al. 2002. Critical roles for interleukin 1 and tumor necrosis factor alpha in antibody-induced arthritis. J. Exp. Med. 196:77–85 77. Nigrovic PA, Binstadt BA, Monach PA, Johnsen A, Gurish M, et al. 2007. Mast cells contribute to initiation of autoantibody-mediated arthritis via IL-1. Proc. Natl. Acad. Sci. USA 104:2325–30 78. Nigrovic PA, Lee DM. 2007. Synovial mast cells: role in acute and chronic arthritis. Immunol. Rev. 217:19–37 79. Kneilling M, Hultner L, Pichler BJ, Mailhammer R, Morawietz L, et al. 2007. Targeted mast cell silencing protects against joint destruction and angiogenesis in experimental arthritis in mice. Arthritis Rheum. 56:1806–16 80. Paniagua RT, Sharpe O, Ho PP, Chan SM, Chang A, et al. 2006. Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J. Clin. Invest. 116:2633–42 81. Shlomchik MJ, Craft JE, Mamula MJ. 2001. From T to B and back again: positive feedback in systemic autoimmune disease. Nat. Rev. Immunol. 1:147–53
Annu. Rev. Immunol. 2008.26:705-739. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-23
732
Sayed et al.
Annu. Rev. Immunol. 2008.26:705-739. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-23
ARI
16 February 2008
14:10
82. Hiromura K, Kurosawa M, Yano S, Naruse T. 1998. Tubulointerstitial mast cell infiltration in glomerulonephritis. Am. J. Kidney Dis. 32:593–99 83. Satoh M, Kumar A, Kanwar YS, Reeves WH. 1995. Anti-nuclear antibody production and immune-complex glomerulonephritis in BALB/c mice treated with pristane. Proc. Natl. Acad. Sci. USA 92:10934–38 84. Satoh M, Reeves WH. 1994. Induction of lupus-associated autoantibodies in BALB/c mice by intraperitoneal injection of pristane. J. Exp. Med. 180:2341–46 85. Richards HB, Satoh M, Shaw M, Libert C, Poli V, Reeves WH. 1998. Interleukin 6 dependence of anti-DNA antibody production: evidence for two pathways of autoantibody formation in pristane-induced lupus. J. Exp. Med. 188:985–90 86. Lin L, Gerth AJ, Peng SL. 2004. Susceptibility of mast cell–deficient W/Wv mice to pristane-induced experimental lupus nephritis. Immunol. Lett. 91:93–97 87. van Loveren H, Meade R, Askenase PW. 1983. An early component of delayed-type hypersensitivity mediated by T cells and mast cells. J. Exp. Med. 157:1604–17 88. Biedermann T, Kneilling M, Mailhammer R, Maier K, Sander CA, et al. 2000. Mast cells control neutrophil recruitment during T cell-mediated delayed-type hypersensitivity reactions through tumor necrosis factor and macrophage inflammatory protein 2. J. Exp. Med. 192:1441–52 89. Sospedra M, Martin R. 2005. Immunology of multiple sclerosis. Annu. Rev. Immunol. 23:683–747 90. Miller SD, Shevach EM. 1998. Immunoregulation of experimental autoimmune encephalomyelitis: editorial overview. Res. Immunol. 149:753–59 91. Vanderlugt CL, Miller SD. 2002. Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat. Rev. Immunol. 2:85–95 92. Sriram S, Steiner I. 2005. Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis. Ann. Neurol. 58:939–45 93. Steinman L, Zamvil SS. 2005. Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis. Trends Immunol. 26:565–71 94. Ferber IA, Brocke S, Taylor-Edwards C, Ridgway W, Dinisco C, et al. 1996. Mice with a disrupted IFN-γ gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J. Immunol. 156:5–7 95. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, et al. 2005. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201:233–40 96. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. 2006. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17producing T cells. Immunity 24:179–89 97. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, et al. 2005. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6:1123–32 98. Park H, Li Z, Yang XO, Chang SH, Nurieva R, et al. 2005. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6:1133–41 99. Ibrahim MZM, Reder AT, Lawand R, Takash W, Sallouh-Khatib S. 1996. The mast cells of the multiple sclerosis brain. J. Neuroimmunol. 70:131–38 100. Rozniecki JJ, Hauser SL, Stein M, Lincoln R, Theoharides TC. 1995. Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients. Ann. Neurol. 37:63–66 101. Tuomisto L, Kilpelainen H, Riekkinen P. 1983. Histamine and histamine-Nmethyltransferase in the CSF of patients with multiple sclerosis. Agents Actions 13:255–55 www.annualreviews.org • Mast Cells in Autoimmunity and Tolerance
733
ARI
16 February 2008
14:10
102. Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, et al. 2002. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8:500–8 103. Gregory GD, Robbie-Ryan M, Secor VH, Sabatino JJ Jr, Brown MA. 2005. Mast cells are required for optimal autoreactive T cell responses in a murine model of multiple sclerosis. Eur. J. Immunol. 35:3478–86 104. Tanzola MB, Robbie-Ryan M, Gutekunst CA, Brown MA. 2003. Mast cells exert effects outside the central nervous system to influence experimental allergic encephalomyelitis disease course. J. Immunol. 171:4385–91 105. McDevitt H. 2001. Closing in on type 1 diabetes. N. Engl. J. Med. 345:1060–61 106. Rees DA, Alcolado JC. 2005. Animal models of diabetes mellitus. Diabet. Med. 22:359–70 107. Esposito I, Friess H, Kappeler A, Shrikhande S, Kleeff J, et al. 2001. Mast cell distribution and activation in chronic pancreatitis. Hum. Pathol. 32:1174–83 108. Esposito I, Kleeff J, Bischoff SC, Fischer L, Collecchi P, et al. 2002. The stem cell factor-c-kit system and mast cells in human pancreatic cancer. Lab. Invest. 82:1481–92 109. Zimnoch L, Szynaka B, Puchalski Z. 2002. Mast cells and pancreatic stellate cells in chronic pancreatitis with differently intensified fibrosis. Hepatogastroenterology 49:1135– 38 110. Parlapiano C, Danese C, Marangi M, Campana E, Pantone P, et al. 1999. The relationship between glycated hemoglobin and polymorphonuclear leukocyte leukotriene B4 release in people with diabetes mellitus. Diabetes Res. Clin. Pract. 46:43–45 111. Wu AJ, Hua H, Munson SH, McDevitt HO. 2002. Tumor necrosis factor-alpha regulation of CD4+ CD25+ T cell levels in NOD mice. Proc. Natl. Acad. Sci. USA 99:12287–92 112. Belghith M, Bluestone JA, Barriot S, Megret J, Bach JF, Chatenoud L. 2003. TGF-βdependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat. Med. 9:1202–8 113. Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, et al. 2006. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J. Exp. Med. 203:883–95 114. Hughes RA, Cornblath DR. 2005. Guillain-Barre syndrome. Lancet 366:1653–66 115. Yu RK, Usuki S, Ariga T. 2006. Ganglioside molecular mimicry and its pathological roles in Guillain-Barre syndrome and related diseases. Infect. Immun. 74:6517–27 116. Maurer M, Gold R. 2002. Animal models of immune-mediated neuropathies. Curr. Opin. Neurol. 15:617–22 117. Pilartz M, Jess T, Indefrei D, Schroder JM. 2002. Adoptive transfer-experimental allergic neuritis in newborn Lewis rats results in inflammatory infiltrates, mast cell activation, and increased Ia expression with only minor nerve fiber degeneration. Acta Neuropathol. 104:513–24 118. Varga J, Abraham D. 2007. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J. Clin. Invest. 117:557–67 119. Arnett FC. 2006. Is scleroderma an autoantibody mediated disease? Curr. Opin. Rheumatol. 18:579–81 120. Ozbilgin MK, Inan S. 2003. The roles of transforming growth factor type β3 (TGF-β3) and mast cells in the pathogenesis of scleroderma. Clin. Rheumatol. 22:189–95 121. Wang HW, Tedla N, Hunt JE, Wakefield D, McNeil HP. 2005. Mast cell accumulation and cytokine expression in the tight skin mouse model of scleroderma. Exp. Dermatol. 14:295–302 122. Bouma G, Strober W. 2003. The immunological and genetic basis of inflammatory bowel disease. Nat. Rev. Immunol. 3:521–33
Annu. Rev. Immunol. 2008.26:705-739. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-23
734
Sayed et al.
Annu. Rev. Immunol. 2008.26:705-739. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-23
ARI
16 February 2008
14:10
123. King T, Biddle W, Bhatia P, Moore J, Miner PB Jr. 1992. Colonic mucosal mast cell distribution at line of demarcation of active ulcerative colitis. Dig. Dis. Sci. 37:490–95 124. Oshitani N, Kamata N, Inagawa M, Yamagami H, Watanabe K, et al. 2006. Significance of activated mast cells in submucosa and muscularis propria of patients with Crohn’s disease detected by a novel antimast cell surface molecule antibody. Aliment. Pharmacol. Ther. 24(Suppl. 4):1–7 125. Raithel M, Matek M, Baenkler HW, Jorde W, Hahn EG. 1995. Mucosal histamine content and histamine secretion in Crohn’s disease, ulcerative colitis and allergic enteropathy. Int. Arch. Allergy Immunol. 108:127–33 126. Bischoff SC, Lorentz A, Schwengberg S, Weier G, Raab R, Manns MP. 1999. Mast cells are an important cellular source of tumour necrosis factor alpha in human intestinal tissue. Gut 44:643–52 127. Middel P, Thelen P, Blaschke S, Polzien F, Reich K, et al. 2001. Expression of the T-cell chemoattractant chemokine lymphotactin in Crohn’s disease. Am. J. Pathol. 159:1751–61 128. Middel P, Reich K, Polzien F, Blaschke V, Hemmerlein B, et al. 2001. Interleukin 16 expression and phenotype of interleukin 16 producing cells in Crohn’s disease. Gut 49:795– 803 129. Kapsenberg ML. 2003. Dendritic-cell control of pathogen-driven T-cell polarization. Nat. Rev. Immunol. 3:984–93 130. Regner M, Lambert PH. 2001. Autoimmunity through infection or immunization? Nat. Immunol. 2:185–88 131. Sayed BA, Brown MA. 2007. Mast cells as modulators of T-cell responses. Immunol. Rev. 217:53–64 132. Wu L, Liu YJ. 2007. Development of dendritic-cell lineages. Immunity 26:741–50 133. Suto H, Nakae S, Kakurai M, Sedgwick JD, Tsai M, Galli SJ. 2006. Mast cell-associated TNF promotes dendritic cell migration. J. Immunol. 176:4102–12 134. Harizi H, Gualde N. 2006. Pivotal role of PGE2 and IL-10 in the cross-regulation of dendritic cell-derived inflammatory mediators. Cell Mol. Immunol. 3:271–77 135. McLachlan JB, Hart JP, Pizzo SV, Shelburne CP, Staats HF, et al. 2003. Mast cell-derived tumor necrosis factor induces hypertrophy of draining lymph nodes during infection. Nat. Immunol. 4:1199–205 136. Jawdat DM, Rowden G, Marshall JS. 2006. Mast cells have a pivotal role in TNFindependent lymph node hypertrophy and the mobilization of Langerhans cells in response to bacterial peptidoglycan. J. Immunol. 177:1755–62 137. Gutzmer R, Diestel C, Mommert S, Kother B, Stark H, et al. 2005. Histamine H4 receptor stimulation suppresses IL-12p70 production and mediates chemotaxis in human monocyte-derived dendritic cells. J. Immunol. 174:5224–32 138. Caron G, Delneste Y, Roelandts E, Duez C, Bonnefoy JY, et al. 2001. Histamine polarizes human dendritic cells into Th2 cell-promoting effector dendritic cells. J. Immunol. 167:3682–86 139. Kitawaki T, Kadowaki N, Sugimoto N, Kambe N, Hori T, et al. 2006. IgE-activated mast cells in combination with proinflammatory factors induce Th2-promoting dendritic cells. Int. Immunol. 18:1789–99 140. Mazzoni A, Young HA, Spitzer JH, Visintin A, Segal DM. 2001. Histamine regulates cytokine production in maturing dendritic cells, resulting in altered T cell polarization. J. Clin. Invest. 108:1865–73 141. Shin EH, Lee HY, Bae YS. 2006. Leukotriene B4 stimulates human monocyte-derived dendritic cell chemotaxis. Biochem. Biophys. Res. Commun. 348:606–11 www.annualreviews.org • Mast Cells in Autoimmunity and Tolerance
735
ARI
16 February 2008
14:10
142. Del Prete A, Shao WH, Mitola S, Santoro G, Sozzani S, Haribabu B. 2007. Regulation of dendritic cell migration and adaptive immune response by leukotriene B4 receptors: a role for LTB4 in up-regulation of CCR7 expression and function. Blood 109:626–31 143. Robbiani DF, Finch RA, Jager D, Muller WA, Sartorelli AC, Randolph GJ. 2000. The leukotriene C(4) transporter MRP1 regulates CCL19 (MIP-3β, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell 103:757–68 144. Jozefowski S, Biedron R, Bobek M, Marcinkiewicz J. 2005. Leukotrienes modulate cytokine release from dendritic cells. Immunology 116:418–28 145. Theiner G, Gessner A, Lutz MB. 2006. The mast cell mediator PGD2 suppresses IL-12 release by dendritic cells leading to Th2 polarized immune responses in vivo. Immunobiology 211:463–72 146. Legler DF, Krause P, Scandella E, Singer E, Groettrup M. 2006. Prostaglandin E2 is generally required for human dendritic cell migration and exerts its effect via EP2 and EP4 receptors. J. Immunol. 176:966–73 147. McIlroy A, Caron G, Blanchard S, Fremaux I, Duluc D, et al. 2006. Histamine and prostaglandin E up-regulate the production of Th2-attracting chemokines (CCL17 and CCL22) and down-regulate IFN-γ-induced CXCL10 production by immature human dendritic cells. Immunology 117:507–16 148. Sa-Nunes A, Bafica A, Lucas DA, Conrads TP, Veenstra TD, et al. 2007. Prostaglandin E2 is a major inhibitor of dendritic cell maturation and function in Ixodes scapularis saliva. J. Immunol. 179:1497–505 149. Yao Y, Li W, Kaplan MH, Chang CH. 2005. Interleukin (IL)-4 inhibits IL-10 to promote IL-12 production by dendritic cells. J. Exp. Med. 201:1899–903 150. Teloni R, Giannoni F, Rossi P, Nisini R, Gagliardi MC. 2007. Interleukin-4 inhibits cyclooxygenase-2 expression and prostaglandin E production by human mature dendritic cells. Immunology 120:83–89 151. Verginis P, Li HS, Carayanniotis G. 2005. Tolerogenic semimature dendritic cells suppress experimental autoimmune thyroiditis by activation of thyroglobulin-specific CD4+ CD25+ T cells. J. Immunol. 174:7433–39 152. Luo X, Tarbell KV, Yang H, Pothoven K, Bailey SL, et al. 2007. Dendritic cells with TGF-β1 differentiate naive CD4+ CD25− T cells into islet-protective Foxp3+ regulatory T cells. Proc. Natl. Acad. Sci. USA 104:2821–26 153. Sato K, Kawasaki H, Nagayama H, Enomoto M, Morimoto C, et al. 2000. TGF-β 1 reciprocally controls chemotaxis of human peripheral blood monocyte-derived dendritic cells via chemokine receptors. J. Immunol. 164:2285–95 154. Borkowski TA, Letterio JJ, Farr AG, Udey MC. 1996. A role for endogenous transforming growth factor β 1 in Langerhans cell biology: the skin of transforming growth factor β 1 null mice is devoid of epidermal Langerhans cells. J. Exp. Med. 184:2417–22 155. Ito T, Wang YH, Duramad O, Hori T, Delespesse GJ, et al. 2005. TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J. Exp. Med. 202:1213–23 156. Katoh N, Soga F, Nara T, Tamagawa-Mineoka R, Nin M, et al. 2006. Effect of serotonin on the differentiation of human monocytes into dendritic cells. Clin. Exp. Immunol. 146:354–61 157. Xia CQ, Kao KJ. 2002. Heparin induces differentiation of CD1a+ dendritic cells from monocytes: phenotypic and functional characterization. J. Immunol. 168:1131–38 158. Bryce PJ, Miller ML, Miyajima I, Tsai M, Galli SJ, Oettgen HC. 2004. Immune sensitization in the skin is enhanced by antigen-independent effects of IgE. Immunity 20:381–92
Annu. Rev. Immunol. 2008.26:705-739. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-23
736
Sayed et al.
Annu. Rev. Immunol. 2008.26:705-739. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-23
ARI
16 February 2008
14:10
159. Nagai H, Inagaki N, Tanaka H. 1999. Role of IgE for the onset of allergic cutaneous response caused by simple chemical hapten in mice. Int. Arch. Allergy Immunol. 118:285– 86 160. Jawdat DM, Albert EJ, Rowden G, Haidl ID, Marshall JS. 2004. IgE-mediated mast cell activation induces Langerhans cell migration in vivo. J. Immunol. 173:5275–82 161. Akdis CA, Blaser K. 2003. Histamine in the immune regulation of allergic inflammation. J. Allergy Clin. Immunol. 112:15–22 162. Mazzoni A, Leifer CA, Mullen GE, Kennedy MN, Klinman DM, Segal DM. 2003. Cutting edge: Histamine inhibits IFN-α release from plasmacytoid dendritic cells. J. Immunol. 170:2269–73 163. Amaral MM, Davio C, Ceballos A, Salamone G, Canones C, et al. 2007. Histamine improves antigen uptake and cross-presentation by dendritic cells. J. Immunol. 179:3425– 33 164. Mazzoni A, Siraganian RP, Leifer CA, Segal DM. 2006. Dendritic cell modulation by mast cells controls the Th1/Th2 balance in responding T cells. J. Immunol. 177:3577–81 165. Gregory GD, Raju SS, Winandy S, Brown MA. 2006. Mast cell IL-4 expression is regulated by Ikaros and influences encephalitogenic Th1 responses in EAE. J. Clin. Invest. 116:1327–36 166. Yang XD, McDevitt HO. 1994. Role of TNF-α in the development of autoimmunity and the pathogenesis of insulin-dependent diabetes mellitus in NOD mice. Circ. Shock 43:198–201 167. Gilliet M, Soumelis V, Watanabe N, Hanabuchi S, Antonenko S, et al. 2003. Human dendritic cells activated by TSLP and CD40L induce proallergic cytotoxic T cells. J. Exp. Med. 197:1059–63 168. Frandji P, Oskeritzian C, Cacraci F, Lapeyre J, Peronet R, et al. 1993. Antigen-dependent stimulation by bone marrow-derived mast cells of MHC class II-restricted T cell hybridoma. J. Immunol. 151:6318–28 169. Fox CC, Jewell SD, Whitacre CC. 1994. Rat peritoneal mast cells present antigen to a PPD-specific T cell line. Cell. Immunol. 158:253–64 170. Jutel M, Watanabe T, Klunker S, Akdis M, Thomet OA, et al. 2001. Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature 413:420–25 171. Steinman L. 2001. Myelin-specific CD8 T cells in the pathogenesis of experimental allergic encephalitis and multiple sclerosis. J. Exp. Med. 194:F27–30 172. Tang XL, Smith TR, Kumar V. 2005. Specific control of immunity by regulatory CD8 T cells. Cell Mol. Immunol. 2:11–19 173. Gombert M, Dieu-Nosjean MC, Winterberg F, Bunemann E, Kubitza RC, et al. 2005. CCL1-CCR8 interactions: an axis mediating the recruitment of T cells and Langerhanstype dendritic cells to sites of atopic skin inflammation. J. Immunol. 174:5082–91 174. Kaur D, Saunders R, Berger P, Siddiqui S, Woodman L, et al. 2006. Airway smooth muscle and mast cell-derived CCL19 mediate airway smooth muscle migration in asthma. Am. J. Respir. Crit. Care Med. 174:1179–88 175. Humrich JY, Humrich JH, Averbeck M, Thumann P, Termeer C, et al. 2006. Mature monocyte-derived dendritic cells respond more strongly to CCL19 than to CXCL12: consequences for directional migration. Immunology 117:238–47 176. Kivisakk P, Mahad DJ, Callahan MK, Sikora K, Trebst C, et al. 2004. Expression of CCR7 in multiple sclerosis: implications for CNS immunity. Ann. Neurol. 55:627–38 www.annualreviews.org • Mast Cells in Autoimmunity and Tolerance
737
ARI
16 February 2008
14:10
177. Bailey SL, Schreiner B, McMahon EJ, Miller SD. 2007. CNS myeloid DCs presenting endogenous myelin peptides ‘preferentially’ polarize CD4+ T(H)-17 cells in relapsing EAE. Nat. Immunol. 8:172–80 178. Engelhardt B. 2006. Molecular mechanisms involved in T cell migration across the bloodbrain barrier. J. Neural. Transm. 113:477–85 179. Taube C, Miyahara N, Ott V, Swanson B, Takeda K, et al. 2006. The leukotriene B4 receptor (BLT1) is required for effector CD8+ T cell-mediated, mast cell-dependent airway hyperresponsiveness. J. Immunol. 176:3157–64 180. Ott VL, Cambier JC, Kappler J, Marrack P, Swanson BJ. 2003. Mast cell-dependent migration of effector CD8+ T cells through production of leukotriene B4. Nat. Immunol. 4:974–81 181. Di Girolamo N, Indoh I, Jackson N, Wakefield D, McNeil HP, et al. 2006. Human mast cell-derived gelatinase B (matrix metalloproteinase-9) is regulated by inflammatory cytokines: role in cell migration. J. Immunol. 177:2638–50 182. Kappler JW, Roehm N, Marrack P. 1987. T cell tolerance by clonal elimination in the thymus. Cell 49:273–80 183. Shevach EM. 2006. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 25:195–201 184. Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, et al. 2000. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J. Clin. Invest. 106:R75–81 185. Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, et al. 2001. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27:18–20 186. Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, et al. 2006. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442:997–1002 187. Grimbaldeston MA, Nakae S, Kalesnikoff J, Tsai M, Galli SJ. 2007. Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with UV B. Nat. Immunol. 8:1095–104 188. Johnson D, Seeldrayers PA, Weiner HL. 1988. The role of mast cells in demyelination. 1. Myelin proteins are degraded by mast cell proteases and myelin basic protein and P2 can stimulate mast cell degranulation. Brain Res. 44:195–98 189. O’Brien PJ, Molino M, Kahn M, Brass LF. 2001. Protease activated receptors: theme and variations. Oncogene 20:1570–81 190. Johnson D, Yasui D, Seeldrayers P. 1991. An analysis of mast cell frequency in the rodent nervous system: Numbers vary between different strains and can be reconstituted in mast cell–deficient mice. J. Neuropathol. Exp. Neurol. 50:227–34 191. Skokos D, Goubran-Botros H, Roa M, Mecheri S. 2002. Immunoregulatory properties of mast cell-derived exosomes. Mol. Immunol. 38:1359–62 192. Tkaczyk C, Frandji P, Botros HG, Poncet P, Lapeyre J, et al. 1996. Mouse bone marrowderived mast cells and mast cell lines constitutively produce B cell growth and differentiation activities. J. Immunol. 157:1720–28 193. Banu Y, Watanabe T. 1999. Augmentation of antigen receptor-mediated responses by histamine H1 receptor signaling. J. Exp. Med. 189:673–82 194. Cao J, Papadopoulou N, Kempuraj D, Boucher WS, Sugimoto K, et al. 2005. Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. J. Immunol. 174:7665–75
Annu. Rev. Immunol. 2008.26:705-739. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-23
738
Sayed et al.
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195. Kempuraj D, Papadopoulou NG, Lytinas M, Huang M, Kandere-Grzybowska K, et al. 2004. Corticotropin-releasing hormone and its structurally related urocortin are synthesized and secreted by human mast cells. Endocrinology 145:43–48 196. Cao J, Cetrulo CL, Theoharides TC. 2006. Corticotropin-releasing hormone induces vascular endothelial growth factor release from human mast cells via the cAMP/protein kinase A/p38 mitogen-activated protein kinase pathway. Mol. Pharmacol. 69:998–1006 197. Micera A, Lambiase A, Rama P, Aloe L. 1999. Altered nerve growth factor level in the optic nerve of patients affected by multiple sclerosis. Mult. Scler. 5:389–94 198. Micera A, Vigneti E, Aloe L. 1998. Changes of NGF presence in nonneuronal cells in response to experimental allergic encephalomyelitis in Lewis rats. Exp. Neurol. 154:41–46 199. Arredondo LR, Deng C, Ratts RB, Lovett-Racke AE, Holtzman DM, Racke MK. 2001. Role of nerve growth factor in experimental autoimmune encephalomyelitis. Eur. J. Immunol. 31:625–33 200. Levi-Montalcini R, Skaper SD, Dal Toso R, Petrelli L, Leon A. 1996. Nerve growth factor: from neurotrophin to neurokine. Trends Neurosci. 19:514–20 201. Zhang J, Li Y, Lu M, Cui Y, Chen J, et al. 2006. Bone marrow stromal cells reduce axonal loss in experimental autoimmune encephalomyelitis mice. J. Neurosci. Res. 84:587–95
www.annualreviews.org • Mast Cells in Autoimmunity and Tolerance
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Annual Review of Immunology
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:705-739. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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T Follicular Helper (TFH) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay Immunology and Inflammation Research Program, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; email:
[email protected],
[email protected],
[email protected] Annu. Rev. Immunol. 2008. 26:741–66
Key Words
First published online as a Review in Advance on January 2, 2008
T cell help, autoimmunity, IL-21, chemokines, immunodeficiency, antibodies
The Annual Review of Immunology is online at immunol.annualreviews.org This article’s doi: 10.1146/annurev.immunol.26.021607.090344 c 2008 by Annual Reviews. Copyright All rights reserved 0732-0582/08/0423-0741$20.00
Abstract T cell help for antibody production is a fundamental aspect of immune responses. Only recently has a better understanding of the cellular and molecular mechanisms for T cell help emerged. A subset of T cells, termed T follicular helper cells (TFH cells), provides a helper function to B cells and represents one of the most numerous and important subsets of effector T cells in lymphoid tissues. TFH cells are distinguishable from Th1 and Th2 cells by several criteria, including chemokine receptor expression (CXCR5), location/migration (B cell follicles), and function (B cell help). Central to the function of CD4+ T cells is IL-21, a “helper” cytokine produced by TFH cells that potently stimulates the differentiation of B cells into Ab-forming cells through IL-21R. Consequently, dysregulation of TFH cell function, and over- or underexpression of TFH cell–associated molecules such as ICOS or IL-21, most likely contributes to the pathogenesis of certain autoimmune diseases or immunodeficiencies.
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INTRODUCTION
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One of the fundamental discoveries of modern immunology was the finding that antibody (Ab) responses require “help” from cells of thymic origin. In these classic experiments (1, 2), cells from different sources were transferred to irradiated recipients. Because irradiation destroyed the recipient’s endogenous immune system, any effect could be attributed to the donor cells. Neither bone marrow cells nor thymocytes alone were sufficient to reconstitute an Ab response to sheep red blood cells. However, irradiated mice that received cells from both bone marrow and thymus responded well. These interacting cells later became known as B and T cells, respectively. Because the bone marrow–derived (B) cells but not the T cells were identified as the actual Ab-forming cells, the response was referred to as T-dependent, and thymus-derived cells were called T “helper” (Th) cells. The generation of Ab-forming cells occurs during a germinal center (GC) reaction (3, 4). GCs are specialized structures that develop within B cell follicles of secondary lymphoid tissues, such as lymph nodes, spleen, tonsils, and the Peyer’s patches of mucosal-associated lymphoid tissues. It is within the GC that critical processes such as somatic hypermutation, class switch recombination, and selection of high-affinity B cells occur (3, 5, 6). The GC reaction is essentially the engine that drives T cell–dependent Ab responses, and the GC is an important site where T cells provide direct help to antigen-specific naive B cells. Importantly, CD4+ T cells are essential for the formation of a GC reaction (7), and they provide developmental cues for the differentiation of antigen-selected high-affinity GC B cells into memory B cells or plasma cells, which together sustain long-term humoral immunity (6–8). Despite the fundamental role of CD4+ T cells in B cell responses and humoral immunity, there was, until recently, little appreciation of the cellular and molecular mechanisms for T cell help. Th2 cells, which produce cytokines such as IL-4 and direct B cells 742
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to undergo Ig isotype switching to IgG and IgE, were long considered to be the cells that provided help to B cells. It is now apparent that a subset of nonpolarized CD4+ T cells termed follicular B helper T cells (TFH ) (also referred to simply as T follicular helper cells) are the true helper cells for Ab responses, although other T cells such as Th2 cells, γδ T cells, and NKT cells may also contribute. The important developments that have driven this field of study have been the discovery of numerous molecules that participate in providing T cell help to B cells. The interaction between CD40 on B cells and CD40L (CD154), transiently expressed on activated CD4+ T cells, stimulates B cell proliferation and, in the presence of appropriate cytokines, isotype switching as well (9). Inducible costimulator (ICOS) is another essential costimulatory molecule expressed on activated CD4+ T cells that, when engaged by its ligand (ICOS-L) on antigen-presenting cells (APCs) including B cells, induces the production of helper cytokines such as IL-2, IL-4, and especially IL-10 (10). However, it was the identification of the chemokine receptor CXCR5 that has provided a particular impetus for the understanding of T cell help for B cells, as CXCR5 serves as a marker for TFH cells and promotes the colocalization of T and B cells in lymphoid follicles. Here, we discuss some of the controversial questions concerning TFH cell differentiation, the relation of TFH cells to other T cell subsets such as Th2 and/or Th17, and the influence of several molecules that are highly expressed by TFH cells and most likely participate in T cell–dependent B cell differentiation. One molecule we discuss in detail is IL-21, which has all the hallmarks of a “helper” cytokine (a separate article in this volume covers the biology of IL-21; see Reference 11). IL-21, despite its roles in other systems, is a TFH cell–secreted cytokine and is one of the most important stimulators of B cell proliferation, isotype switching, and differentiation (12). Indeed, the fields of IL-21 and CD4+ T cell help are rapidly converging.
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Finally, we argue that many immunological disorders, including autoimmune diseases, immunodeficiencies, and malignancies, relate to dysfunction of TFH cells or their associated effector molecules. Thus, targeting of TFH cell molecules should offer new opportunities for the therapeutic manipulation of immune responses.
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CXCR5 AND THE IDENTIFICATION OF TFH CELLS The identification of the true CD4+ helper T cell for B cells followed the discovery of CXCR5. CXCR5 is a chemokine receptor expressed by all mature B cells as well as a subset of antigen-experienced CD4+ T cells in lymphoid tissues. CXCR5 is largely absent from CD8+ T cells and naive CD4+ T cells. CXCR5 is responsible for the positioning of B and T cells in the follicular areas of lymphoid tissues (13) through recognition of its ligand, the chemokine CXCL13, which is produced by follicular stromal cells, including follicular dendritic cells (FDCs) (14, 15). Remarkably, ∼50% of CD4+ T cells in activated lymphoid tissues, such as human tonsils, are CXCR5+ , and a subset of these localizes to the GC (16–18). Indeed, following antigen stimulation, the quantity of CXCR5+ CD4+ T cells in lymphoid tissues far exceeds that of any other type of effector T cell. CXCR5+ CD4+ T cells isolated from human tonsils are efficient at providing help to B cells, thereby facilitating their differentiation into plasma cells (17– 21). Because of their ability to provide B cell help, their clear phenotypic distinction from Th1 and Th2 cells, and their predominant localization to B cell follicles, CD4+ CXCR5+ T cells were termed T follicular helper (TFH ) cells (17–19).
ORIGIN OF TFH CELLS AND THEIR RELATION TO Th1, Th2, Th17, AND Treg CELLS Perhaps the most pertinent yet unresolved issue pertaining to TFH cells is their relation-
ship to other T cell subsets, such as Th1, Th2, Th17, and T regulatory (Treg) cells (see Figure 1). Various transcription factors determine effector T cell differentiation, and the five main effector T cell subsets express distinct transcription factors (Figure 1). The five effector T cell subsets depicted in Figure 1 secrete different cytokines, express different chemokine receptors, and localize to diverse sites. These functions relate to the cells’ specialized roles in immune defense. For instance, Th2 cells produce cytokines associated with defense against large extracellular parasites (Figure 1). T cell help for B cells was long attributed to Th2 cells because Th2 clones support Ab production in vitro better than Th1 clones (22) and because IL-4, a Th2 cytokine, stimulates B cell proliferation and class switching and induces upregulation of costimulatory molecules such as CD40 and MHC class II. However, B cell help still occurs in the absence of IL-4, inasmuch as IL-4deficient mice can generate T-dependent Ab responses (23, 24). A revised model for T cell help shows that TFH cells are the predominant helper cells for B cells, and that Th1 or Th2 cytokines serve to skew responses in particular directions. For instance, IL-4 promotes Ig isotype switching to IgE, which is important for antiparasite responses, whereas IFN-γ favors isotypes important for antiviral immunity. Figure 1 depicts a relatively simple model for the differentiation of the various T effector subsets; however, the point at which functional TFH cells emerge is uncertain. The development of a follicular homing capability by activated T cells is the first event in the process. Naive T cells are CXCR5− and use the chemokine receptor CCR7 to enter secondary lymphoid organs and migrate to T cell zones (25). CXCR5 is transiently upregulated on CD4+ T cells following their activation, thereby endowing them with a follicular homing capability. This upregulation occurs prior to proliferation and differentiation and is dependent on costimulatory signals delivered through CD28, OX40, and ICOS www.annualreviews.org • T Follicular Helper Cells
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Function
Th1 T-bet
Th2 IL-12
IFN-γ TNF
Antiviral, bacterial immunity
IL-4 IL-13
Immunity to extracellular parasites
TGF-β
Regulation/ tolerance
IL-17
Inflammation, fungal immunity
IL-21
T cell help for B cells
CXCR3 CCR5
GATA-3 STAT-6 CrTh2
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IL-4 Primed T
Naive T
CCR7
CXCR5
Treg
TGF-β
Foxp3
TGF-β IL-6 IL-23
Th17 RORγT
?
CCR4
TFH Bcl-6? CXCR5
Figure 1 Effector T cell differentiation and the expression of transcription factors, effector cytokines, and chemokine receptors. Transcription factors for each subset have been placed in the nucleus (note that the role of Bcl-6 in TFH cell development still requires confirmation). The list of chemokine receptors, or cytokines, for each of the subsets is not exhaustive. Adapted with additions from Reference 32.
(26–30) (see also Figure 3 below). However, CXCR5 expression on activated T cells is only transient, and fully polarized Th1 and Th2 cells do not express this chemokine receptor (31). Several different fates are possible for activated T cells. Many lose expression of CXCR5 and either follow the Th1/Th2 (or Th17/Treg) differentiation pathways or leave the secondary lymphoid tissues to become circulating memory T cells. A fraction of cells, however, retains CXCR5 expression. These antigen-primed cells develop into effector T cells that can home to B cell follicles 744
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and, ultimately, provide help to B cells. The capacity to provide help must relate to acquisition of the relevant molecules— such as ICOS, CD40L, and IL-21—that have functional roles in humoral immunity (discussed below). However, these molecules can also be expressed by other T cell subsets, and so the differentiation steps leading to the generation of TFH effector cells are still largely unclear. A possible scenario for the generation of TFH cells has all T helper subsets (i.e., Th1, Th2, Th17, and TFH cells) arising independently from naive T cells, as suggested in Figure 1. In this
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scenario, activated CXCR5+ T cells serve as an intermediate cell type that gives rise to all the effector subsets depending on additional stimuli. Nevertheless, it must be stressed that a precise understanding of how Th cell fate is determined is still unclear. Activation of transcription factors, which determine cellular fate, must occur at certain points, and we propose that Bcl-6 is the transcription factor most likely to be required for the development of TFH cells. It is likely that after the initial activation by antigen-loaded APCs in the T cell zone, T cells destined to become TFH cells must receive additional signal(s) provided by cells located in or close to the B cell follicles. Two distinct cell types are excellent candidates for this role: B cells and CD4+ CD3− accessory cells. B cells may influence the differentiation of T cells into TFH cells. Abundant evidence also confirms that B cells direct T cell development, polarization, and memory (33–37). B cells may also influence further differentiation of TFH cells into Th1 or Th2 effector cells, as B cells are capable of producing IL-12 and IL-4 (38, 39), which may induce T cell polarization. CD4+ CD3− accessory cells could also provide the secondary signals for the differentiation of activated CXCR5+ T cells into TFH effector cells (40). These cells are of a nondendritic lineage and interact with antigen-specific CD4+ T cells that have been previously primed by dendritic cells (DCs). This interaction may depend on signals through OX40 and CD30. Furthermore, they are localized at the sites of T-B collaboration: B cell follicles and the T-B interface (40). A particularly controversial topic is the relationship of TFH cells to Th17 cells. Th17 cells rely on the transcription factor RORγt and cytokines such as TGF-β together with either IL-6 or IL-21 for their differentiation and function, which are clearly distinct from those used by Th1 or Th2 cells (Figure 1). Even though Th17 cells were not defined when TFH cells were discovered, TFH cells do show some striking similarities
to Th17 cells, particularly autocrine stimulation by IL-21 and provision of B cell help (41) (discussed below). Nevertheless, TFH cells are clearly distinguishable from Th17 cells in that they do not express Th17 cytokines such as IL-17 and IL-22, and Th17 cells do not express CXCR5 (120). However, many of the molecules that characterize TFH cells are also involved in functions associated with other effector subsets, including Th17 cells. Our analysis of TFH cell gene transcription using Affymetrix microarrays has failed to identify many of the gene transcripts associated with Th17 cells, such as RORγt, IL-17, IL-22, IL23R, or CCR6 (C.R. Mackay, unpublished data).
MOLECULES ASSOCIATED WITH TFH CELL FUNCTION The features of CXCR5+ TFH cells that distinguish them from Th1, Th2, Th17, or other T cells (42) are summarized in Figure 2. Like other effector T cells, TFH cells in lymphoid tissues express markers indicative of activation, such as CD69, CD95, and ICOS, and also express low levels of CCR7 and CD62L (similar to Th1 and Th2 cells). They also have effector function, namely provision of help for Ab production (16–18, 20, 21). Furthermore, although CXCR5+ T cells have a very limited repertoire of cytokine secretion, they do express IL-21, which, despite its association with NKT cells (43) and Th17 cells (44, 45), is highly associated with TFH cells (Figure 2) (discussed below). The primary function of TFH cells—provision of help for the differentiation of B cells into effector cells during a GC reaction—is substantiated by reports that TFH cells, compared with nonTFH cells, express increased levels of CD40L, ICOS, and IL-10 (17, 18, 20, 46). These molecules positively regulate B cell differentiation, and humoral immune responses are compromised in mice or humans with mutations in the CD40L and ICOS genes (47–50). www.annualreviews.org • T Follicular Helper Cells
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B cell
IL-21 staining of tonsil tissue CXCR5
T
ICOS-L
CD40
CXCL13
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IL-21R
CD84 IL-21 ICOS CD40L
SAP
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TFH cell Other important TFH-expressed molecules PD-1 Bcl-6 CD200 CD30L
CD57 Fyn CDK5r1 GPR18
IL-6R IL-21R BTLA Sialyltransferase 8A
Figure 2 Important molecules for TFH cell function. (Left) Human tonsil stained for IL-21 expression using an anti-IL-21 mAb. Regions of the tonsil are indicated, including T cell areas (T), the B cell follicle (B), and the germinal center (GC). Note the positioning of IL-21-expressing cells at the rim of the GC. IL-21 expression is not restricted to the GC, and numerous cells in the T cell zone express IL-21. Whether these represent TFH -like cells or Th17 cells remains to be determined. (Right) Some of the best-characterized interacting molecules for TFH and B cells. Listed below are numerous other molecules overexpressed in TFH cells that presumably play an important role in their function.
Interestingly, circulating TFH cells are deficient in humans with mutations in CD40L or ICOS genes (29). Recent microarray analyses showed that TFH cells express an extensive array of genes that distinguishes them from Th1- and Th2type CD4+ T cells (51–54). For instance, compared with conventional CD4+ T cells, human TFH cells express higher levels of IL-21, the intracellular adaptor protein SAP (SLAM-associating protein), SAP-associating transmembrane receptors CD84 and CD229 (Ly9), the protein tyrosine kinase FynT, as well as the GC-restricted transcription factor Bcl-6 (51, 52, 54) (see also Figure 2). Using the Roquin mouse, which has expanded TFH cells as a result of a defect in degradation of ICOS transcripts (discussed below), Vinuesa et al. (53) showed that mouse TFH cells have a molecular profile remarkably similar to that of human TFH cells, as they also prefer746
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entially express transcripts for IL-21, CD84, CXCL13, Bcl-6, PD-1, and many others. The relevance of some of the more important TFH cell-expressed molecules is discussed below.
Bcl-6 Transcription factors determine T cell fate, and the important elements that drive Th1, Th2, Th17, and Treg cell differentiation have now been identified (see Figure 1). For instance, T-bet determines Th1 cell lineage commitment and cytokine production, and GATA-3 and c-Maf drive Th2 cytokine production (55). Th17 differentiation is initiated by TGF-β and either IL-6 or IL-21, which activate signal transduction and activator of transcription (STAT) 3 and induce expression of the transcription factor RORγt, ultimately resulting in lineage specification (56, 57). Currently there is no definitive
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evidence for a particular transcription factor directing the commitment of naive CD4+ T cells to the TFH cell lineage, although circumstantial evidence favors Bcl-6. The expression of Bcl-6 is tightly regulated and is largely confined to GC B cells (58–60). Also, Bcl-6 is preferentially expressed by TFH cells but not by Th1 or Th2 cells (51). In B cells, Bcl-6 is a master regulator of GC lineage commitment and is a suppressor of plasma cell differentiation (61). Bcl-6-deficient mice display defective T-dependent Ab responses and have limited Ab affinity maturation owing to the absence of GCs (62, 63). Bcl-6 expression also represses GATA-3 and downregulates secretion of IL-4 by T cells, thus providing further support of a dynamic role for Bcl-6 in T cell differentiation and fate (64). However, expression of Bcl-6 by T cells in follicles is by no means uniform: Only 10%–15% of CD4+ T cells in GCs appear to express Bcl-6 protein (65). It is conceivable that Bcl-6 determines TFH commitment at stages before or after Th1, Th2, or Th17 differentiation.
ICOS ICOS is a CD28-like costimulatory molecule with an important role in T-dependent Ab responses. Expression of ICOS is regulated during T cell activation and differentiation, such that ICOS upregulation occurs following the receipt of signals during T cell activation (Figure 3). T cells stimulated through the T cell receptor (TCR), CD28, and ICOS proliferate and produce cytokines, such as IL4 and IL-10, that facilitate T:B interactions and antibody production (10, 37, 66). ICOS is expressed at very high levels on TFH cells within the light zone of GCs (10, 17, 67), and a direct correlation exists between the expression of ICOS by CD4+ T cells and the amount of IL-10 produced (37, 68). This correlation suggests an important role for this pair of effector molecules in regulating B cell responses. Indeed, ICOS deficiency is associated with impaired IL-10 production in human and murine CD4+ T cells (48, 69, 70).
ICOS is also expressed by other T cells, notably Th2 cells, whereas its ligand, ICOSL, is expressed on APCs, including B cells (71, 72). In contrast to CD28, ICOS is not constitutively expressed, but is instead induced after T cell activation (10) (Figure 3). ICOS signaling enhances T cell proliferation, the secretion of cytokines, especially IL-10, as well as the upregulation of cell-cell interaction molecules. The genes upregulated following engagement of ICOS are similar to those upregulated by CD28 in both human- and murine-stimulated CD4+ T cells, although the magnitude of gene upregulation induced by ICOS is less than that induced by CD28 (73, 74). Probably the most important difference between signals delivered through CD28 and ICOS is that their ligands are expressed at high levels on different cell types (DCs and B cells, respectively). This difference relates to the specific roles of these two molecules, first for the regulation of T cell priming, and subsequently for T-B interactions (see Figure 3). Homozygous loss of ICOS is associated with late-onset common variable immunodeficiency (CVID) in humans (49). Patients with CVID due to ICOS deficiency lack GC in their lymph nodes, consequently show a dramatic reduction in the number of IgM-expressing memory B cells, and are essentially devoid of isotype-switched memory cells. Interestingly, these patients also have a deficiency in the number of CXCR5+ CD4+ T cells in their peripheral blood. This finding may explain the reduced production of IL-10 and IL-17 by their CD4+ T cells (29, 49). Consistent with these results, mice deficient in ICOS or ICOS-L also have impaired GC formation and isotype switching, diminished TFH cell numbers in their spleens, and reduced production of B cell helper cytokines, such as IL-4 and IL-10 (29, 30, 48, 78–81). These findings suggest that ICOS signaling is important for the maintenance and/or generation of TFH cells (29, 30) and reinforce the association between ICOS expression and IL-10 production. In support of this www.annualreviews.org • T Follicular Helper Cells
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Figure 3 Multiple signals and steps for the generation of TFH cells and T-dependent antibody responses. CD28 and ICOS, together with IL-21, costimulate T cells activated through the T cell receptor (TCR). The ordered expression of the various costimulatory molecules, cytokines, and receptors facilitates the various steps in the process of TFH cell differentiation and function. (a) In the T cell zone of lymphoid tissues, mature DCs expressing B7.1 and B7.2 present peptide-MHC class II (pMHCII) ligand to the TCR of naive CD4+ T cells, which constitutively express CD28 (CD28c). CD28 provides the early costimulatory signal that, with TCR stimulation, induces expression of other costimulatory receptors belonging to the Ig and TNFR/TNF superfamilies (75). Ligation of CD28 amplifies the TCR signal rather than delivering a qualitatively different signal (75, 76). (b) Activated CD4+ T cells produce IL-21 and induce expression of CD28 (CD28i) and ICOS. (c) Sustained signaling of activated CD4+ T cells through the TCR, CD28, and IL-21R in the T zone and at the T-B cell interface leads to modulation of the expression of molecules important for migration, such as CXCR5, CCR7, and costimulatory receptors including ICOS, CD40L, and OX40 (28, 75, 77). (d ) Migration of functional TFH cells to follicles and delivery of T cell help support the selection of activated Ig-secreting B cells in germinal centers.
association, one study showed that the B helper activity of tonsillar TFH cells corresponded with a high level of expression of ICOS, such that only the CXCR5hi ICOShi CD4+ T cells were potent inducers of IgG production by cocultured B cells (82). Thus, the reduced GC response associated with ICOS deficiency might simply result from reduced numbers of TFH cells. The high expression of both ICOS and IL-21 are defining features of TFH cells, and ICOS expression defines the subsets of Th cells that are prolific producers of IL-21. However, where these two axes meet at the 748
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level of TFH cell generation remains unclear. On the one hand, IL-21 may drive ICOS expression. We think this is unlikely because IL21-deficient mice have a defect in TFH cell generation but express an abundance of ICOS on all CXCR5− CD4+ T cells (A. Vogelzang & C. King, submitted manuscript). On the other hand, the assumption that ICOS expression is necessary for IL-21 production is also unlikely because blockade of ICOS:ICOSL interactions significantly reduces but does not eliminate IL-21 production, and T cells from ICOS-deficient mice can produce limited amounts of IL-21 (H. McGuire
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& C. King, submitted manuscript). Our view is that both IL-21 and ICOS are necessary for TFH cell generation and that T helper cells utilize ICOS:ICOS-L interactions that quantitatively contribute to IL-21 production.
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CD57 Immunohistochemical studies performed over the past two decades identified a small population of CD4+ T cells that were distinguishable by their coexpression of the NK cell marker CD57. These cells comprise ∼10% of all tonsil CD4+ T cells and localize to GCs (20, 21, 83, 84). Interestingly, all tonsillar CD4+ CD57+ T cells also express CXCR5 and thus represent ∼20% of the CXCR5+ subset (20, 21). Furthermore, CD4+ CXCR5+ CD57+ T cells in human tonsils express the activation molecules CD69, ICOS, HLA-DR, PD-1, OX40, and CD45RO and downregulate CCR7 and CD62L (20, 85; S. G. Tangye, unpublished observations), suggestive of an activated phenotype and/or effector function. Accordingly, CD57 has been described as a defining marker for T helper cells for B cells (20, 83). Despite these observations, the function of the CD57 molecule remains uncertain, and inconsistent findings have prompted researchers to question whether CD57 is actually a valid marker for TFH cells. For instance, CD57+ CD4+ T cells are incapable of producing B cell helper cytokines such as IL-4 and IL-10, and they are inefficient at inducing differentiation of cocultured autologous B cells into Ig-secreting cells in vitro (85–91). These findings are consistent with the proposal that CD57+ GC T cells are anergic (88) and exhibit regulatory activity by suppressing the function of CD4+ CD57− T cells (92). In contrast, other recent studies have reported that CXCR5+ CD57+ CD4+ T cells isolated from human tonsils exhibit increased cytokine production and induce greater B cell differentiation than do CXCR5+ CD57− CD4+ T cells (20, 46, 83, 93, 94). The
use of CD57+ CD4+ T cells from blood in some studies and from tonsils in others may have produced some of these differences. The fact that CXCR5+ and CXCR5− CD4+ T cells in blood and lymphoid tissues differ substantially with respect to their function and phenotype may have also contributed to the varying results. Our own studies have revealed that both tonsillar CXCR5+ CD57− and CXCR5+ CD57+ CD4+ T cells can induce differentiation of autologous B cells in vitro, whereas CXCR5− CD57− CD4+ T cells cannot. However, more Ig secretion was detected in cultures containing CXCR5+ CD57− T cells than in those with CXCR5+ CD57+ T cells (21). The most likely cause of these differences is the fact that CXCR5+ CD57+ CD4+ T cells undergo apoptosis more rapidly than CXCR5+ CD57− CD4+ T cells (46, 54, 95). Furthermore, expression of CD95 and PD-1 is higher on CXCR5+ CD57+ T cells than on CXCR5+ CD57− CD4+ T cells (S.G. Tangye, unpublished data), suggesting that in addition to the heightened intrinsic susceptibility of CXCR5+ CD57+ T cells to death, these cells may undergo greater apoptosis following engagement of death receptors by ligands expressed on B and T cells. High expression of ICOS, rather than CD57, probably better defines TFH cells capable of inducing Ig secretion from B cells (46, 51). Because ICOS is expressed at the highest level on CXCR5+ CD57+ T cells (S.G. Tangye, unpublished data), CXCR5+ CD57+ and CXCR5+ ICOShi + CD4 T cells probably share many phenotypic and functional characteristics.
IL-21: A TFH CELL–EXPRESSED HELPER CYTOKINE IL-21 was recently identified as a cytokine that costimulates lymphocyte proliferation and drives the differentiation of NK cells in vitro (96). IL-21 is a member of the common γ chain (γc)-signaling family of cytokines (96; see also Reference 11, in this volume). The www.annualreviews.org • T Follicular Helper Cells
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receptor for IL-21 (IL-21R) can be expressed by many cell types (97), but it is found predominantly on B cells as well as on some NK cells and T cells (51, 96, 98, 99). The IL-21R consists of a unique cytokine-binding protein (IL-21Rα) and the γc (98, 100), which is also a component of receptor complexes for IL-2, IL-4, IL-7, IL-9, and IL-15 (101). In vivo and in vitro studies have demonstrated a central role for IL-21 in lymphocyte activation, survival, and differentiation. Initial studies of the in vitro effects of IL-21 focused on its ability to enhance effector functions, such as IFN-γ production and cytotoxic function of CD8+ T cells and NK cells (102). More recently, IL-21 was shown to play a role in NKT cell and CD4+ T cell effector function (43). Notably, IL-21 greatly enhanced proliferation of human CD4+ CD25− T cells, rendering them resistant to Treg-mediated suppression (103). The ability of IL-21 to enhance the proliferation of T cells is in marked contrast to other γc-signaling cytokines such as IL-2 and IL-15 because IL-21 does not induce proliferation in the absence of stimulation through the TCR (96). Thus, IL-21 is a genuine T cell costimulator, and its potential for amplifying signals through the TCR is supported by evidence demonstrating that IL-21:IL-21R interactions generate signals through the Jak-STAT, MAPK, and PI3K pathways (104). The study of the role of IL-21 in Th cell differentiation is a rapidly evolving field, and the findings from a number of studies resonate with the important role of IL-21 in humoral responses. Recent studies have revealed that IL-21 is important for the generation and migration of Th2 cells (105–107), and TFH cells, in turn, express significantly greater amounts of IL-21 than do Th1 or Th2 subsets (51). Our own work with IL-21and IL-21R-deficient mice indicates that IL21 is an autocrine growth factor for TFH cells (Figure 3) (A. Vogelzang & C. King, submitted manuscript). IL-21 is a crucial component of TFH cell generation through its abil-
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ity to modulate expression of the chemokine receptors CXCR5 and CCR7 on activated T cells (A. Vogelzang & C. King, submitted manuscript). A defect in TFH cell generation in IL-21-deficient mice suggests a role for IL21 that precedes the upregulation of CXCR5 and movement of TFH cells into the B cell follicle. Collectively, these studies indicate that IL-21 has a fundamental role in T helper cell differentiation. One major target of IL-21 is B cells. Studies of ex vivo isolated human and murine B cells have demonstrated that IL-21 greatly enhances proliferation induced by ligation of CD40 (96, 108–110). In contrast, IL-21 inhibits proliferation of murine B cells induced by TLR ligands, namely LPS and CpG, by inducing apoptosis (108, 111, 112). Interestingly, some of the pro- and antiproliferative effects of IL-21 on murine B cells appear to be strain specific (108). IL-21 also modulates isotype switching and Ig production by human and murine B cells, as it can act as a switch factor for secretion of IgG1 and IgG3 by human B cells stimulated with anti-CD40 mAb (113), and induces differentiation of murine and human naive, GC and memory B cells into Ig-secreting cells (21, 110, 114). Although IL-10 had been considered the most potent inducer of plasma cell differentiation on human B cells, IL-21 exceeds its effects on CD40-stimulated human B cells by up to 100-fold (21). Human B cells stimulated with CD40 mAb and IL-21 are induced to express the enzyme activationinduced cytidine deaminase (AID) and the transcription factor B-lymphocyte maturation protein-1 (Blimp-1) (110), which play critical roles in Ig isotype switching and commitment to the plasma cell lineage, respectively. Importantly, the ability of human tonsillar TFH cells to provide B cell help for their differentiation into plasma cells is IL-21 dependent, as this effect was greatly reduced by neutralizing endogenous IL-21 present in these cultures (21). The action of IL-21 on the differentiation of human naive B cells into Ig-secreting cells could be reduced by
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IL-4 (21, 110)—through the ability of IL-4 to antagonize the IL-21-induced expression of Blimp-1 (21)—whereas the combination of IL-4 and IL-21 resulted in increased production of IgE in cultures of enriched human B cells (113, 115). In contrast to its effects on human B cells, IL-21 inhibited IgE production by murine B cells stimulated with LPS and IL4 (116). Together, these findings demonstrate a dynamic interplay among several different γc-binding cytokines. Several of the findings from in vitro cultures have been confirmed in vivo. For instance, mice transgenic for expression of human IL-21 have increased numbers of splenic B cells, including Ig isotype–switched cells and plasma cells (114). However, a deficiency of either IL-21 or its receptor results in an impaired ability to produce antigenspecific IgG following immunization with a T cell–dependent antigen. Furthermore, the levels of total as well as antigen-specific IgE are elevated in the serum of these mice (117, 118). This finding confirms the negative regulatory effects of IL-21 on IgE production by murine B cells (116, 117). Notably, Tdependent immune responses are completely abrogated in mice deficient in IL-4 and IL21R (117), suggesting that signaling through both IL-4R and IL-21R is necessary for optimal humoral immune responses. Recently, IL-21 was described as an essential autocrine factor for the generation and differentiation of Th17 cells (44, 45, 119), challenging a previous study that demonstrated unimpeded Th17-driven experimental autoimmune myocarditis in the absence of IL-21R signaling (105). These dramatic new findings bring into question the precise role of IL-21 and the relationship between TFH cells and Th17 cells. If Th17 cells produce copious amounts of IL-21, as indicated, it would imply that these T cells may also deliver a helper signal to B cells. However, one factor that may limit the interaction of Th17 cells with B cells is their expression of chemokine receptors: Th17 cells express CCR4 and CCR6 but lack CXCR5 (41, 120), which would recruit
Th17 cells to sites of inflammation but would exclude them from entry into B cell follicles.
MIGRATION AND LOCALIZATION OF TFH EFFECTOR AND MEMORY CELLS Chemoattraction to the CXCR5 ligand CXCL13 allows TFH cells to localize to B cell follicles, where they can directly provide help to B cells. CXCR5 is also expressed by most B cells and is required for the development of B cell follicles in secondary lymphoid tissues. Mice lacking either CXCR5 or CXCL13 show major aberrations in follicular architecture and reduced numbers of lymph nodes and Peyer’s patches (13, 121). Expression of CXCR5 is transiently upregulated when T cells interact with peptide-MHC class II and with costimulatory molecules on APCs (122, 123), and levels of CXCR5 expression following priming may reflect qualitative or quantitative aspects of this stimulation. For instance, antigen-specific TCRtransgenic CD4+ T cells exhibit a higher and more homogenous expression of CXCR5 following immunization than do their polyclonal counterparts (123). One factor that distinguishes TFH from recently activated CD4+ T cells is their continued expression of CXCR5. Further interaction with peptideMHC class II ligand and costimulatory molecules on B cells at the B cell/T cell interface and within the GC is likely to preserve CXCR5 expression on TFH cells. Interaction between effector T cells and B cells occurs first in T cell areas and later in B cell follicles within secondary lymphoid organs (3, 4, 124). After the first engagement, B cells either migrate to extrafollicular foci, where they differentiate into plasma cells that rapidly secrete low-affinity antibodies, or they migrate (along with T cells) into follicles and form GCs, where somatic mutation and affinity maturation occur. As emphasized previously, the GC reaction is strongly dependent on help from antigen-specific T cells, www.annualreviews.org • T Follicular Helper Cells
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which must migrate into the follicle to support this response (123–126). The chemoattractant receptor characteristically expressed by TFH cells is CXCR5, which facilitates TFH cell migration to follicles. However, the conditions under which TFH cells localize to follicles may vary. Naive T cells that recirculate through lymphoid tissues gain entry primarily through their expression of L-selectin and the chemokine receptor CCR7. T cells colocalize with DCs in the T cell zone, allowing unprimed T cells to first receive signals from professional APCs rather than from B cells. A remarkable sequence of cellular movements follows successful T cell priming (15): Activated T cells (which have upregulated CXCR5) migrate to the B cell follicles and position themselves at the edge of the follicle, where they meet antigen-primed B cells that have specifically migrated outward. Physical interactions then facilitate CD40-CD40L-dependent B cell activation. Thereafter, antigen-primed T cells are distributed throughout the entire follicle, including the GC, to provide helper signals to B cells. Whether TFH cells can enter follicles directly from the blood is an interesting but unresolved question. Although TFH cells have all the hallmarks of an activated, effector subset of T cells, unresolved issues remain: The exact proportion of CXCR5+ CD4+ T cells in lymphoid tissues that can provide help to B cells and the precise location of these T cells are unknown. Certainly, CXCR5+ CD4+ T cells in GC can be considered true TFH cells; however, T cells closely related in phenotype and function most likely exist outside of follicles (for instance, note the large numbers of IL-21+ cells in the T cell zone shown in Figure 2). Moreover, at least six different follicular T cell subsets have been identified on the basis of surface markers and/or anatomical location (reviewed in Reference 42). In human tonsils, follicular T cells are located in the mantle zone, the outer zone, and the light zone of the GC. Although they are all defined by CXCR5 expression, they differentially ex-
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press other markers such as CD57 and ICOS (discussed below). A subset of CXCR5+ CD4+ T cells also exists in blood (∼10%) (16), but these cells are in a resting state and are incapable of providing help to B cells. They coexpress CD62L and CCR7 and probably represent a subset of TFH cell–derived memory T cells. The fate of TFH cells following the GC response has significant implications for immunological memory, vaccine development, and autoimmunity. Until recently, TFH cells were considered fully differentiated cells, prone to apoptosis due to high expression of CD95 (54). However, a recent study demonstrated that a local memory CXCR5+ CD69+ TFH cell compartment is retained in B cell follicles after resolution of the GC response (127). A population of high-affinity CXCR5+ T cells remained for an extended period of time in the proximity of CXCL13-expressing FDCs and were reactivated upon secondary immunization (127). Thus, immunological memory associated with TFH cells probably differs markedly from memory associated with other types of T cells. Furthermore, because the site for TFH cell function is lymphoid tissue, it would not be surprising if immunological memory in this T cell population were more sessile than that in, for instance, a CD8+ T cell or Th1 population. Although the possibility that CXCR5 expression on TFH memory cells becomes fixed during differentiation remains, it is more likely that the microenvironment supplies some factor(s) that maintains their CXCR5hi phenotype. TFH memory cells were found in the vicinity of peptide-MHC class II depots in draining lymph nodes after immunization (127), suggesting that local triggering of TCR maintains expression of CXCR5 and CD69 on TFH cells. The maintenance of CXCR5 expression on TFH cells would be consistent with a continued interaction between a small number of remaining antigen-specific T cells and B cells, or other APCs, near the FDC network after resolution of the GC. However, the level of ongoing stimulation was not
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adequate to maintain expression of TFH effector cell molecules such as ICOS and IL21, which require antigen challenge for their reexpression. Thus, TFH effector cells differ markedly in their localization and recirculation patterns compared with other effector T cell subsets (128). Whereas most effector T cells, such as IFN-γ-producing Th1 cells or cytotoxic CD8+ T cells, localize to peripheral tissues or inflammatory lesions, TFH effector or memory cells localize to lymphoid tissues, particularly B cell follicles.
CXCR5+ γδ T CELLS Although T cell help for B cells has historically been viewed in the context of conventional CD4+ αβ TCR+ cells, the fact that αβ T cell–deficient mice can mount Ab responses to T-dependent Ag suggests that other lymphocytes may provide help for B cells (129). Subsequent studies demonstrated that γδ T cells underlie the ability of αβ T cell– deficient mice to produce GCs and relatively normal levels of serum Ig (129). Researchers (130) also recently found that ∼15% and 50% of γδ T cells present in peripheral blood and tonsils, respectively, express CXCR5. These frequencies are similar to those of CXCR5+ CD4+ T cells in these sites. Furthermore, CXCR5+ γδ T cells in tonsils display a phenotype, helper cytokine profile, and effector function that resemble those of tonsillar CXCR5+ CD4+ T cells: CXCR5+ γδ T cells express CD45RO, CD27, HLA-DR, CD40L, and ICOS, but not CCR7 and CD62L (130); they produce vast amounts of IL-4 and IL10, but low levels of IFN-γ and TNF-α; and they have the ability to induce differentiation of cocultured B cells (130). The in vitro findings are consistent with the detection of γδ T cells within the FDC network of established GC in human lymphoid tissues (131). Determining whether IL-21 plays any role in the helper function of CXCR5+ γδ T cells may provide some interesting insights. Of note, γδ T cells express IL-21R and CXCL13 (a signature molecule of TFH cells)
when stimulated with IL-21 (132). Autocrine production of IL-21 by TFH cells may also regulate their production of CXCL13, and together these molecules guide both γδ and αβ CXCR5+ T cells to follicular areas of lymphoid tissues, where they would be positioned to provide B cell help. Because αβ and γδ T cells recognize different repertoires of Ag, the compartmentalization of a subset of each of these populations capable of inducing Ig secretion would provide a mechanism whereby humoral immune responses could be elicited against a diverse array of Ag irrespective of the type of responding T cell.
TFH CELL DYSREGULATION AND DEVELOPMENT OF AUTOIMMUNITY New B cell receptor specificities, including those with autoreactivity, arise continuously during the GC reaction. Ab-forming cells that emerge from the GC reaction need to be tightly controlled, owing to their longevity and production of high-affinity antibodies. Consequently, most B cell responses depend on T cell help. The absence of T cell help during B cell priming leads to apoptosis, rather than differentiation of B cells into GC cells or plasma cells. Thus, self-reactive follicular B cells are usually precluded from differentiation within GCs and are normally absent from the memory and plasma cell compartments (133). B cells must compete for T cell help, and the presence of self-reactive T cells leads to the emergence of high-affinity self-reactive B cells. Accordingly, any dysregulation of T cell function or tolerance induction can have a significant effect on the selection of Ab specificities. There is substantial evidence for a T cell basis for autoantibody responses in certain autoimmune diseases. GC formation has been described in many autoimmune strains of mice, and these arise during onset of autoantibody production (134). In patients with autoimmune diseases, for example systemic lupus erythematosus (SLE), www.annualreviews.org • T Follicular Helper Cells
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self-reactive B cells survive within GCs and differentiate to plasma cells and memory cells (133). The involvement of TFH cells in autoantibody production is evident in various strains of mice that either over- or underexpress important TFH cell–associated molecules such as CD40L, ICOS, SAP, and IL-21. Blocking CD40CD40L interactions prevents GC formation, autoantibody production, and the aberrant accumulation of GC-like B cells and plasmablasts in the peripheral blood of patients with SLE (135) as well as in murine models of lupus (134). Moreover, two different murine models of human lupus are characterized by a TFH cell–like transcriptome in their spleens (53, 136). IL-21 is also overexpressed in BXSB mice, which develop murine lupus (114). Interestingly, human SLE patients and lupus-prone mice have an increased frequency of ICOS+ CD4+ T cells in their peripheral blood (137) and spleens (138), respectively, suggesting an expansion of TFH cells in these pathogenic conditions. Likewise, Roquin−/− mice exhibit a clear increase in numbers of TFH cells as a result of excessive signaling through ICOS. It is unclear whether dysregulated signaling though ICOS results in the characteristic increase in il-21 message noted for lupus-prone mice. However, because blocking ICOS/ICOS-L interactions (138) or neutralizing IL-21 (139, 140) ameliorates disease in animal models of human lupus and rheumatoid arthritis, increased expression of ICOS may augment production of IL-21, which subsequently promotes B cell activation and secretion of pathogenic autoantibodies. In summary, immunological tolerance among T cells appears to be particularly relevant for the control of autoimmune antibody specificities, and it is likely that TFH cells provide inappropriate helper signals to selfreactive B cells in cases of antibody-mediated autoimmune diseases. Beyond their restricted role in T cell help for B cells, TFH cells may also promote chronic inflammation. Prototypic TFH cells express CXCR5 and localize to B cell folli-
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cles in lymphoid tissues. These two factors distinguish them from Th17 cells, which localize to nonlymphoid tissues. However, in dysregulated immune responses, TFH cells have been identified in nonlymphoid tissues, particularly in autoimmune diseases; this may result from CXCL13 production at these sites. TFH and Th17 cells both express high levels of ICOS, and the costimulation provided by IL-21 promotes their generation (see Figure 3). In this context, dysregulated TFH cells producing large amounts of IL-21 at nonlymphoid sites could elicit widespread effects that contribute to chronic T cell–mediated autoimmune inflammation, including the bystander generation of Th17 cells. Human autoimmune diseases mostly affect nonlymphoid tissues, which often contain large numbers of infiltrating, activated lymphocytes (141), as well as lymphoidlike tissues with an ectopic GC (134, 142– 145). These ectopic GCs may be a site for generating high-affinity antibodies through somatic hypermutation. Understanding the mechanisms that enable the development of these outposts of lymphoid tissue in peripheral tissues, and the mechanisms that favor their maintenance rather than resolution, remains relevant for also understanding the pathogenesis of certain autoimmune diseases. Chemokines produced in ectopic GCs as well as in other lymphoid tissues are likely to be instrumental for the development and maintenance of these structures. TNF-α and lymphotoxin play a well-established role in lymphoid neogenesis, mediated in part through regulated production of the homeostatic chemokines CXCL13, CCL19, and CCL21 (146). Analysis of CXCL13, CCL19, and CCL21 expression in synovium of patients with rheumatoid arthritis suggests that the formation of a GC is dependent on the concentrations of both CXCL13 and lymphotoxin (147). CXCL13 is usually produced by FDCs in secondary lymphoid tissues. However, in rheumatoid arthritis, CXCL13producing cells were identified as vascular
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endothelium and synoviocytes (147, 148). A possible scenario within inflamed tissue is that TNF-α, secreted by infiltrating inflammatory cells, induces production of CXCL13 by vascular endothelium and synoviocytes, and the CXCL13 then recruits circulating B cells and TFH cells and induces expression of lymphotoxin and development of ectopic GC.
MECHANISM FOR REGULATION OF TFH CELLS Normally, various mechanisms operate to prevent delivery of inappropriate help to selfreactive B cells. For instance, follicular CD4+ CD25+ CD69− Tregs that express CXCR5 localize to the follicles and suppress the helper effects of follicular CXCR5+ CD57+ cells for Ab production by GC B cells (149). Another mechanism hinges on the suppressive effects of Roquin, a ubiquitin ligase that prevents differentiation and activation of self-reactive TFH cells (53) Large numbers of T cells in sanroque mice (which bear a single base pair substitution in roquin) develop a TFH phenotype and accumulate in the follicles. These T cells resemble human TFH cells in that they express high levels of ICOS, CXCR5, CD200 and PD1 and transcripts for IL-21 (53). sanroque mice form spontaneous GCs and develop an autoimmune-like syndrome associated with high levels of autoantibodies. Roquin negatively regulates ICOS expression in T cells by promoting the degradation of Icos mRNA. A conserved segment in the Icos 3 untranslated mRNA is important for regulation by Roquin. This segment comprises a 47–base pair region complementary to T cell–expressed microRNAs. The repressive activity of this segment is disrupted by base pair inversions in sanroque mice, which are predicted to abrogate miR-101 binding (150). These findings highlight the central role of ICOS mRNA regulation (and, indirectly, TFH cells) in the pathogenesis of T-dependent Ab-mediated autoimmune diseases.
TFH CELLS AND IMMUNODEFICIENCIES Ineffective T cell help to B cells appears to underlie certain humoral immunodeficiencies. Examples of such immunodeficiencies include X-linked lymphoproliferative disease (XLP), ICOS deficiency, and CVID, conditions in which affected individuals experience progressive hypogammaglobulinemia as well as an impaired ability to form GCs and generate long-lived memory B cells and serological immunity (49, 69, 70, 151, 152). Such defects are also observed in mice that have been rendered deficient in genes associated with TFH cells, such as CXCR5, CD40/CD40L, ICOS/ICOS-L, and SAP (79, 153–155). Interestingly, CXCR5+ CD4+ T cells are deficient in mice and humans lacking functional CD40-L (29), ICOS (29, 30), or CD28 (28). Furthermore, CD4+ T cells from patients with XLP and from sap−/− mice are unable to upregulate ICOS expression in vivo and in vitro and are defective in production of B helper cytokines, such as IL-4 and IL-10 (70, 152, 156). These findings have shed light on some of the molecular requirements for the generation and effector function of TFH cells. Because TFH cells express an array of molecules involved in the provision of B cell help—ICOS, CD40L, OX40, IL-21, SAP— it is likely that compromised development or function of TFH cells contributes to impaired B cell differentiation and humoral immunity in conditions of immunodeficiency.
TFH CELLS AND LYMPHOMAS Human TFH cells have a distinct phenotype and genotype (Figure 2) (discussed above). Accordingly, several recent studies that have compared the transcriptome or phenotype of malignant T cells have recognized that the malignant cell phenotype in angioimmunoblastic T cell lymphoma (AITL) shares many similarities with that of TFH cells. Specifically, malignant AITL cells are CD4+ T cells that express Bcl-6 (65, 157, 158), www.annualreviews.org • T Follicular Helper Cells
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CXCR5, CD40L, OX40, and PD1 (159–161) and produce CXCL13 (162). However, the malignant cells in AITL are unique in their expression of CD10 (163). This marker may therefore serve as a means of discriminating between normal and malignant TFH cells. Hallmarks of AITL are B cell activation, hyperplastic B cell follicles within lymph nodes, hypergammaglobulinemia, and proliferation of FDCs (163). Furthermore, within reactive lymph nodes of patients with AITL, the malignant T cells are in close association with activated B cell follicles and FDCs (163). For these reasons, researchers (159, 162) recently proposed that the dysregulated production of CXCL13 and constitutive expression
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of CD40L by malignant TFH cells may result in the increased recruitment of B cells into follicles, their aberrant activation, and subsequent hypergammaglobulinemia. It is certainly possible that CXCL13 produced by malignant CD4+ TFH cells is responsible for recruiting large numbers of B cells into reactive follicles in lymph nodes of patients with AITL. However, given the potent effects of IL-21 on the activation and differentiation of human B cells into Ig-secreting cells (109, 110, 113), the sustained production of IL-21, rather than CXCL13, by TFH cells may more likely underlie the exaggerated B cell activation and hypergammaglobulinemia characteristic of this disease.
SUMMARY POINTS 1. TFH cells are one of the most numerous and important subsets of effector T cells. TFH cells are distinguishable from Th1 and Th2 cells in several respects: chemokine receptor expression (CXCR5), location and migration (follicles), function (B cell help), cytokine production (IL-21), and expression of transcription factors (Bcl-6). 2. IL-21 serves as a “helper” cytokine produced by TFH cells that stimulates B cells through IL-21R. IL-21 may also serve as an autocrine factor for TFH cells. 3. Many of the important molecules for TFH cell function, such as ICOS and IL-21, contribute to the pathogenesis of autoimmune diseases or immunodeficiencies. 4. The identification of TFH cells and the molecules they express provides opportunities for new therapeutic approaches to autoimmune diseases. Indeed, a number of companies are targeting TFH -associated molecules such as IL-21 and ICOS.
FUTURE ISSUES 1. Is Bcl-6 a transcription factor for TFH cells and does it determine their differentiation? 2. TFH cells are only now becoming accepted as a bona fide subset distinct from Th2 or Th1 cells; however, their relation to Th17 requires further clarification. 3. The study of the precise role of IL-21 in TFH cell differentiation and function, and its effects on other cell types, is a rapidly evolving field. IL-21 has been implicated in the function of numerous T cell subsets. Is IL-21 a classical “helper” cytokine that facilitates T cell help to many lymphocyte types, other than B cells? 4. How effective will inhibitors of TFH cell effector molecules be for the treatment of human autoimmune diseases?
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DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENT This work was supported by the Australian National Health and Medical Research Council and the Juvenile Diabetes Research Foundation.
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LITERATURE CITED 1. Claman HN, Chaperon EA, Triplett RF. 1966. Thymus-marrow cell combinations: synergism in antibody production. Proc. Soc. Exp. Biol. Med. 122:1167–71 2. Miller JF, Mitchell GF. 1968. Cell to cell interaction in the immune response. I. Hemolysin-forming cells in neonatally thymectomized mice reconstituted with thymus or thoracic duct lymphocytes. J. Exp. Med. 128:801–20 3. MacLennan IC. 1994. Germinal centers. Annu. Rev. Immunol. 12:117–39 4. Hess J, Laumen H, Muller KB, Wirth T. 1998. Molecular genetics of the germinal center reaction. J. Cell. Physiol. 177:525–34 5. Kelsoe G. 1995. In situ studies of the germinal center reaction. Adv. Immunol. 60:267–88 6. Liu YJ, Malisan F, de Bouteiller O, Guret C, Lebecque S, et al. 1996. Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. Immunity 4:241–50 7. Liu YJ, Banchereau J. 1996. The paths and molecular controls of peripheral B-cell development. The Immunologist 4:55–66 8. Manz RA, Hauser AE, Hiepe F, Radbruch A. 2005. Maintenance of serum antibody levels. Annu. Rev. Immunol. 23:367–86 9. van Kooten C, Banchereau J. 2000. CD40-CD40 ligand. J. Leukoc. Biol. 67:2–17 10. Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, et al. 1999. ICOS is an inducible T-cell costimulator structurally and functionally related to CD28. Nature 397:263–66 11. Spolski R, Leonard WJ. 2008. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu. Rev. Immunol. 26:57–79 12. Leonard WJ, Spolski R. 2005. Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nat. Rev. Immunol. 5:688–98 13. Forster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M. 1996. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87:1037–47 14. Gunn MD, Ngo VN, Ansel KM, Ekland EH, Cyster JG, Williams LT. 1998. A B-cellhoming chemokine made in lymphoid follicles activates Burkitt’s lymphoma receptor-1. Nature 391:799–803 15. Cyster JG, Ansel KM, Reif K, Ekland EH, Hyman PL, et al. 2000. Follicular stromal cells and lymphocyte homing to follicles. Immunol. Rev. 176:181–93 16. Forster R, Emrich T, Kremmer E, Lipp M. 1994. Expression of the G-protein–coupled receptor BLR1 defines mature, recirculating B cells and a subset of T-helper memory cells. Blood 84:830–40 www.annualreviews.org • T Follicular Helper Cells
757
ARI
16 February 2008
14:14
17. Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B. 2000. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192:1553–62 18. Breitfeld D, Ohl L, Kremmer E, Ellwart J, Sallusto F, et al. 2000. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 192:1545–52 19. Mackay CR. 2000. Follicular homing T helper (Th) cells and the Th1/Th2 paradigm. J. Exp. Med. 192:F31–34 20. Kim CH, Rott LS, Clark-Lewis I, Campbell DJ, Wu L, Butcher EC. 2001. Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells. J. Exp. Med. 193:1373–81 21. Bryant VL, Ma CS, Avery DT, Li Y, Good KL, et al. 2007. Cytokine-mediated regulation of human B-cell differentiation into Ig-secreting cells: predominant role of IL-21 produced by CXCR5+ T follicular helper cells. J. Immunol. 179:8180–90 22. Abbas AK, Urioste S, Collins TL, Boom WH. 1990. Heterogeneity of helper/inducer T lymphocytes. IV. Stimulation of resting and activated B cells by Th1 and Th2 clones. J. Immunol. 144:2031–37 23. Kopf M, Le Gros G, Coyle AJ, Kosco-Vilbois M, Brombacher F. 1995. Immune responses of IL-4, IL-5, IL-6 deficient mice. Immunol. Rev. 148:45–69 24. Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, et al. 1996. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380:630–33 25. Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, et al. 1999. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99:23–33 26. Flynn S, Toellner KM, Raykundalia C, Goodall M, Lane P. 1998. CD4 T cell cytokine differentiation: The B cell activation molecule, OX40 ligand, instructs CD4 T cells to express interleukin 4 and upregulates expression of the chemokine receptor, Blr-1. J. Exp. Med. 188:297–304 27. Brocker T, Gulbranson-Judge A, Flynn S, Riedinger M, Raykundalia C, Lane P. 1999. CD4 T cell traffic control: in vivo evidence that ligation of OX40 on CD4 T cells by OX40-ligand expressed on dendritic cells leads to the accumulation of CD4 T cells in B follicles. Eur. J. Immunol. 29:1610–16 28. Walker LS, Gulbranson-Judge A, Flynn S, Brocker T, Raykundalia C, et al. 1999. Compromised OX40 function in CD28-deficient mice is linked with failure to develop CXC chemokine receptor 5–positive CD4 cells and germinal centers. J. Exp. Med. 190:1115–22 29. Bossaller L, Burger J, Draeger R, Grimbacher B, Knoth R, et al. 2006. ICOS deficiency is associated with a severe reduction of CXCR5+ CD4 germinal center Th cells. J. Immunol. 177:4927–32 30. Akiba H, Takeda K, Kojima Y, Usui Y, Harada N, et al. 2005. The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo. J. Immunol. 175:2340–48 31. Moser B, Ebert L. 2003. Lymphocyte traffic control by chemokines: follicular B helper T cells. Immunol. Lett. 85:105–12 32. Steinman L. 2007. A brief history of TH 17, the first major revision in the TH 1/TH 2 hypothesis of T cell-mediated tissue damage. Nat. Med. 13:139–45 33. Linton PJ, Harbertson J, Bradley LM. 2000. A critical role for B cells in the development of memory CD4 cells. J. Immunol. 165:5558–65 34. Tsitoura DC, Yeung VP, DeKruyff RH, Umetsu DT. 2002. Critical role of B cells in the development of T cell tolerance to aeroallergens. Int. Immunol. 14:659–67
Annu. Rev. Immunol. 2008.26:741-766. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
ANRV338-IY26-24
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ANRV338-IY26-24
ARI
16 February 2008
14:14
35. Stockinger B, Zal T, Zal A, Gray D. 1996. B cells solicit their own help from T cells. J. Exp. Med. 183:891–99 36. Harris DP, Haynes L, Sayles PC, Duso DK, Eaton SM, et al. 2000. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat. Immunol. 1:475–82 37. Ebert LM, Horn MP, Lang AB, Moser B. 2004. B cells alter the phenotype and function of follicular-homing CXCR5+ T cells. Eur. J. Immunol. 34:3562–71 38. Harris DP, Haynes L, Sayles PC, Duso DK, Eaton SM, et al. 2000. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat. Immunol. 1:475–82 39. Johansson-Lindbom B, Borrebaeck CA. 2002. Germinal center B cells constitute a predominant physiological source of IL-4: implication for Th2 development in vivo. J. Immunol. 168:3165–72 40. Kim MY, Gaspal FM, Wiggett HE, McConnell FM, Gulbranson-Judge A, et al. 2003. CD4+ CD3− accessory cells costimulate primed CD4 T cells through OX40 and CD30 at sites where T cells collaborate with B cells. Immunity 18:643–54 41. Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, et al. 2007. Phenotypic and functional features of human Th17 cells. J. Exp. Med. 204(8):1849–61 42. Vinuesa CG, Tangye SG, Moser B, Mackay CR. 2005. Follicular B helper T cells in antibody responses and autoimmunity. Nat. Rev. Immunol. 5:853–65 43. Coquet JM, Kyparissoudis K, Pellicci DG, Besra G, Berzins SP, et al. 2007. IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production. J. Immunol. 178:2827–34 44. Korn T, Bettelli E, Gao W, Awasthi A, Jager A, et al. 2007. IL-21 initiates an alternative pathway to induce proinflammatory TH 17 cells. Nature 448:484–87 45. Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, et al. 2007. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448:480– 83 46. Lim HW, Kim CH. 2007. Loss of IL-7 receptor a on CD4+ T cells defines terminally differentiated B cell-helping effector T cells in a B cell-rich lymphoid tissue. J. Immunol. 179:7448–56 47. Gulino AV, Notarangelo LD. 2003. Hyper IgM syndromes. Curr. Opin. Rheumatol. 15:422–29 48. Mak TW, Shahinian A, Yoshinaga SK, Wakeham A, Boucher LM, et al. 2003. Costimulation through the inducible costimulator ligand is essential for both T helper and B cell functions in T cell-dependent B cell responses. Nat. Immunol. 4:765–72 49. Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, et al. 2003. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat. Immunol. 4:261–68 50. Grimbacher B, Warnatz K, Peter HH. 2003. The immunological synapse for B-cell memory: the role of the ICOS and its ligand for the longevity of humoral immunity. Curr. Opin. Allergy Clin. Immunol. 3:409–19 51. Chtanova T, Tangye SG, Newton R, Frank N, Hodge MR, et al. 2004. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J. Immunol. 173:68–78 52. Kim CH, Lim HW, Kim JR, Rott L, Hillsamer P, Butcher EC. 2004. Unique gene expression program of human germinal center T helper cells. Blood 104:1952– 60 53. Vinuesa CG, Cook MC, Angelucci C, Athanasopoulos V, Rui L, et al. 2005. A RINGtype ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435:452–58 www.annualreviews.org • T Follicular Helper Cells
759
ARI
16 February 2008
14:14
54. Rasheed AU, Rahn HP, Sallusto F, Lipp M, Muller G. 2006. Follicular B helper T cell activity is confined to CXCR5hi ICOShi CD4 T cells and is independent of CD57 expression. Eur. J. Immunol. 36:1892–903 55. Ho IC, Glimcher LH. 2002. Transcription: tantalizing times for T cells. Cell 109(Suppl.):S109–20 56. Weaver CT, Hatton RD, Mangan PR, Harrington LE. 2007. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25:821– 52 57. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, et al. 2006. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–33 58. Allman D, Jain A, Dent A, Maile RR, Selvaggi T, et al. 1996. BCL-6 expression during B-cell activation. Blood 87:5257–68 59. Cattoretti G, Chang CC, Cechova K, Zhang J, Ye BH, et al. 1995. BCL-6 protein is expressed in germinal-center B cells. Blood 86:45–53 60. Onizuka T, Moriyama M, Yamochi T, Kuroda T, Kazama A, et al. 1995. BCL-6 gene product, a 92- to 98-kD nuclear phosphoprotein, is highly expressed in germinal center B cells and their neoplastic counterparts. Blood 86:28–37 61. Shaffer AL, Yu X, He Y, Boldrick J, Chan EP, Staudt LM. 2000. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13:199–212 62. Dent AL, Shaffer AL, Yu X, Allman D, Staudt LM. 1997. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 276:589– 92 63. Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, et al. 1997. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat. Genet. 16:161–70 64. Kusam S, Toney LM, Sato H, Dent AL. 2003. Inhibition of Th2 differentiation and GATA-3 expression by BCL-6. J. Immunol. 170:2435–41 65. Ree HJ, Kadin ME, Kikuchi M, Ko YH, Suzumiya J, Go JH. 1999. Bcl-6 expression in reactive follicular hyperplasia, follicular lymphoma, and angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers: heterogeneity of intrafollicular T-cells and their altered distribution in the pathogenesis of angioimmunoblastic T-cell lymphoma. Hum. Pathol. 30:403–11 66. Rousset F, Garcia E, Defrance T, Peronne C, Vezzio N, et al. 1992. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc. Natl. Acad. Sci. USA 89:1890–93 67. Breitfeld D, Ohl L, Kremmer E, Ellwart J, Sallusto F, et al. 2000. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 192:1545–52 68. Lohning M, Hutloff A, Kallinich T, Mages HW, Bonhagen K, et al. 2003. Expression of ICOS in vivo defines CD4+ effector T cells with high inflammatory potential and a strong bias for secretion of interleukin 10. J. Exp. Med. 197:181–93 69. Warnatz K, Bossaller L, Salzer U, Skrabl-Baumgartner A, Schwinger W, et al. 2006. Human ICOS-deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood 107:3045–52 70. Ma CS, Hare NJ, Nichols KE, Dupre L, Andolfi G, et al. 2005. Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells. J. Clin. Investig. 115:1049–59
Annu. Rev. Immunol. 2008.26:741-766. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
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ANRV338-IY26-24
ARI
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71. Liang L, Porter EM, Sha WC. 2002. Constitutive expression of the B7h ligand for inducible costimulator on naive B cells is extinguished after activation by distinct B cell receptor and interleukin 4 receptor-mediated pathways and can be rescued by CD40 signaling. J. Exp. Med. 196:97–108 72. Aicher A, Hayden-Ledbetter M, Brady WA, Pezzutto A, Richter G, et al. 2000. Characterization of human inducible costimulator ligand expression and function. J. Immunol. 164:4689–96 73. Diehn M, Alizadeh AA, Rando OJ, Liu CL, Stankunas K, et al. 2002. Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation. Proc. Natl. Acad. Sci. USA 99:11796–801 74. Riley JL, Mao M, Kobayashi S, Biery M, Burchard J, et al. 2002. Modulation of TCRinduced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proc. Natl. Acad. Sci. USA 99:11790–95 75. Acuto O, Michel F. 2003. CD28-mediated costimulation: a quantitative support for TCR signalling. Nat. Rev. Immunol. 3:939–51 76. Michel F, Attal-Bonnefoy G, Mangino G, Mise-Omata S, Acuto O. 2001. CD28 as a molecular amplifier extending TCR ligation and signaling capabilities. Immunity 15:935– 45 77. Sharpe AH, Freeman GJ. 2002. The B7-CD28 superfamily. Nat. Rev. Immunol. 2:116–26 78. Coyle AJ, Lehar S, Lloyd C, Tian J, Delaney T, et al. 2000. The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. Immunity 13:95– 105 79. Dong C, Juedes AE, Temann UA, Shresta S, Allison JP, et al. 2001. ICOS costimulatory receptor is essential for T-cell activation and function. Nature 409:97–101 80. Dong C, Temann UA, Flavell RA. 2001. Cutting edge: critical role of inducible costimulator in germinal center reactions. J. Immunol. 166:3659–62 81. Tafuri A, Shahinian A, Bladt F, Yoshinaga SK, Jordana M, et al. 2001. ICOS is essential for effective T-helper-cell responses. Nature 409:105–9 82. Rasheed AU, Rahn HP, Sallusto F, Lipp M, Muller G. 2006. Follicular B helper T cell activity is confined to CXCR5hi ICOShi CD4 T cells and is independent of CD57 expression. Eur. J. Immunol. 36:1892–903 83. Kim JR, Lim HW, Kang SG, Hillsamer P, Kim CH. 2005. Human CD57+ germinal center-T cells are the major helpers for GC-B cells and induce class switch recombination. BMC Immunol. 6:3 84. Casamayor-Palleja M, Khan M, MacLennan IC. 1995. A subset of CD4+ memory T cells contains preformed CD40 ligand that is rapidly but transiently expressed on their surface after activation through the T cell receptor complex. J. Exp. Med. 181:1293–301 85. Bowen MB, Butch AW, Parvin CA, Levine A, Nahm MH. 1991. Germinal center T cells are distinct helper-inducer T cells. Hum. Immunol. 31:67–75 86. Velardi A, Mingari MC, Moretta L, Grossi CE. 1986. Functional analysis of cloned germinal center CD4+ cells with natural killer cell-related features. Divergence from typical T helper cells. J. Immunol. 137:2808–13 87. Andersson E, Dahlenborg K, Ohlin M, Borrebaeck CA, Carlsson R. 1996. Immunoglobulin production induced by CD57+ GC-derived helper T cells in vitro requires addition of exogenous IL-2. Cell. Immunol. 169:166–73 88. Johansson-Lindbom B, Ingvarsson S, Borrebaeck CA. 2003. Germinal centers regulate human Th2 development. J. Immunol. 171:1657–66 www.annualreviews.org • T Follicular Helper Cells
761
ARI
16 February 2008
14:14
89. Andersson E, Ohlin M, Borrebaeck CA, Carlsson R. 1995. CD4+ CD57+ T cells derived from peripheral blood do not support immunoglobulin production by B cells. Cell. Immunol. 163:245–53 90. Bouzahzah F, Bosseloir A, Heinen E, Simar LJ. 1995. Human germinal center CD4+ CD57+ T cells act differently on B cells than do classical T-helper cells. Dev. Immunol. 4:189–97 91. Velardi A, Tilden AB, Millo R, Grossi CE. 1986. Isolation and characterization of Leu 7+ germinal-center cells with the T helper-cell phenotype and granular lymphocyte morphology. J. Clin. Immunol. 6:205–15 92. Marinova E, Han S, Zheng B. 2007. Germinal center helper T cells are dual functional regulatory cells with suppressive activity to conventional CD4+ T cells. J. Immunol. 178:5010–17 93. Butch AW, Chung GH, Hoffmann JW, Nahm MH. 1993. Cytokine expression by germinal center cells. J. Immunol. 150:39–47 94. Toellner KM, Scheel-Toellner D, Sprenger R, Duchrow M, Trumper LH, et al. 1995. The human germinal centre cells, follicular dendritic cells and germinal centre T cells produce B cell-stimulating cytokines. Cytokine 7:344–54 95. Marinova E, Han S, Zheng B. 2006. Human germinal center T cells are unique Th cells with high propensity for apoptosis induction. Int. Immunol. 18:1337–45 96. Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, et al. 2000. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408:57–63 97. Parrish-Novak J, Foster DC, Holly RD, Clegg CH. 2002. Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses. J. Leukoc. Biol. 72:856–63 98. Ozaki K, Kikly K, Michalovich D, Young PR, Leonard WJ. 2000. Cloning of a type I cytokine receptor most related to the IL-2 receptor β chain. Proc. Natl. Acad. Sci. USA 97:11439–44 99. Ueda M, Imada K, Imura A, Koga H, Hishizawa M, Uchiyama T. 2005. Expression of functional interleukin-21 receptor on adult T-cell leukaemia cells. Br. J. Haematol. 128:169–76 100. Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, et al. 2001. Cutting edge: the common γ-chain is an indispensable subunit of the IL-21 receptor complex. J. Immunol. 167:1–5 101. Leonard WJ. 2001. Cytokines and immunodeficiency diseases. Nat. Rev. Immunol. 1:200– 8 102. Kasaian MT, Whitters MJ, Carter LL, Lowe LD, Jussif JM, et al. 2002. IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity 16:559–69 103. Peluso I, Fantini MC, Fina D, Caruso R, Boirivant M, et al. 2007. IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes. J. Immunol. 178:732–39 104. Zeng R, Spolski R, Casas E, Zhu W, Levy DE, Leonard WJ. 2007. The molecular basis of IL-21-mediated proliferation. Blood 109:4135–42 ¨ 105. Frohlich A, Marsland BJ, Sonderegger I, Kurrer M, Hodge MR, et al. 2007. IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo. Blood 109:2023–31 106. Wurster AL, Rodgers VL, Satoskar AR, Whitters MJ, Young DA, et al. 2002. Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon γ-producing Th1 cells. J. Exp. Med. 196:969–77
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107. Pesce J, Kaviratne M, Ramalingam TR, Thompson RW, Urban JF Jr, et al. 2006. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J. Clin. Investig. 116:2044–55 108. Jin H, Carrio R, Yu A, Malek TR. 2004. Distinct activation signals determine whether IL21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis. J. Immunol. 173:657–65 109. Good KL, Bryant VL, Tangye SG. 2006. Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21. J. Immunol. 177:5236– 47 110. Ettinger R, Sims GP, Fairhurst AM, Robbins R, da Silva YS, et al. 2005. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. J. Immunol. 175:7867–79 111. Mehta DS, Wurster AL, Whitters MJ, Young DA, Collins M, Grusby MJ. 2003. IL-21 induces the apoptosis of resting and activated primary B cells. J. Immunol. 170:4111– 18 112. Jin H, Malek TR. 2006. Redundant and unique regulation of activated mouse B lymphocytes by IL-4 and IL-21. J. Leukoc. Biol. 80:1416–23 113. Pene J, Gauchat JF, Lecart S, Drouet E, Guglielmi P, et al. 2004. Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells. J. Immunol. 172:5154–57 114. Ozaki K, Spolski R, Ettinger R, Kim HP, Wang G, et al. 2004. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J. Immunol. 173:5361–71 115. Pene J, Guglielmi L, Gauchat JF, Harrer N, Woisetschlager M, et al. 2006. IFN-γmediated inhibition of human IgE synthesis by IL-21 is associated with a polymorphism in the IL-21R gene. J. Immunol. 177:5006–13 116. Suto A, Nakajima H, Hirose K, Suzuki K, Kagami S, et al. 2002. Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line Cε transcription of IL-4stimulated B cells. Blood 100:4565–73 117. Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, et al. 2002. A critical role for IL-21 in regulating immunoglobulin production. Science 298:1630–34 118. Shang XZ, Ma KY, Radewonuk J, Li J, Song XY, et al. 2006. IgE isotype switch and IgE production are enhanced in IL-21-deficient but not IFN-γ-deficient mice in a Th2-biased response. Cell. Immunol. 241:66–74 119. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, et al. 2007. IL-6 programs TH -17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8:967–74 120. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, et al. 2007. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat. Immunol. 8:639–46 121. Ansel KM, Ngo VN, Hyman PL, Luther SA, Forster R, et al. 2000. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406:309–14 122. Sallusto F, Kremmer E, Palermo B, Hoy A, Ponath P, et al. 1999. Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells. Eur. J. Immunol. 29:2037–45 123. Ansel KM, McHeyzer-Williams LJ, Ngo VN, McHeyzer-Williams MG, Cyster JG. 1999. In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J. Exp. Med. 190:1123–34 www.annualreviews.org • T Follicular Helper Cells
763
ARI
16 February 2008
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124. Garside P, Ingulli E, Merica RR, Johnson JG, Noelle RJ, Jenkins MK. 1998. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281:96–99 125. Gulbranson-Judge A, MacLennan I. 1996. Sequential antigen-specific growth of T cells in the T zones and follicles in response to pigeon cytochrome c. Eur. J. Immunol. 26:1830–37 126. Fuller KA, Kanagawa O, Nahm MH. 1993. T cells within germinal centers are specific for the immunizing antigen. J. Immunol. 151:4505–12 127. Fazilleau N, Eisenbraun MD, Malherbe L, Ebright JN, Pogue-Caley RR, et al. 2007. Lymphoid reservoirs of antigen-specific memory T helper cells. Nat. Immunol. 8:753–61 128. Fazilleau N, McHeyzer-Williams LJ, McHeyzer-Williams MG. 2007. Local development of effector and memory T helper cells. Curr. Opin. Immunol. 19:259–67 129. Wen L, Pao W, Wong FS, Peng Q, Craft J, et al. 1996. Germinal center formation, immunoglobulin class switching, and autoantibody production driven by “non α/β” T cells. J. Exp. Med. 183:2271–82 130. Caccamo N, Battistini L, Bonneville M, Poccia F, Fournie JJ, et al. 2006. CXCR5 identifies a subset of Vγ9Vδ2 T cells which secrete IL-4 and IL-10 and help B cells for antibody production. J. Immunol. 177:5290–95 131. Brandes M, Willimann K, Lang AB, Nam KH, Jin C, et al. 2003. Flexible migration program regulates γδ T-cell involvement in humoral immunity. Blood 102:3693–701 132. Vermijlen D, Ellis P, Langford C, Klein A, Engel R, et al. 2007. Distinct cytokine-driven responses of activated blood γδ T cells: insights into unconventional T cell pleiotropy. J. Immunol. 178:4304–14 133. Pugh-Bernard AE, Silverman GJ, Cappione AJ, Villano ME, Ryan DH, et al. 2001. Regulation of inherently autoreactive VH4–34 B cells in the maintenance of human B cell tolerance. J. Clin. Investig. 108:1061–70 134. Luzina IG, Atamas SP, Storrer CE, daSilva LC, Kelsoe G, et al. 2001. Spontaneous formation of germinal centers in autoimmune mice. J. Leukoc. Biol. 70:578–84 135. Grammer AC, Slota R, Fischer R, Gur H, Girschick H, et al. 2003. Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154CD40 interactions. J. Clin. Investig. 112:1506–20 136. Subramanian S, Tus K, Li QZ, Wang A, Tian XH, et al. 2006. A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. Proc. Natl. Acad. Sci. USA 103:9970– 75 137. Hutloff A, Buchner K, Reiter K, Baelde HJ, Odendahl M, et al. 2004. Involvement of inducible costimulator in the exaggerated memory B cell and plasma cell generation in systemic lupus erythematosus. Arthritis Rheum. 50:3211–20 138. Iwai H, Abe M, Hirose S, Tsushima F, Tezuka K, et al. 2003. Involvement of inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis. J. Immunol. 171:2848–54 139. Young DA, Hegen M, Ma HL, Whitters MJ, Albert LM, et al. 2007. Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum. 56:1152–63 140. Herber D, Brown TP, Liang S, Young DA, Collins M, Dunussi-Joannopoulos K. 2007. IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL21R.Fc reduces disease progression. J. Immunol. 178:3822–30 141. Mackay IR, Burnet FM. 1963. Autoimmune Diseases. Pathogenesis, Chemistry and Therapy. Springfield, IL: Charles C. Thomas 142. Weyand CM, Goronzy JJ. 2003. Ectopic germinal center formation in rheumatoid synovitis. Ann. NY Acad. Sci. 987:140–49
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143. Drayton DL, Liao S, Mounzer RH, Ruddle NH. 2006. Lymphoid organ development: from ontogeny to neogenesis. Nat. Immunol. 7:344–53 144. Lee Y, Chin RK, Christiansen P, Sun Y, Tumanov AV, et al. 2006. Recruitment and activation of naive T cells in the islets by lymphotoxin β receptor-dependent tertiary lymphoid structure. Immunity 25:499–509 145. Kendall PL, Yu G, Woodward EJ, Thomas JW. 2007. Tertiary lymphoid structures in the pancreas promote selection of B lymphocytes in autoimmune diabetes. J. Immunol. 178:5643–51 146. Ansel KM, McHeyzer-Williams LJ, Ngo VN, McHeyzer-Williams MG, Cyster JG. 1999. In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J. Exp. Med. 190:1123–34 147. Takemura S, Braun A, Crowson C, Kurtin PJ, Cofield RH, et al. 2001. Lymphoid neogenesis in rheumatoid synovitis. J. Immunol. 167:1072–80 148. Shi K, Hayashida K, Kaneko M, Hashimoto J, Tomita T, et al. 2001. Lymphoid chemokine B cell-attracting chemokine-1 (CXCL13) is expressed in germinal center of ectopic lymphoid follicles within the synovium of chronic arthritis patients. J. Immunol. 166:650–55 149. Lim HW, Hillsamer P, Kim CH. 2004. Regulatory T cells can migrate to follicles upon T cell activation and suppress GC-Th cells and GC-Th cell-driven B cell responses. J. Clin. Investig. 114:1640–49 150. Yu D, Tan AH-M, Hu X, Athanasopoulos V, Simpson N, et al. 2007. Roquin represses autoimmunity by limiting inducible T cell costimulator messenger mRNA. Nature 450:299– 303 151. Notarangelo LD, Giliani S, Mazzolari E, Gulino AV. 2003. Primary immune deficiencies unravel the molecular basis of immune response. Rev. Clin. Exp. Hematol. 7:84–111 152. Ma CS, Nichols KE, Tangye SG. 2007. Regulation of cellular and humoral immune responses by the SLAM and SAP families of molecules. Annu. Rev. Immunol. 25:337– 79 153. Xu J, Foy TM, Laman JD, Elliott EA, Dunn JJ, et al. 1994. Mice deficient for the CD40 ligand. Immunity 1:423–31 154. McAdam AJ, Greenwald RJ, Levin MA, Chernova T, Malenkovich N, et al. 2001. ICOS is critical for CD40-mediated antibody class switching. Nature 409:102–5 155. Crotty S, Kersh EN, Cannons J, Schwartzberg PL, Ahmed R. 2003. SAP is required for generating long-term humoral immunity. Nature 421:282–87 156. Cannons JL, Yu LJ, Jankovic D, Crotty S, Horai R, et al. 2006. SAP regulates T cellmediated help for humoral immunity by a mechanism distinct from cytokine regulation. J. Exp. Med. 203:1551–65 157. de Leval L, Savilo E, Longtine J, Ferry JA, Harris NL. 2001. Peripheral T-cell lymphoma with follicular involvement and a CD4+ /bcl-6+ phenotype. Am. J. Surg. Pathol. 25:395– 400 158. de Leval L, Rickman DS, Thielen C, de Reynies A, Huang YL, et al. 2007. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T cells (TFH ). Blood 109:4952–63 159. Krenacs L, Schaerli P, Kis G, Bagdi E. 2006. Phenotype of neoplastic cells in angioimmunoblastic T-cell lymphoma is consistent with activated follicular B helper T cells. Blood 108:1110–11 160. Dorfman DM, Brown JA, Shahsafaei A, Freeman GJ. 2006. Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am. J. Surg. Pathol. 30:802–10 www.annualreviews.org • T Follicular Helper Cells
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161. Dupuis J, Boye K, Martin N, Copie-Bergman C, Plonquet A, et al. 2006. Expression of CXCL13 by neoplastic cells in angioimmunoblastic T-cell lymphoma (AITL): a new diagnostic marker providing evidence that AITL derives from follicular helper T cells. Am. J. Surg. Pathol. 30:490–94 162. Grogg KL, Attygalle AD, Macon WR, Remstein ED, Kurtin PJ, Dogan A. 2005. Angioimmunoblastic T-cell lymphoma: a neoplasm of germinal-center T-helper cells? Blood 106:1501–2 163. Dogan A, Attygalle AD, Kyriakou C. 2003. Angioimmunoblastic T-cell lymphoma. Br. J. Haematol. 121:681–91
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Contents
Volume 26, 2008
Frontispiece K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x Doing What I Like K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Protein Tyrosine Phosphatases in Autoimmunity Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert, and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57 Forward Genetic Dissection of Immunity to Infection in the Mouse S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81 Regulation and Functions of Blimp-1 in T and B Lymphocytes Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133 Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin, and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171 T Cell Trafficking in Allergic Asthma: The Ins and Outs Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205 The Actin Cytoskeleton in T Cell Activation Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233 Mechanism and Regulation of Class Switch Recombination Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261 Migration of Dendritic Cell Subsets and their Precursors Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
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The APOBEC3 Cytidine Deaminases: An Innate Defensive Network Opposing Exogenous Retroviruses and Endogenous Retroelements Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317 Thymus Organogenesis Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355 Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389 Annu. Rev. Immunol. 2008.26:741-766. Downloaded from arjournals.annualreviews.org by Shanghai Information Center for Life Sciences on 04/28/08. For personal use only.
Monocyte-Mediated Defense Against Microbial Pathogens Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421 The Biology of Interleukin-2 Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453 The Biochemistry of Somatic Hypermutation Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa, Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481 Anti-Inflammatory Actions of Intravenous Immunoglobulin Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513 The IRF Family Transcription Factors in Immunity and Oncogenesis Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535 Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585 Development of Secondary Lymphoid Organs Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627 Immunity to Citrullinated Proteins in Rheumatoid Arthritis Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov, and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651 PD-1 and Its Ligands in Tolerance and Immunity Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677 The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705 T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune Responses Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
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Contents