IL-15 Receptor

IL-15 Receptor Thomas A. Waldmann* and Yutaka Tagaya Metabolism Branch, National Cancer Institute, NIH Building 10, Room 4N115, 10 Center Drive, MSC 1374, Bethesda, MD 20892-1374, USA * corresponding author tel: 301-496-6653, fax: 301-496-9956, e-mail: [email protected] DOI: 10.1006/rwcy.2000.14008.

SUMMARY IL-15 uses two distinct receptor and signaling pathways. In T and NK cells, the type 1 IL-15 receptor includes the IL-2/15R subunit shared with IL-2, the c subunit shared with IL-2, IL-4, IL-7, and IL-9, as well as an IL-15-specific receptor subunit IL-15R. Thus type 1 receptor uses a JAK1/JAK3 and STAT3/STAT5 signaling system. Mast cells respond to IL-15 with a type 2 receptor system that does not share elements with IL-2R but uses a novel 60±65 kDa IL-15RX subunit. This type 2 receptor signaling involves JAK2/STAT5 activation. In addition to the other functional activities in immune and nonimmune cells, signaling through the type 1 IL-15 receptor plays a pivotal role in the development, survival, and activation of NK cells.

BACKGROUND

Discovery IL-15 is a 14±15 kDa member of the four  helix bundle family of cytokines. IL-15 utilizes two distinct receptor and signaling pathways (Figure 1). In T and NK cells the type 1 IL-15 receptor includes the c shared with IL-2, IL-4, IL-7, IL-9, and the IL-2/15R subunit shared with IL-2. Furthermore, it involves an IL-15-specific receptor subunit, IL-15R. In contrast, mast cells respond to IL-15 using a receptor system that does not share elements with the IL-2R system but involves a novel 60±65 kDa IL-15RX subunit. In mast cells IL-15 signaling involves JAK2 and STAT5 activation rather than the JAK1/JAK3 and STAT3/STAT5 that are used by IL-15 in activated T and NK cells.

The IL-2/15R chain and the c chain were defined as part of an analysis of the IL-2 receptor system. Using radiolabeled IL-2 in crosslinking studies Tsudo et al. (1986) and Sharon et al. (1986) discovered IL-2R , a 70±75 kDa binding subunit. Grabstein et al. (1994) and Bamford et al. (1994) used IL-2R -specific antibodies to demonstrate that IL-15 requires this subunit for its action in T and NK cells. Takeshita et al. (1992) defined and cloned the c receptor and showed that it was a component of the IL-2 receptor. It was subsequently demonstrated that IL-2R (now termed common gamma or c) is not only an essential element of high- and intermediate-affinity receptors for IL-2, but is also required for the actions of IL-4, IL-7, and IL-9 (Kondo et al., 1993; Noguchi et al., 1993). Giri et al. (1994) demonstrated in cells transfected with IL-2R subunits that c as well as IL-2R are required for IL-15 binding and signaling. IL-15 does not use the  subunit of the IL-2 receptor. However, a novel IL-15-specific binding protein termed IL-15R was identified and its cDNA cloned by Giri et al. (1995). Thus in T and NK cells the IL-15 Figure 1

IL-15 receptors.

Type 1 (T/NK cells)

Type 2 (Mast cells)

IL-15

IL-15

γc

IL-15 RX

JAK1

JAK3

JAK2

STAT3

STAT5

IL-15 Rα

IL-2 15Rβ

STAT5

IL-15 receptors

?

1522 Thomas A. Waldmann and Yutaka Tagaya receptor was shown to involve an IL-15-specific subunit IL-15R, the IL-2/15R subunit shared with IL-2, and the c subunit shared with IL-2, IL-4, IL-7, and IL-9. Tagaya et al. (1996a,b) demonstrated that IL-15 uses a distinct type 2 receptor/signal transduction pathway in mast cells. Mast cells were shown to respond to IL-15 with a receptor system that does not share elements with the IL-2R but uses a novel 60±65 kDa IL-15RX subunit.

Alternative names The chain shared by IL-2 and IL-15 is frequently called IL-2R . It is also referred to as IL-2/15R . The common gamma chain, c, was initially termed IL2R prior to the demonstration of its use by other cytokines. The IL-15-specific receptor in T and NK cells is termed IL-15R, whereas the chain involved in the type 2 receptor of mast cells is IL-15RX.

Structure IL-2/15R and c are members of the cytokine I superfamily of receptors that contain four conserved cystines and the canonical WSXWS (Trp-Ser-X-TrpSer) motif. IL-15R is a type 1 membrane protein that is not a member of the cytokine receptor superfamily. However, a comparison of IL-2R and IL-15R revealed the shared presence of a conserved motif known as the GP-1 motif or a SUSHI domain (Giri et al., 1995). The structure of the mast cell type 2 IL-15RX receptor subunit has not been defined.

Main activities and pathophysiological roles Through its action on its receptor, IL-15 stimulates the proliferation of activated CD4ÿCD8ÿ, CD4+ CD8+, CD4+ and CD8+ cells, and dendritic epidermal T cells (Burton et al., 1994; Grabstein et al., 1994; Edelbaum et al., 1995; Garcia et al., 1998). It was recently reported that IL-15 preferentially propagates CD8 memory T cells (Zhang et al., 1998). Although IL-15 does not have an effect on resting B cells it induces proliferation and immunoglobulin synthesis by B cells costimulated by PMA or by an immobilized antibody to immunoglobulin M (Armitage et al., 1995). One of the most critical functions of IL-15 acting through the type 1 receptor is a pivotal role in the development, survival, and activation of NK cells.

IL-15 acting through the type 2 receptor stimulates mast cells proliferation. IL-15 also acts on skeletal muscle (Quinn et al., 1997), endothelial cells, and microglia (Lee et al., 1996; Hanisch et al., 1997).

GENE

Accession numbers GenBank: Human IL-15R: NM_002189 Human IL-2/15R : NM_000878 Human c: NM_000206 Mouse IL-15R: U22339 Mouse IL-2/15R : M28052 Mouse c: U21795

Sequence Nucleotide sequences for the IL-15R components can be found in GenBank. The accession numbers are shown above.

Chromosome location and linkages Human : 10 p15-14; : 22q11.2-q12; c: Xq13 Mouse : 2; : 15: c: X The chromosomal localization of IL-15RX has not been defined.

Relevant linkages IL-15R and IL-2R are linked in humans on chromosome 10 p15-14 and in mice on chromosome 2 (Anderson et al., 1995).

PROTEIN

Accession numbers Human IL-15R: NP_002180 Human IL-2/15R : NP_000869 Human c: NP_000197 Mouse IL-15R: AAC52240 Mouse IL-2/15R : AAA39283 Mouse c: AAA64279

IL-15 Receptor 1523 motif. IL-15RX is a 60±65 kDa receptor whose structure has not been defined.

Sequence See Figure 2.

Description of protein IL-15R is a type 1 membrane protein with a predicted signal peptide of 32 amino acids, a 173 amino acid extracellular domain, a single membrane-spanning region of 21 amino acids, and a 37 amino acid cytoplasmic domain (mouse IL-15R). In contrast to IL-2/15R and c, IL-15R is not a member of the cytokine receptor superfamily. However, IL-15R contains a motif known as a GP-1 motif or a SUSHI domain (Giri et al., 1995). The human IL-2/15R mRNA encodes a primary translation product of 551 amino acids (Hatakeyama et al., 1989). The receptor contains a 26 amino acid signal peptide and a mature human IL-2/15R is composed of 525 amino acids with an extracellular segment of 214 amino acids, a hydrophobic transmembrane stretch of 25 amino acids, and a 286 amino acid cytoplasmic domain. The human c cDNA contains an open reading frame encoding a 369 amino acid residue polypeptide (Takeshita et al., 1992). This protein contains a 22 amino acid signal peptide, a 233 amino acid extracellular domain, a 28 amino acid hydrophobic transmembrane domain, and an 86 amino acid terminal cytoplasmic domain. IL-2/15R and c are members of the hematopoietin or cytokine superfamily of receptors that contain four conserved cystines and canonical WSXWS (Trp-Ser-X-Trp-Ser)

Relevant homologies and species differences IL-2/15R and c are members of the hematopoietin or cytokine superfamily of receptors. IL-15R shares with IL-2R the presence of the GP-1 or SUSHI domain motif. Furthermore, the IL-2R and IL15R genes have a similar intron±exon organization. Moreover, they are closely linked on both human (10p-15-14) and murine genomes (chromosome 2) (Anderson et al., 1995).

Affinity for ligand(s) IL-15R binds IL-15 with a very high affinity (dissociation constant Kd ˆ 10ÿ11 M) (Anderson et al., 1995; Giri et al., 1995). This affinity was not dramatically altered by the simultaneous presence of IL-2/15R or c. IL-2/15R and c acting together in the absence of IL-15R bind IL-15 with an intermediate affinity (approximately Kd ˆ 10ÿ9 M). IL-15RX binds IL-15 with an intermediate affinity (Kd ˆ 10ÿ9 M) (Tagaya et al., 1996b).

Cell types and tissues expressing the receptor IL-15R has a wide cellular distribution. Its expression is observed in T cells, B cells, macrophages, and

Figure 2 The amino acid sequences for human IL-15R (Anderson et al., 1995) and mouse IL-15R (Giri et al., 1995). The transmembrane domain is underlined.

1524 Thomas A. Waldmann and Yutaka Tagaya in thymic stroma cells and bone marrow stroma cells (Anderson et al., 1995). In addition, IL-15R mRNA is widespread in such tissues as liver, heart, spleen, lung, skeletal muscle, and activated vascular endothelial cells (Giri et al., 1995). IL-15R mRNA is increased in T cells after addition of IL-2, an antiCD3 antibody or phorbol-myristate acetate (PMA) (Giri et al., 1995). Furthermore, IL-15R expression is augmented in macrophage cell lines after treatment with IFN . IL-2/15R is constitutively expressed by NK cells, monocytes, and resting CD8 cells but is not expressed by resting CD4 cells although it is inducible in such cells. The common gamma chain is expressed by most hematopoietic cells.

Regulation of receptor expression IL-2/15R : Promoter/enhancer region contains putative binding sites for Ets-1, GABP, SP-1 and Egr-1 (Lin and Leonard, 1997).

c: The c gene has a constitutive activation promoter that contains an Ets-binding site. IL-15R: The 50 regulatory region of this gene is not defined.

Release of soluble receptors In contrast to the release of IL-2R, there is little release of IL-2/15R or c. Although levels have not been quantitated, it has been suggested that IL-15R is released from the cell surface and may act to inhibit IL-15 action.

SIGNAL TRANSDUCTION

Associated or intrinsic kinases The type 1 IL-15 receptors in T and NK cells, like most cytokine receptors, do not possess intrinsic protein tyrosine kinase (PTK) domains, yet receptor stimulation invokes rapid tyrosine phosphorylation of intracellular proteins including the receptors themselves. In T and NK cells, IL-15 activates JAK1 and JAK3 of the tyrosine kinase family members (Witthuhn et al., 1994; Johnston et al., 1995). Furthermore, the addition of IL-15 to such receptor-expressing T cells led to the tyrosine phosphorylation and nuclear translocation of STAT 3 and STAT5 (Johnston et al., 1995; Lin et al., 1995). The IL-15-signaling pathway in T cells also involves the phosphorylation of the Src-related cytoplasmic

tyrosine kinases p56lck and p72syk, the induction of the expression of the Bcl-2 anti-apoptotic protein and the stimulation of the Ras/Raf/MAP kinase pathway leading to fos/jun activation (Miyazaki et al., 1995). Mast cells respond to IL-15 with a type 2 receptor system that uses a novel 60±65 kDa IL-15RX subunit. This type 2 receptor involves JAK2/STAT5 activation rather than the JAK1/JAK3 and STAT3/STAT5 system used by the type 1 receptor in T/NK cells.

DOWNSTREAM GENE ACTIVATION

Transcription factors activated IL-15 through the type 1 receptor activates jun/fos AP-1 complex. It also activates STAT3, STAT5a, and STAT5b transcription factors (Lin et al., 1995). The type 2 receptor signaling activates STAT5a and b molecules.

Genes induced The genes induced by IL-15R include IL-2R (Treiber-Held et al., 1996), CC chemokines and receptors (Perera et al., 1999), bcl-2/bcl-XL antiapoptotic genes, caspase 8/FLICE (Perera and Waldmann, 1998), Pim-1, CIS/SIS/SOCS family member proteins, and c-myc.

Promoter regions involved The promoter regions involved are the STAT5 consensus sequence and AP-1 sites.

BIOLOGICAL CONSEQUENCES OF ACTIVATING OR INHIBITING RECEPTOR AND PATHOPHYSIOLOGY

Unique biological effects of activating the receptors For more detail on the biological effects of IL-15 receptor, see the review by Waldmann and Tagaya (1999). IL-15 acting through the type 1 receptor stimulates the proliferation of activated CD4ÿCD8ÿ, CD4+

IL-15 Receptor 1525 CD8+, CD4+, and CD8+ cells (Burton et al., 1994; Grabstein et al., 1994; Edelbaum et al., 1995; Zhang et al., 1998; Garcia et al., 1998). IL-15 also has an effect on activated but not resting T cells, inducing proliferation and immunoglobulin synthesis in cells costimulated by PMA or by an immobilized antibody to IgM (Armitage et al., 1995). IL-15 may be an essential factor for the development of NK cells (Carson et al., 1994). NK cells are absent in mice made deficient in elements required for IL-15 action, including IL-2/15R (Suzuki et al., 1997), c (Cao et al., 1995; DiSanto et al., 1995), IRF-1ÿ/ÿ (Ogasawara et al., 1998; Ohteki et al., 1998), JAK3 (Biron et al., 1989; Russell et al., 1995; Macchi et al., 1995), or STAT5a/b (Imada et al., 1998; Teglund et al., 1998). Furthermore, IL-15 is effective in inducing bone marrow progenitor differentiation into NK cells (MroÂzek et al., 1996; Cavazzana-Calvo et al., 1996). In a similar way, the addition of IL-15 to immature postnatal thymocytes or to fetal thymic organ cultures led to the development of NK cells (Mingari et al., 1997). IL-15 also has unique functions on nonlymphoid cells. Acting through the type 2 receptor it stimulates mast cell proliferation (Tagaya et al., 1996a,b). Although the type of receptor has not been defined, IL-15 also has actions on muscle, inducing skeletal muscle fiber hypertrophy (Quinn et al., 1997), vascular endothelial cells promoting angiogenesis (Angiolillo et al., 1997), and on brain microglia and astrocytes (Lee et al., 1996; Hanisch et al., 1997).

Phenotypes of receptor knockouts and receptor overexpression mice IL-15R-null (IL-15Rÿ/ÿ) mice are markedly lymphopenic despite grossly normal T and B lymphocyte development (Lodolce et al., 1998). This lymphopenia is due to decreased proliferation and decreased homing of IL-15Rÿ/ÿ lymphocytes to peripheral lymph nodes. These mice are also deficient in NK cells, natural killer T cells, CD8+ lymphocytes, and TCR /-intraepithelial lymphocytes. In addition, memory phenotype CD8+ T cells are selectively reduced in number. Mice lacking the IL-2/15R chain are deficient in functions mediated by either IL-2 or IL-15 since this receptor is shared by these two cytokines. Mice lacking this receptor lack NK cells. Furthermore, they manifest spontaneously activated T cells, increased differentiation of B cells into plasma cells, and high serum concentrations of immunoglobulins IgG and IgE as well as autoantibodies that cause hemolytic

anemia (Suzuki et al., 1997). These animals manifested marked infiltrative granulopoiesis and died after about 12 weeks. The c chain is shared by IL-2, IL-4, IL-7, IL-9, and IL-15; thus mice deficient in this chain lack the ability to respond to all of these cytokines. Mice made deficient in this cytokine or its membrane-proximal signaling element, JAK3, manifest severe combined immunodeficiency disease with a virtual absence of NK cells markedly deficient T cell numbers and function and abnormalities of B cell function, presumably due to the lack of IL-7 function in early T/B cell development.

Human abnormalities No patients with deficiency of IL-15R, IL-2/15R , or IL-15RX have been defined. Patients deficient in

c manifest X chromosome-linked severe combined immunodeficiency disease (X-SCID) (Schorle et al., 1991; Noguchi et al., 1993). Patients with this disorder have a dramatic reduction in T and NK cells but have at least normal numbers of B cells that are functionally abnormal. Deficiency of JAK3 in humans yields an autosomal disorder with the same phenotype.

THERAPEUTIC UTILITY

Effect of treatment with soluble receptor domain The injection of an IL-15 antagonist with the soluble form of IL-15R into DBS/1 mice suppressed their development of collagen-induced arthritis (Ruchatz et al., 1998).

Effects of inhibitors (antibodies) to receptors An IL-15 receptor antagonist has been produced by mutating glutamine residues within the C-terminus of IL-15 to aspartic acid, completely inhibiting IL-15triggered cell proliferation (Kim et al., 1998). This IL-15 mutant protein markedly attenuated antigenspecific delayed hypersensitivity responses in Balb/c mice and enhanced the acceptance of islet cell allografts. An antibody (Mik 1) directed toward IL-2/IL-15R inhibits the actions of IL-15 but not those mediated by IL-2 through the high-affinity IL-2 receptor. A humanized version of this antibody

1526 Thomas A. Waldmann and Yutaka Tagaya prolonged renal allograft survival in cynomolgus monkeys (Tinubu et al., 1994). The clinical application of new therapeutic agents that target IL-15 or the receptor and signaling elements shared by IL-15 and other T cell stimulatory cytokines may provide a new perspective for the treatment of tropical spastic paraparesis HTLV-Iassociated myelopathy (TSP/HAM), rheumatoid arthritis, and inflammatory bowel disease where abnormalities of IL-15 expression have been demonstrated.

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LICENSED PRODUCTS A polyclonal antibody against human and murine IL15R peptide may be obtained from Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA. Antibodies against human IL-2/15R molecule Mik 2 and 3 monoclonal antibodies are available from PharMingen (San Diego, CA, USA).

1528 Thomas A. Waldmann and Yutaka Tagaya Polyclonal antibodies against IL-2/15 peptides are available from Santa Cruz Biotechnology (Santa Cruz, CA, USA).

Antibodies against human c molecule A monoclonal anti-human c antibody is available from PharMingen.

Antibodies against murine IL-2/15R molecule Two monoclonal anti-murine IL-2/15R antibodies may be obtained from PharMingen. Santa Cruz carries anti-mouse IL-2/15R polyclonal IgGs that are raised against synthetic peptides from this molecule.

Antibodies against murine c molecule Monoclonal antibodies recognizing the murine c molecule are available from PharMingen. Polyclonal anti-mouse c peptides are available from Santa Cruz Biotechnology.