from the editors
E
xcessive inflammatory responses can be horribly destructive. Unsurprisingly, therefore, immune responses are dampened down and fine-tuned in a multitude of ways to minimize their damaging effects. Four articles in this issue provide examples of such
immune regulation on four different levels. Wolfgang Junger (page 201) explains that cells take it upon themselves
to control their behaviour to extracellular cues through autocrine feedback loops involving purinergic receptors. ATP or adenosine released by immune cells following stimulation feeds back on the cells through activating or suppressive purinergic receptors that fine-tune cell functions and activation. Luke O’Neill and colleagues (page 163) suggest that microRNAs acting on
▶ Cover: ‘Fine‑tuning’ by Simon Bradbrook,
inspired by the Reviews on pages 163 and 201.
mRNAs may be as important as transcription factors in controlling the protein content of a cell and therefore in regulating cell responses. They focus on the roles of microRNAs in the regulation of Toll-like receptor signalling and during the switch from a pro-inflammatory response to the resolution of inflammation. A fine balance between protective immunity and inflammatory pathology is also achieved through synergistic and antagonistic signalling crosstalk
LuCy bird
between innate immune receptors. The Review on page 187 illustrates
kirsty Minton
how pathogens can undermine this fine-tuning for their benefit through various mechanisms; for example, by co-opting inhibitory receptors, inducing immunosuppressive mediators, promoting safe pathogen uptake and oLive LeAvy
disrupting cooperative receptor interactions involved in host protection.
yvonne bordon
Finally, in an Essay on page 221, Polly Matzinger and Tirumalai Kamala propose that immune responses are regulated at the level of the tissues in which an insult occurs. They suggest that tissue cells are responsible for tailoring the effector class of an immune response to suit the tissue, thereby protecting it from the destructive consequences of inflammatory responses.
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ReseaRch highlights Nature Reviews Immunology | AOP, published online 18 February 2011; doi:10.1038/nri2948
muCOSAL ImmuNOLOGy
Acid attack Immune responses in the intestine must be tightly controlled to prevent harmful attacks against commensal organisms, food proteins and self antigens. Previous studies have shown that dendritic cells (DCs) contribute to immune homeostasis in the intestine by constitutively generating high levels of retinoic acid, which, together with transforming growth factor-β (TGFβ), promotes the development of regulatory T (TReg) cells. However, a recent paper in Nature exposes another side to retinoic acid, showing that this vitamin A metabolite can team up with interleukin-15 (IL-15) to drive pro-inflammatory responses against food antigens. Patients with coeliac disease (who develop intestinal pathology owing to aberrant immune responses to dietary gluten) have increased levels of IL-15 in the gut mucosa, so DePaolo et al. explored whether this cytokine could affect the ability of intestinal DCs to promote TReg cell conversion. Compared with untreated controls, IL-15-treated intestinal DCs were less efficient in driving TReg cell differentiation in vitro and, unexpectedly, the addition of retinoic acid to the IL-15-treated DCs further limited their capacity to induce TReg cells. The authors extended these findings in vivo by using IL-15-transgenic mice that overexpress IL-15 in the intestinal lamina propria and
mesenteric lymph nodes (MLNs). Feeding wild-type mice ovalbumin (OVA) led to the appearance of OVA-specific TReg cells in MLNs, but significantly fewer OVA-specific TReg cells were detected in the MLNs of OVA-fed IL-15-transgenic mice. Moreover, TReg cell induction was further inhibited if IL-15-transgenic mice were fed retinoic acid together with OVA. Using splenic DCs, which do not constitutively produce retinoic acid, the authors found that retinoic acid synergized with IL-15 to promote DC-mediated production of the proinflammatory cytokines IL-12p70 and IL-23. In keeping with this, intestinal lamina propria cells from OVAfed IL-15-transgenic mice, but not from wild-type controls, produced interferon-γ (IFNγ) in response to stimulation with OVA in vitro. This antigen-specific production of IFNγ was enhanced if the IL-15-trangenic mice were fed retinoic acid along with OVA. In a series of further experiments, the authors showed that retinoic acid could synergize with IL-15 and either IL-12p70 or IL-6 to promote the development of a T helper 1 (TH1)- or TH17-type response, respectively. Exploration of the signalling mechanisms involved showed that retinoic acid and IL-15 synergized
NATURE REVIEwS | Immunology
to promote pro-inflammatory DC responses in a JUN N-terminal kinase (JNK)-dependent manner. Finally, DePaolo et al. addressed a question that has long puzzled immunologists. Although approximately 40% of the population express HLA-DQ2 and HLA-DQ8 (the MHC molecules that are associated with coeliac disease), only 2% of these individuals develop this disease. So what promotes the breakdown of tolerance to dietary gluten in this minority? The authors crossed IL-15-transgenic mice with HLA-DQ8-transgenic mice and found that the double-transgenic mice developed several hallmarks of early-stage coeliac disease in response to gluten feeding. These features included the development of gluten-specific antibodies and gluten-specific TH1 cells. Notably, the gluten-specific TH1 cell response was enhanced by retinoic acid, suggesting that in the presence of IL-15, retinoic acid can contribute to the breakdown of tolerance to food antigens. This study suggests that retinoic acid is not simply an agent of tolerance, but synergizes with other cytokines present in the intestinal environment to potentiate both pro- and anti-inflammatory DC responses. In addition, the authors propose that in the HLA-DQ8 and IL-15 double-transgenic mice, immunologists may finally have a physiologically relevant mouse model of coeliac disease. Yvonne Bordon
ORIGINAL RESEARCH PAPER DePaolo, R. W. et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 10 Feb 2011 (doi:10.1038/nature09849)
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ReseaRch highlights
MacMIllan South afRIca
Nature Reviews Immunology | AOP, published online 18 February 2011; doi:10.1038/nri2945
tumOuR ImmuNOLOGy
Early exposure is inflammatory Sunburn during childhood has been associated with an increased risk of melanoma development, and in a recent Nature paper, M. Raza Zaidi, Glenn Merlino and colleagues have shown that changes in the immune response in the skin of young mice after exposure to ultraviolet B (UVB) light could help to promote melanoma development and progression. Melanocytes (pigment-producing cells) constitute approximately 1% of skin cells, making their biology and behaviour difficult to study in vivo. To overcome this, the authors generated a transgenic mouse model in which the expression of green fluorescent protein (GFP) in melanocytes could be switched on and off. These mice were then exposed to either UVB or UVA wavelengths at postnatal day 1,
immuno histochemical analyses of 27 human melanoma samples indicated that 19 contained substantial numbers of macrophages that expressed IFNγ
and skin samples were examined. UVB but not UVA triggered melanocyte activation (increased proliferation and migration to the epidermis), and this response lasted for at least 10 days. To further understand this, the authors isolated GFP+ melanocytes 1 day and 6 days after exposure to UVB and carried out an expression microarray. Although stress response genes showed increased expression 1 day after UVB exposure as expected, a subset of genes indicative of a response to interferon-γ (IFNγ) showed a delayed response to UVB at 6 days. To verify the involvement of IFNγ, the authors blocked both type I (IFNα and IFNβ) and type II (IFNγ) responses in young mice ahead of UVB exposure, and found that inhibition of the IFNγ response blocked melanocyte activation. So, which cells in the skin produce IFNγ after exposure to UVB? Immunohistochemical analyses of the skin from young mice 6 days after UVB exposure showed that the majority of immune cells in the skin were CD11b+F4/80+GR1– macrophages, and approximately 28% of these cells expressed IFNγ. The microarray data showed that the UVB-exposed melanocytes expressed ligands that bind the CC-chemokine receptors CCR2 and CCR5, and both of these receptors were expressed by the infiltrating macrophages. However, only CCR2-deficient mice showed a defect in the recruitment of F4/80+ macrophages after exposure to UVB. Moreover, the expression of CCL8, a CCR2 ligand, was substantially increased in
NATURE REVIEWS | Immunology
activated melanocytes at a time that corresponded to the arrival of the CCR2-expressing macrophages. So, are CCR2 and CCL8 important to melanoma development? Ectopic expression of CCL8 in mouse UV-induced melanoma cells promoted macrophage recruitment, and activated macrophages increased the growth rate of UV-melanoma cells in syngeneic mice, primarily by inhibiting apoptosis of the melanoma cells. Mice treated with IFNγ-specific antibodies showed reduced melanoma growth and, importantly, immunohistochemical analyses of 27 human melanoma samples indicated that 19 contained substantial numbers of macrophages that expressed IFNγ. On the basis of these findings, and the fact that the activated melanocytes showed an increased expression of genes that are involved in evasion of the immune response, the authors propose that sunburn in young skin enables melanocytes to evade immune-mediated elimination. Thus, these cells may survive in a state of equilibrium with the immune system prior to the development of a clinically apparent melanoma (an example of the immunoediting paradigm of tumour development). Whether patients with malignant melanoma might benefit from anti-IFNγ therapies needs to be addressed.
Nicola McCarthy Chief Editor, Nature Reviews Cancer
ORIGINAL RESEARCH PAPER Zaidi, M. R. et al. Interferon-γ links ultraviolet radiation to melanomagenesis in mice. Nature 469, 548–553 (2011)
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ReseaRch highlights
in brief R E G U L AT O RY T C E L L S
Killer cell Ig-like receptor (KIR) 3DL1 downregulation enhances inhibition of type 1 diabetes by autoantigen-specific regulatory T cells Qin, H. et al. Proc. Natl Acad. Sci. USA 108, 2016–2021 (2011)
Killer cell immunoglobulin-like receptors (KIRs) are expressed by natural killer (NK) cells. This study identified the inhibitory receptor KIR3DL1 on a subset of autoantigen-specific CD4+FOXP3– regulatory T cells (referred to as 2D2 TReg cells) in non-obese diabetic (NOD) mice, a mouse model of type 1 diabetes. Knockdown of KIR3DL1 expression resulted in increased interleukin-10 secretion by the 2D2 TReg cells, thereby enhancing their suppressive function. Moreover, adoptive transfer of KIR3DL1-deficient 2D2 TReg cells into NOD mice delayed or prevented the onset of type 1 diabetes. Thus, the authors suggest that KIR expression is not restricted to NK cells and that KIRs may negatively regulate the function of TReg cells in autoimmunity. T CELLS
CD4+ T cell help and innate-derived IL-27 induce Blimp-1-dependent IL-10 production by antiviral CTLs Sun, J. et al. Nature Immunol. 6 Feb 2011 (doi:10.1038/ni.1996)
Recent studies indicate that production of the anti-inflammatory cytokine interleukin-10 (IL-10) by cytotoxic T lymphocytes (CTLs) is important for counter-regulating their pro-inflammatory activity during infection. This paper now identifies the signals that drive IL-10 production by CTLs. Experiments with gene-deficient mice revealed that IL-27 (but not IL-12, IL-21, IL-35 or interferon-γ) was required for the induction of IL-10-producing CTLs following influenza virus infection. Also necessary were CD4+ T cells, which ‘helped’ CTL-mediated IL-10 production through local IL-2 production. In vivo experiments confirmed the requirement for IL-2 receptor signalling in IL-10-producing lung CTLs, and also found that innate cells were the source of IL-27. Finally, the findings that CTLs lacking the transcriptional regulator B lymphocyte-induced maturation protein 1 (BLIMP1; also known as PRDM1) failed to produce IL-10 in the presence of IL-2 and IL-27 and that BLIMP1-deficient mice showed enhanced pulmonary inflammation during infection support an important physiological role for BLIMP1-dependent IL-10 production by antiviral CTLs. i N N AT E i M M U N i T Y
Erythropoietin contrastingly affects bacterial infection and experimental colitis by inhibiting nuclear factor-κBinducible immune pathways Nairz, M. et al. Immunity 34, 61–74 (2011)
Erythropoietin (EPO) regulates erythrocyte production. However, EPO receptors (EPORs) are also expressed on non-erythroid cells, including immune cells. This study identifies an anti-inflammatory effect of EPO-induced signals on macrophages. Nairz et al. report that EPO suppresses the production of pro-inflammatory mediators by dampening nitric oxide synthase 2 (Nos2) transcription in activated macrophages. Mechanistically, Janus kinase 2 (JAK2) activation in response to EPO treatment inhibits the phosphorylation of NF-κB inhibitor-α (IκBα), thereby reducing nuclear factor-κB (NF-κB) transcriptional activity. This anti-inflammatory effect of EPO administration leads to impaired clearance of Salmonella Typhimurium by macrophages. Similarly, EPO inhibits pro-inflammatory gene expression in lamina propria myeloid cells, thereby reducing the severity of experimental colitis. Thus, the authors suggest that EPO and EPO derivatives could be used in the treatment of pathological inflammation.
nature reviews | Immunology
volume 11 | march 2011 © 2011 Macmillan Publishers Limited. All rights reserved
ReseaRch highlights
M AC R O P H AG E S
Iron macrophages Macrophages contribute to wound healing through the processes of inflammation, matrix deposition and tissue remodelling. However, local accumulation of activated macrophages and macrophagederived pro-inflammatory factors can also lead to chronic inflammation, which impairs tissue repair. Recent research sheds light on the local factors that influence the contribution of macrophages to wound healing or chronic inflammation. Sindrilaru et al. first studied the phenotype of human macrophages from chronic venous leg ulcers (CVUs) and investigated the involvement of microenvironmental factors in macrophage-mediated pathogenesis. CVUs are known to contain high levels of iron and, interestingly, the authors found that macrophages in CVUs express high levels of the haemoglobin scavenger receptor CD163, which mediates the endocytosis of haemoglobin– haptoglobin complexes, leading to the accumulation of iron in intracellular stores. In addition, this CD163hi population was shown to
express molecules associated with the M1 macrophage subset, such as tumour necrosis factor (TNF), interleukin-12, CC-chemokine receptor 2 and inducible nitric oxide synthase. The authors hypothesized that the increased iron deposition in CVUs induces an unrestrained pro-inflammatory M1 macrophage population, thereby contributing to chronic inflammation in the lesions. To support this hypothesis they established a mouse model of CVU pathogenesis, in which repeated treatment of mice with iron dextran led to iron accumulation in macrophages. Indeed, iron-loaded mouse macrophages exhibited the same pro-inflammatory M1 phenotype as human CVU macrophages. High TNF production by this macrophage population was shown to be responsible for impaired wound healing, as TNF neutralization disrupted an autocrine feedback loop that maintains macrophages in an activated proinflammatory state and rescued the wound healing response. Similarly,
NATURe ReVIewS | Immunology
specific macrophage depletion dampened inflammation and improved tissue repair. Finally, Sindrilaru et al. clarified the mechanism by which unrestrained pro-inflammatory M1 macrophages cause chronic wounds. They showed that iron-induced reactive oxygen and nitrogen species are produced in CVUs and in the skin of iron-loaded mice in a TNF- and macrophagedependent manner, where they cause oxidative DNA damage and enhance protein nitration. Moreover, the production of reactive oxygen species by iron-loaded macrophages correlates with increased levels of the ageing markers phosphorylated histone H2AX (γH2AX) and INK4A in fibroblasts from CVUs and skin lesions. Therefore, the authors suggest that iron-loaded macrophages induce DNA damage and senescence in skinresident fibroblasts, thereby impairing their capacity for tissue repair. So this study describes how iron present in a chronic inflammatory microenvironment promotes TNF-mediated pro-inflammatory macrophage activation, which results in senescence in skin fibroblasts and restrains wound healing. Based on this research, novel targets for the treatment of CVUs and other chronic inflammatory diseases are revealed. Maria Papatriantafyllou ORIGINAL RESEARCH PAPER Sindrilaru, A. et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J. Clin. Invest. 7 Feb 2011 (doi:10.1172/JCI44490)
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ReseaRch highlights Nature Reviews Immunology | AOP, published online 18 February 2011; doi:10.1038/nri2949
ImmuNE RESPONSES
IL‑7 goes antiviral It is well appreciated that inter‑ leukin‑7 (IL‑7) has essential roles in lymphocyte development and homeo‑ stasis. A new study in Cell shows that IL‑7 also has potent pro‑immune functions during viral infection. Many chronic viral infections, such as those established in individu‑ als infected with HIV or hepatitis C virus (HCV), are characterized by an upregulation of inhibitory immune pathways. Pellegrini et al. hypothesized that IL‑7, which overcomes inhibitory mechanisms to promote homeostatic immune cell expansion, might also have the ability to overcome the inhibitory networks that develop during chronic viral infection. To explore this, they thera‑ peutically administered IL‑7 to mice with established chronic lymphocytic choriomeningitis virus (LCMV) clone 13 infection. Although control animals that received PBS were unable to clear LCMV clone 13 even several months after the initial infec‑ tion, mice that received IL‑7 therapy cleared LCMV clone 13 from the spleen, liver and other chronic viral
reservoirs shortly after the comple‑ tion of 3 weeks of treatment. IL‑7 seemed to promote antiviral immunity by increasing the numbers of LCMV‑specific CD8+ T cells, as well as by enhancing the effector func‑ tions of these cells. Treatment with IL‑7 also led to a marked expansion of B cells and non‑LCMV‑specific T cells, but cell depletion experi‑ ments showed that only CD4+ and CD8+ T cells were essential for the promotion of viral clearance in mice in response to IL‑7 therapy. Using transgenic reporter mice, the authors showed that IL‑7 expanded non‑ virus‑specific naive T cell populations during LCMV infection by promoting increased export of T cells from the thymus. Interestingly, although the total number of regulatory T (TReg) cells also increased in response to IL‑7 treatment, the proportion of TReg cells within the total T cell population was reduced in IL‑7‑treated mice. However, conditional depletion of TReg cells did not affect viral loads or lead to greater immunopathology in either of the treatment groups.
NATURe ReVIewS | Immunology
The authors next investigated cytokine responses and found that the levels of several inflam‑ matory cytokines, including IL‑6, IL‑17 and interferon‑γ, were dramatically increased in the serum of IL‑7‑treated mice. Notably, this elevated pro‑inflammatory cytokine response appeared to promote antiviral immunity without induc‑ ing increased immunopathology in infected tissues. This seemed to be due to IL‑7‑mediated upregula‑ tion of the cytoprotective cytokine IL‑22; indeed, antibody‑mediated blockade of IL‑22 in LCMV‑infected IL‑7‑treated mice caused significant hepatitis in these animals. Finally, having observed such a marked increase in inflammatory cytokine production, the authors asked whether IL‑7 might repress inhibitors of cytokine signalling. In support of this, they showed that T cells aberrantly upregulate suppres‑ sor of cytokine signalling 3 (SOCS3) during chronic LCMV infection, but IL‑7 treatment led to reduced expression of SOCS3 by T cells. Further experiments suggested that IL‑7 may repress SOCS3 indirectly by downregulating forkhead box O (FOXO) transcription factors and, strikingly, when mice with a T cell‑specific deletion of Socs3 were infected with LCMV, they were able to clear infection without any notable immunopathology, in a similar manner to the IL‑7‑treated mice. These findings indicate that IL‑7 promotes antiviral immunity by suppressing T cell expression of inhibitory molecules, such as SOCS3. The efficacy of therapeutic IL‑7 in this study is particularly exciting, as it suggests that IL‑7 therapy could be used for managing HIV or HCV infections in humans.
Yvonne Bordon
ORIGINAL RESEARCH PAPER Pellegrini, M. et al. IL‑7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 3 Feb 2011 (doi:10.1016/j.cell.2011.01.011)
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ReseaRch highlights
In the news KEEPING HIV OUT HIV infection paralyses the host’s immune system, resulting in a fatal susceptibility to infections. According to a recent study, it is not only HIV-positive individuals who are unprotected against infections. Christine E. Jones et al. report that uninfected infants who were prenatally exposed to HIV display lower levels of antibodies against infectious agents, such as Haemophilus influenzae type b, than unexposed infants (JAMA, 9 Feb 2011). The low antibody levels were attributed to the defective maternal immune system, as Jones reports that “once the HIV-exposed, uninfected babies received their routine vaccinations, they had antibody levels similar to, or higher than, HIV unexposed infants” (Bloomberg, 8 Feb 2011). Therefore, the researchers suggest that it is now imperative “to establish whether babies exposed prenatally to HIV could be better protected against infections through earlier vaccination, or through vaccine shots given to mothers” (Bloomberg, 8 Feb 2011). Also this month, our progress in the battle against HIV infection is reinforced by the findings of French scientists. Bomsel et al. report that a vaccine comprised of envelope subunit gp41 antigens contained in virosomes blocks the entry of the virus at mucosal sites before primary infection takes place (Immunity, 10 Feb 2011). “Our results clearly challenge the paradigm that mucosal protection requires significantly high levels of antibodies with virus neutralizing capacity in the blood”, concludes Bomsel (ScienceDaily, 10 Feb 2011). The vaccine induced IgA and IgG production in the mucosa, and this could stop viral entry. Interestingly, the authors suggest that “these findings may help to explain why a small population of highly exposed, but HIV-negative, women who exhibit gp41-specific IgA in their vaginal secretions are protected from infection” (ScienceDaily, 10 Feb 2011). Maria Papatriantafyllou
nature reviews | Immunology
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ReseaRch highlights
in brief E VO L U T I O N
A thymus candidate in lampreys Bajoghli, B. et al. Nature 470, 90–94 (2011)
The adaptive immune system of lampreys consists of lymphocyte-like cells that express somatically diversified antigen receptors, termed variable lymphocyte receptors (VLRs). Distinct forms of these receptors are expressed by different lymphocyte lineages: T-like lymphocytes express VLRA genes and B-like lymphocytes express VLRB genes. Boehm and colleagues now show that lampreys also contain thymus-like structures in which lymphocytes undergo VLRA assembly and expression. These structures, termed thymoids, were found in the gill basket of lamprey larvae and were shown to express forkhead box N1 (FOXN1) and delta-like B (DLL-B), which is reminiscent of thymic epithelial cells in jawed vertebrates. Lymphocytes expressing cytosine deaminase 1 (CDA1; which encodes the T-like lymphocyte-specific mediator of gene conversion in lampreys) were found in close proximity to DLL-B+ epithelial cells. Furthermore, non-functional VLRA gene rearrangement was found to only occur in the thymoids, suggesting that the thymoids are the sites of T-like lymphocyte development in lampreys. B CELLS
IL‑33 activates B1 cells and exacerbates contact sensitivity Komai-Koma, M. et al. J. Immunol. 186, 2584–2591 (2011)
Interleukin-33 (IL-33) is a new member of the IL-1 cytokine family that is produced by various tissue stromal cells. Here, the authors provide evidence for a role for IL-33 in the activation of B1 cells. First, the IL-33 receptor subunit ST2 (also known as IL-1RL1) was found to be expressed by activated B1 but not B2 cells. Second, intraperitoneal injection of IL-33 led to a marked increase in B1 but not B2 cells, together with higher levels of the B1 cell products IgM, IL-5 and IL-13. This effect was shown to depend on ST2 expression, as it was abolished in ST2-deficient mice. IL-33-induced B1 cell proliferation also required IL-5, which was probably produced by T cells or mast cells in response to IL-33. Last, physiological relevance for the effect of IL-33 on B1 cells was supported by the finding that ST2-deficient mice developed less severe hapten-induced contact sensitivity (which is known to involve B1 cell-derived IgM), and IL-33 treatment exacerbated the sensitivity response in wild-type mice in a B1 cell-dependent manner. R E G U L AT O RY T C E L L S
Aire‑dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development Lei, Y. et al. J. Exp. Med. 7 Feb 2011 (doi:10.1084/jem.20102327)
In this study, the authors assessed the factors involved in the accumulation of dendritic cells (DCs) in the thymic medulla and their contribution to self-tolerance. By screening for chemokine receptor expression by isolated thymic DCs and analysing various chemokine-deficient mice, the authors identified chemokine XC receptor 1 (XCR1; expressed by thymic DCs) and its ligand XCL1 (expressed by medullary thymic epithelial cells) as having important roles in the accumulation of thymic DCs. XCL1-deficient mice had impaired development of natural regulatory T cells, and thymocytes from these mice promoted inflammatory lesions in the lacrimal glands of nude mice (which lack mature T cells), suggesting a breakdown in self-tolerance in XCL1-deficient mice. Finally, thymic DC accumulation and the generation of natural regulatory T cells were diminished in autoimmune regulator (AIRE)-deficient mice owing to defective XCL1 expression.
nature reviews | Immunology
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ReseaRch highlights Nature Reviews Immunology | AOP, published online 11 February 2011; doi:10.1038/nri2942
t CELLS
Plastic TH17 cells Interleukin‑17 (IL‑17)‑producing T helper cells (TH17 cells) are a unique subset of effector CD4+ T cells. However, TH17 cells that are generated in vitro have remarkable plasticity and can produce the TH1 cell‑associated cytokine interferon‑γ (IFNγ) and/ or may lose the ability to produce IL‑17. It remains unclear whether TH17 cell plasticity also exists in vivo. Using mice in which the fate of cells that have expressed IL‑17A can be permanently traced, Stockinger and colleagues show that TH17 cells are plastic in vivo and that the functional fate of these cells is shaped by the inflammatory environment. In the fate‑reporter mice gener‑ ated for this study, cells that express IL‑17A are indelibly marked with enhanced yellow fluorescence protein (eYFP). Following the induc‑ tion of experimental autoimmune encephalomyelitis (EAE; a chronic inflammatory disease of the central nervous system) in these mice, the authors found that the numbers of eYFP+ TH17 cells in the
draining lymph nodes and spinal cord increased with disease progression, as expected. However, about half of these cells had stopped producing IL‑17A (referred to as ex‑TH17 cells). Conversely, the expression of IFNγ by eYFP+CD4+ T cells increased over time. In fact, almost all of the IFNγ‑ producing CD4+ T cells in the spinal cord were ex‑TH17 cells. So, TH17 cells give rise to both IL‑17+IFNγ– and IL‑17–IFNγ+ T cells during EAE. Further analysis revealed that eYFP+ T cells progressed from being mainly IL‑17+IFNγ– to being IL‑17+IFNγ+ and finally to express‑ ing IFNγ alone during the course of EAE. Moreover, only eYFP+ (and not eYFP–) T cells produced additional pro‑inflammatory cytokines (such as GM‑CSF (granulocyte–macrophage colony stimulating factor) and TNF (tumour necrosis factor)). Of note, IFNγ‑producing ex‑TH17 cells could be distinguished from eYFP–IFNγ+ TH1 cells by the expression of aryl hydrocarbon receptor and IL‑1 receptor type 1. IL‑23 is thought to contribute to TH17 cell plasticity in vitro, and the authors found that eYFP+ T cells isolated from IL‑23p19‑deficient fate‑reporter mice with EAE lacked IFNγ expression. Furthermore, loss of IL‑23p19 prevented the upregula‑ tion of T‑bet (a transcription factor that is essential for IFNγ produc‑ tion) by eYFP+ T cells. So, IL‑23 is required for the switch in cytokine production by TH17 cells from IL‑17A to IFNγ during chronic inflammation.
But does this switch occur during acute inflammatory responses that resolve quickly? Cutaneous infection of fate‑reporter mice with Candida albicans hyphae, which leads to an acute infection that is rapidly cleared, resulted in the accumula‑ tion of IL‑17‑producing TH17 cells (after an early IL‑17A response mediated by γδ T cells). IFNγ was also produced during this acute infection, but in contrast to the chronic inflammatory setting, none of the IFNγ‑expressing CD4+ T cells were eYFP+. Furthermore, by the time the pathogen was cleared, most eYFP+ T cells had stopped produc‑ ing IL‑17A and the absolute number of T cells in the skin was greatly reduced. Analysis of local antigen‑ presenting cells showed that they expressed high levels of the mRNA encoding the anti‑inflammatory cytokine IL‑10 and low levels of Il23 mRNA. So, the data show that during chronic inflammation TH17 cells deviate to express additional pro‑ inflammatory cytokines, whereas during an acute resolving inflam‑ matory response TH17 cells shut off IL‑17A production and rapidly disappear. In addition, IL‑23 seems to have an important role in driving the plasticity of TH17 cells during chronic inflammation.
Olive Leavy
ORIGINAL RESEARCH PAPER Hirota, K. et al. Fate mapping of IL‑17‑producing T cells in inflammatory responses. Nature Immunol. 30 Jan 2011 (doi:10.1038/ni.1993)
STUDIO 8
NATURE REvIEwS | Immunology
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ReSeaRch highlightS
B CELLS
Short- and long-term memory
JOH N FO XX IMAGES
In a recent study in Science, Marc Jenkins and colleagues identify two populations of memory B cells that differ in terms of frequency, lifespan and activation potential. In a classical primary immune response, naive IgM+ B cells specific for the target antigen enter a germinal centre, where they undergo affinity maturation and immunoglobulin class switching. The cells then emerge as immunoglobulin-secreting plasmablasts or as surface-switchedimmunoglobulin (swIg)+ memory B cells, which generate plasmablasts after subsequent exposure to antigen. However, there is also evidence for the existence of IgM+ memory B cells, the derivation and function of which are unclear. To comprehensively analyse all memory B cell populations in normal mice, the authors tracked the fate of phycoerythrin-specific B cells using a new antigenbased enrichment method. Naive C57BL/6 mice had ~20,000 phycoerythrinspecific IgM+CD38+GL7– B cells in the spleen and lymph nodes. After subcutaneous injection with
phycoerythrin plus adjuvant, the number of phycoerythrin-specific B cells increased markedly to a peak of ~106 cells by day 13 and then declined to a stable population of ~150,000 cells. At day 8 after antigen injection, the phycoerythrin-specific B cells could be divided into IgM+ and swIg+ populations, both of which contained plasmablasts with high intracellular immunoglobulin concentrations, CD38–GL7+ germinal centre cells and CD38+GL7– memory cells. The number of IgM+ and swIg+ plasmablasts and germinal centre B cells peaked around day 13 and then declined, but the memory B cells had different dynamics according to their immunoglobulin phenotype. swIg+ memory B cells peaked on day 30 at ~60,000 cells and declined to very low numbers by day 450, whereas IgM+ memory B cells peaked on day 10 at ~120,000 cells and the population then remained stable until at least day 450. Adoptive transfer studies showed that both memory B cell populations in isolation could mount a memory response in recipient mice. However, different results were obtained when both memory B cell populations were present in mice that had been previously primed with phycoerythrin. On day 320 after priming, the mice contained 100,000 IgM+ and 2,000 swIg+ antigen-specific memory B cells. When these mice were rechallenged, the number of swIg+ memory cells increased 150-fold to generate 25,000 swIg+ plasmablasts (but no germinal centre
NATure revIeWs | Immunology
cells), whereas the number of IgM+ cells increased less than twofold. The poor secondary response of IgM+ memory B cells was attributed to the presence during the challenge of phycoerythrin-specific antibody (produced by swIg+ plasmablasts), which was shown to inhibit germinal centre formation by both naive B cells and IgM+ memory B cells. These results illustrate some analogies between how we think about humoral and neurological memories. In neuroscience, short-term memory is the capacity for holding a small amount of information in an active, readily available state for a short period of time. This is akin to the small number of short-lived but readily activated swIg+ memory B cells. By contrast, long-term memories can be retained for much longer, akin to the IgM+ memory B cells. The authors speculate that IgM+ memory B cells do not contribute to the secondary response until the immunoglobulin levels produced by swIg+ memory B cells have declined. As long-term memory is subject to fading, several recalls of memory might be required to prevent forgetting. In a similar manner, IgM+ memory B cells can form germinal centres to repopulate the reservoir of humoral immune memory.
Kirsty Minton
ORIGINAL RESEARCH PAPER Pape, K. A. et al. Different B cell populations mediate early and late memory during an endogenous immune response. Science 10 Feb 2011 (doi:10.1126/ science.1201730)
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Early and late protection from TB
The one approved vaccine against tuberculosis (known as the Mycobacterium bovis bacillus Calmette–Guérin (BCG) vaccine) and those currently in clinical trials are designed to protect against initial infection, as they incorporate Mycobacterium tuberculosis antigens that are expressed early in the disease process. However, they do not prevent the establishment of latent persistent infection or the reactivation of clinical disease — a major need both for infected patients and for reducing further transmission. Reporting in Nature Medicine, Aagaard and colleagues show that a vaccine containing antigens that are expressed in the early and late stages of tuberculosis protects against
late-stage infection in both pre- and post-exposure mouse models. The vaccine (termed H56) comprises a fusion protein (Ag85B–ESAT6–Rv2660c) and a cationic adjuvant (CAF01). Ag58B and ESAT6 are well known M. tuberculosis antigens that are secreted early in infection and have previously been shown to provide protective immunity. Rv2660c was identified in this study as one of the factors expressed at constant levels throughout infection. The authors proposed that simultaneous vaccination with these three antigens could produce multistage effects, enabling the immune system to mount a response to both the early and late phases of tuberculosis.
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In the early stage of infection (
