HGNC Approved Gene Symbol: IL15RA
Cytogenetic location: 10p15.1 Genomic coordinates (GRCh38): 10:5,948,900-5,978,741 (from NCBI)
Interleukin-2 (IL2; 147680) and interleukin-15 (IL15; 600554) are cytokines with overlapping but distinct biologic effects. Their receptors share 2 subunits, the IL2R beta (146710) and gamma (308380) chains, which are essential for signal transduction. The IL2 receptor requires an additional IL2-specific alpha subunit (IL2RA; 147730) for high-affinity IL2 binding. Giri et al. (1995) identified and cloned a murine IL15-specific alpha subunit and showed that it is structurally related to IL2R-alpha.
Anderson et al. (1995) isolated 3 differentially spliced human IL15R-alpha variants.
Using RT-PCR, Dubois et al. (1999) cloned 8 IL15RA isoforms, including the 3 reported by Anderson et al. (1995). The first 4 isoforms include the full-length form containing exons 1 through 7 and forms lacking exon 2, exon 3, or both exons 2 and 3. The remaining 4 isoforms are identical to the first 4 except that they contain an alternative C-terminal exon, exon 7-prime, that is 100 bp shorter than exon 7. These 8 isoforms were detected in most cell lines and tissues examined. Western blot analysis using cDNAs encoding the full-length isoform and the isoform lacking exon 2 (exon 7 forms of both) showed that both proteins were extensively N- and O-glycosylated. Confocal microscopy demonstrated that full-length IL15RA was associated primarily with the nuclear membrane, with part of the receptor having an intranuclear localization. Isoforms lacking exon 2, which encodes a protein-binding sushi domain with a putative nuclear localization signal, showed extranuclear localization in the endoplasmic reticulum, Golgi, and cytoplasmic vesicles. Loss of exon 3 had no effect on IL15RA localization. Immunoprecipitation analysis indicated that smaller amounts of IL15RA and IL15RA lacking exon 2 were expressed as glycosylated proteins on the cell surface.
Giri et al. (1995) found that the murine IL15R-alpha subunit alone bound IL15 with a 1,000-fold higher affinity than that seen with IL2R-alpha and IL2.
Anderson et al. (1995) found that all 3 human IL15R-alpha variants they identified were capable of high-affinity binding of IL15. The cytoplasmic domain of IL15R-alpha, like that of IL2R-alpha, was dispensable for mitogenic signaling, suggesting that the primary role of the alpha chains is to confer high-affinity binding. At high concentrations, IL15, like IL2, was able to signal through a complex of IL2R-beta and -gamma in the absence of the alpha subunit.
Dubois et al. (1999) found that, in contrast to full-length IL15RA, IL15RA isoforms lacking exon 2 were unable to bind IL15.
Using radioimmunoassays, Mortier et al. (2004) identified a 42-kD soluble form of IL15RA released by a proteolytic shedding mechanism from the plasma membrane. The soluble receptor displayed high affinity for IL15 and inhibited both binding of IL15 to the membrane receptor and IL15-induced cell proliferation.
Mortier et al. (2006) found that, in contrast to the behavior of the natural soluble form of IL15RA, a recombinant, soluble sushi domain of IL15RA behaved as a potent IL15 agonist by enhancing binding of IL15 to the IL2RB/IL2RG complex and increasing IL15 bioactivity. A fusion protein of IL15 and the IL15RA sushi domain was an even stronger agonist of the IL2RB/IL2RG complex.
Rubinstein et al. (2006) found that stimulation of mouse memory-phenotype Cd8-positive T cells, which express high levels of Cd44 (107269) and Il2rb, with a complex of either human or mouse soluble IL15/IL15RA resulted in a strong lymphoproliferative response that was greater than the response to IL15 alone. The lymphoproliferative response was mediated solely through the Il2rb/Il2rg receptor. Administration of mouse soluble Il15/Il15ra in vivo caused nearly all transferred memory-phenotype Cd8-positive cells to divide multiple times, whereas only about half did so in response to Il15 alone. In contrast to the ability of soluble IL15RA to potentiate the function of IL15, soluble IL2RA blocked the function of IL2. Rubinstein et al. (2006) concluded that the IL15/IL15RA complex has enhanced effects on T-cell survival compared with IL15 alone.
To examine whether tolerant T cells could be rescued and functionally restored for use in therapy of established tumors, Teague et al. (2006) studied a transgenic T-cell receptor mouse model in which Cd8-positive T cells specific for a candidate tumor antigen also expressed in liver were tolerant. FACS analysis showed that these tolerant T cells expressed Il15ra, and treatment of the cells with Il15 induced proliferation and Il2 secretion. Such proliferation abrogated tolerance, and the rescued cells could effectively treat leukemia. Teague et al. (2006) concluded that high-affinity CD8-positive T cells are not necessarily deleted by encounter with self-antigen in the periphery and can be rescued and expanded for use in tumor immunotherapy.
By flow cytometric and confocal microscopy analyses, Brilot et al. (2007) found that cell-to-cell contact between mature dendritic cells (DCs) and natural killer (NK) cells occurred rapidly and induced intracellular calcium release and upregulation of CD69 (107273). Formation of a synapse between the 2 cell types required the adhesion molecules LFA1 (see 153370) and LFA3 (153420), induced expression of IL15RA, and was necessary for NK cell survival. Il15ra-deficient NK cells obtained from donors with a history of infectious mononucleosis or IL15RA-positive NK cells treated with anti-IL15RA showed reduced NK survival after coculture with mature DCs. Brilot et al. (2007) concluded that mature DCs interact with and activate resting NK cells via formation of a regulatory synapse. They proposed that IL15RA expression on NK cells is required for optimal NK/DC interaction and that IL15RA mediates cell contact-dependent NK cell survival.
Pistilli et al. (2011) found that loss of Il15ra in male mice of different strains resulted in remodeling of fast skeletal muscles to a more oxidative phenotype, which manifested as greater exercise capacity and resistance to fatigue due, in part, to adaptations in mitochondria. Studies of male and female endurance athletes revealed that a nonsynonymous SNP in exon 3 of IL15RA, rs2228059, was associated with endurance status in specific sports. Pistilli et al. (2011) concluded that IL15RA has a role in defining the phenotype of fast skeletal muscles in vivo.
Crystal Structure
Chirifu et al. (2007) noted that IL2 and IL15 are recognized by the alpha units of their receptors (IL2RA and IL15RA, respectively), but that signaling is mediated by the common gamma chain, IL2RG. The receptors for the 2 cytokines also share the beta unit, IL2RB. Chirifu et al. (2007) determined the 1.85-angstrom crystal structure of the IL15-IL15RA complex. The findings highlighted the importance of water in generating the high-affinity complex and revealed that the topologies of the IL15-IL15RA and IL2-IL2RA complexes are similar.
Dubois et al. (1999) determined that the IL15RA gene contains 8 exons, including an alternative C-terminal exon that they designated exon 7-prime.
Anderson et al. (1995) stated that the IL15RA and IL2RA genes have a similar intron/exon organization and are closely linked in both human and murine genomes. The IL2RA gene had been previously mapped to chromosome 10p15-p14 and its mouse homolog to chromosome 2. Anderson et al. (1995) mapped the human IL15RA gene to chromosome 10p15-p14 by FISH and the mouse Il15ra gene to chromosome 2 by interspecific backcross mapping.
Anderson, D. M., Kumaki, S., Ahdieh, M., Bertles, J., Tometsko, M., Loomis, A., Giri, J., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Valentine, V., Shapiro, D. N., Morris, S. W., Park, L. S., Cosman, D. Functional characterization of the human interleukin-15 receptor alpha chain and close linkage of IL15RA and IL2RA genes. J. Biol. Chem. 270: 29862-29869, 1995. [PubMed: 8530383] [Full Text: https://doi.org/10.1074/jbc.270.50.29862]
Brilot, F., Strowig, T., Roberts, S. M., Arrey, F., Munz, C. NK cell survival mediated through the regulatory synapse with human DCs requires IL-15R-alpha. J. Clin. Invest. 117: 3316-3329, 2007. [PubMed: 17948125] [Full Text: https://doi.org/10.1172/JCI31751]
Chirifu, M., Hayashi, C., Nakamura, T., Toma, S., Shuto, T., Kai, H., Yamagata, Y., Davis, S. J., Ikemizu, S. Crystal structure of the IL-15-IL-15R-alpha complex, a cytokine-receptor unit presented in trans. Nature Immun. 8: 1001-1007, 2007. [PubMed: 17643103] [Full Text: https://doi.org/10.1038/ni1492]
Dubois, S., Magrangeas, F., Lehours, P., Raher, S., Bernard, J., Boisteau, O., Leroy, S., Minvielle, S., Godard, A., Jacques, Y. Natural splicing of exon 2 of human interleukin-15 receptor alpha-chain mRNA results in a shortened form with a distinct pattern of expression. J. Biol. Chem. 274: 26978-26984, 1999. [PubMed: 10480910] [Full Text: https://doi.org/10.1074/jbc.274.38.26978]
Giri, J. G., Kumaki, S., Ahdieh, M., Friend, D. J., Loomis, A., Shanebeck, K., DuBose, R., Cosman, D., Park, L. S., Anderson, D. M. Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha of the IL-2 receptor. EMBO J. 14: 3654-3663, 1995. [PubMed: 7641685] [Full Text: https://doi.org/10.1002/j.1460-2075.1995.tb00035.x]
Mortier, E., Bernard, J., Plet, A., Jacques, Y. Natural, proteolytic release of a soluble form of human IL-15 receptor alpha-chain that behaves as a specific, high affinity IL-15 antagonist. J. Immun. 173: 1681-1688, 2004. [PubMed: 15265897] [Full Text: https://doi.org/10.4049/jimmunol.173.3.1681]
Mortier, E., Quemener, A., Vusio, P., Lorenzen, I., Boublik, Y., Grotzinger, J., Plet, A., Jacques, Y. Soluble interleukin-15 receptor alpha (IL-15R-alpha)-sushi as a selective and potent agonist of IL-15 action through IL-15R-beta/gamma: hyperagonist IL-15-IL-15R-alpha fusion proteins. J. Biol. Chem. 281: 1612-1619, 2006. [PubMed: 16284400] [Full Text: https://doi.org/10.1074/jbc.M508624200]
Pistilli, E. E., Bogdanovich, S., Garton, F., Yang, N., Gulbin, J. P., Conner, J. D., Anderson, B. G., Quinn, L. S., North, K., Ahima, R. S., Khurana, T. S. Loss of IL-15 receptor alpha alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles. J. Clin. Invest. 121: 3120-3132, 2011. [PubMed: 21765213] [Full Text: https://doi.org/10.1172/JCI44945]
Rubinstein, M. P., Kovar, M., Purton, J. F., Cho, J.-H., Boyman, O., Surh, C. D., Sprent, J. Converting IL-15 to a superagonist by binding to soluble IL-15R-alpha. Proc. Nat. Acad. Sci. 103: 9166-9171, 2006. [PubMed: 16757567] [Full Text: https://doi.org/10.1073/pnas.0600240103]
Teague, R. M., Sather, B. D., Sacks, J. A., Huang, M. Z., Dossett, M. L., Morimoto, J., Tan, X., Sutton, S. E., Cooke, M. P., Ohlen, C., Greenberg, P. D. Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nature Med. 12: 335-341, 2006. [PubMed: 16474399] [Full Text: https://doi.org/10.1038/nm1359]