HGNC Approved Gene Symbol: IL15
Cytogenetic location: 4q31.21 Genomic coordinates (GRCh38): 4:141,636,583-141,733,987 (from NCBI)
Interleukin-15 (IL15) is a cytokine that affects T-cell activation and proliferation similarly to IL2 (147680). The latter interacts with a specific cell surface receptor (IL2R) that contains at least 3 subunits: alpha (IL2RA; 147730), beta (IL2RB, or CD122; 146710), and gamma (IL2RG; 308380). A number of other cytokines also stimulate T-cell proliferation, and some of these may use components of the IL2 receptor, including IL15.
Grabstein et al. (1994) obtained partial amino acid sequence of purified IL15 protein and, with degenerate PCR primers, obtained a partial cDNA product. A cDNA library of Rhesus monkey CV-1/EBNA cells was screened and a full-length clone obtained. IL15 is transcribed in a variety of cell types including fibroblasts, epithelial cells, and monocytes, but not primary T cells (Grabstein et al., 1994).
Anderson et al. (1995) characterized mouse Il15 cDNA and genomic clones.
Grabstein et al. (1994) showed that antibodies to the IL2R beta chain inhibited the biologic activity of IL15 and that IL15 competed for binding with IL2.
Giri et al. (1994) showed that IL2RB and IL2RG, but not IL2RA, transduce signals by IL15 in addition to IL2.
Memory T cells maintain their numbers for long periods after antigen exposure. Ku et al. (2000) demonstrated that CD8 (see CD8-alpha; 186910)-positive T cells of memory phenotype divide slowly in animals. This division requires interleukin-15 and is markedly increased by inhibition of interleukin-2. The authors therefore suggested that the numbers of CD8-positive memory T cells in animals are controlled by a balance between IL15 and IL2.
Using flow cytometric analysis, Roberts et al. (2001) demonstrated that freshly isolated CD8-alpha/-beta (186730)-positive, T-cell receptor (TCR)-alpha (see 186880)/-beta (see 186930)-positive jejunal intraepithelial T lymphocytes (IELs) did not express the CD28 (186760) costimulatory receptor but did express the CD45 (151460) memory marker and low levels of NKG2D (602893). Exposure to IL15 induced a rapid increase in expression of NKG2D and CD94 (KLRD1; 602894) but not of other natural killer cell receptors in IELs. These effects were not observed with other cytokines except for high levels of IL2. IL15-prestimulated IELs exhibited potent NKG2D-mediated cytolysis. Stimulation of TCR in the presence of IL15 enhanced cytokine secretion and proliferation by IELs. Roberts et al. (2001) concluded that NKG2D can function as a potent costimulator of TCR-mediated activation of IELs. In addition, they suggested that IL15, which is secreted by intestinal epithelial cells upon inflammation or viral infection, can induce excessive NKG2D expression if uncontrolled, leading to the development of autoimmune disease against MICA (600169)-/MICB (602436)-expressing epithelial cells.
Meresse et al. (2004) studied intestinal cytotoxic T lymphocytes (CTLs) obtained from healthy subjects and patients with celiac disease (CD; 212750). They noted that, in CD patients, intraepithelial CTLs are constitutively exposed to high levels of IL15. Meresse et al. (2004) found that, in the effector stage, CD8-positive CTLs from healthy subjects could be armed for NKG2D-mediated lysis by IL15. Intraepithelial CTLs from CD patients, unless they were on a gluten-free diet, also expressed high levels of NKG2D, as well as MIC and DAP10 (604089), and exhibited significant NK-like activity accompanied by ERK (see 176948) activation.
Cryptosporidiosis presents as a self-limited diarrhea after infection with the protozoan C. parvum in healthy hosts. In immunocompromised individuals, however, infection leads to a chronic and often fatal illness for which there is no direct treatment. In studies with experimentally infected healthy volunteers, White et al. (2000) detected gamma-interferon (IFNG; 147570) expression predominantly in previously exposed individuals with serum IgG specific for C. parvum in lamina propria lymphocytes after reinfection. IFNG expression was associated with resistance to infection and reduced oocyst excretion. Infected seronegative individuals rarely expressed mucosal IFNG. To characterize IFNG-independent mechanisms in control of infection, Robinson et al. (2001) studied immunocompetent volunteers experimentally challenged with C. parvum for expression of IL15 and IL4 (147780). In situ hybridization and immunohistochemical analysis of jejunal biopsies showed expression of IL15 in epithelial layer cells only in previously uninfected symptomatic individuals 1 week after infection. This expression was correlated with reduced oocyst shedding. Robinson et al. (2001) proposed that IL15 is a critical component of the effector response in individuals not previously sensitized, while IFNG is critical in the anamnestic response on reexposure to the organism.
Using immunofluorescent microscopy, Ferlazzo et al. (2004) demonstrated that NK cells and DEC205 (LY75; 604524)-positive dendritic cells (DCs) are localized in T- rather than B-cell areas of normal human lymph nodes. They showed that DEC205-positive DCs induce IFNG expression by lymph node NK cells through IL12 (see 161560), whereas IL15 expressed at the DC surface mediates lymph node NK cell proliferation.
Rubinstein et al. (2006) noted that IL15 is normally presented in vivo as a cell-associated cytokine bound to IL15RA (601070). They 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.
Zhao et al. (2005) found that Il15, but not Il2, could restore gamma (TCRG; see 186970)-delta (TCRD; see 186810) T-cell development in cultured fetal thymi from Il7r (146661)-deficient mice, and all these gamma-delta T cells expressed the variable gamma-5 (Vg5) TCR chain, the main type found in intestinal gamma-delta cells. Flow cytometric and RT-PCR analyses demonstrated that Il15-transgenic Il7r-deficient mice produced Vg5 gamma-delta T cells in thymus, spleen, and intestine only. Chromatin immunoprecipitation analysis showed modifications of chromatin, with Il15 stimulating Vg5 gene segment-associated histone acetylation in a Stat5 (601511)-dependent manner at a chromatin domain distinct from that regulated by Il7 (146660). Zhao et al. (2005) proposed that cytokines direct tissue-specific TCR repertoire as a possible substitute mechanism for the major histocompatibility complex selection process by selective control of local V gene chromatin accessibility.
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.
Orinska et al. (2007) used the mouse cecal ligation and puncture model of sepsis to identify an important aspect of mast cell-dependent, innate immune defenses against gram-negative bacteria by demonstrating that mast cell protease activity is regulated by IL15. Mouse mast cells express both constitutive and LPS-inducible IL15 and store it intracellularly. Deletion of Il15 in mice markedly increased chymase activities, leading to greater mast cell bactericidal responses, increased processing, and activation of neutrophil-recruiting chemokines, and significantly higher survival rates of mice after septic peritonitis. Orinska et al. (2007) concluded that their results identified an unexpected breach in mast cell-dependent innate immune defenses against sepsis, and suggested that inhibiting intracellular IL15 in mast cells may improve survival from sepsis.
Using flow cytometry and Western blot analysis, Rafei et al. (2009) demonstrated that treatment of mouse splenocytes with a synthetic 'fusokine' consisting of Gmcsf (138960) and Il15 and termed GIFT15 generated regulatory CD19-positive (107265) B cells that expressed class I and II MHC molecules and secreted Il10 (124092), but lost expression of the transcription factor Pax5 (167414), which was coupled to upregulation of CD138 (SDC1; 186355) and suppression of CD19. Treatment of mice with experimental autoimmune encephalomyelitis with Gift15 resulted in complete remission and suppression of neuroinflammation. Rafei et al. (2009) proposed that GIFT15 B regulatory cells may be useful as a treatment for autoimmune ailments, including multiple sclerosis.
Using flow cytometric analysis, Casetti et al. (2009) demonstrated that, like alpha-beta T cells, gamma-delta cells can also function as regulatory T cells (Tregs) that express FOXP3 (300292) when stimulated with phosphoantigen in the presence of TGFB1 (190180) and IL15.
In mice, DePaolo et al. (2011) found that in conjunction with IL15, a cytokine greatly upregulated in the gut of celiac disease (212750) patients, retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8, 601158) phosphorylation and release the proinflammatory cytokines IL12p70 (see 161561) and IL23 (see 605580). As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather then prevented inflammatory cellular and humoral responses to fed antigen. DePaolo et al. (2011) concluded that their data showed an unexpected role for retinoic acid and IL15 in the abrogation of tolerance to dietary antigens.
Abadie et al. (2020) described a mouse model that reproduces the overexpression of IL15 in the gut epithelium and lamina propria that is characteristic of active celiac disease, expresses the predisposing HLA-DQ8 molecule (see 146880), and develops villous atrophy after ingestion of gluten. Overexpression of IL15 in both the epithelium and the lamina propria is required for the development of villous atrophy, which demonstrates the location-dependent central role of IL15 in the pathogenesis of celiac disease. In addition, CD4+ T cells and HLA-DQ8 have a crucial role in the licensing of cytotoxic T cells to mediate intestinal epithelial cell lysis. Abadie et al. (2020) also demonstrate a role for the cytokine interferon-gamma (IFNG; 147570) and the enzyme transglutaminase-2 (TGM2; 190196) in tissue destruction.
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.
Anderson et al. (1995) found that the mouse Il15 gene has 8 exons. Intron positions in a partial human genomic clone matched those of the mouse gene structure.
Anderson et al. (1995) mapped the mouse Il15 gene to chromosome 8 by interspecific backcross analysis. Anderson et al. (1995) mapped the human gene to 4q31 by fluorescence in situ hybridization.
Dijkstra et al. (2014) identified an intact third IL2/IL15 family member, Il15l, in reptiles and some mammals, including the agricultural mammals horse, cow, sheep, and pig. In mice and human, the ORF of IL15L is incapacitated. Il15l proteins share only about 21% amino acid identity with IL15, but key residues for interaction with IL15RA are retained. Dijkstra et al. (2014) concluded that the species lineage leading to mammals began with the 3 similar cytokines IL2, IL15, and IL15L. Later in evolution, IL2 and IL2RA acquired a new and specific binding mode, and IL15L was lost in some, but not all, groups of mammals.
Using flow cytometry, Taki et al. (2005) examined NK-cell development in mice deficient in either Irf2 (147576) or Il15. They found that Il15 was essential for early expansion of NK cells in bone marrow. In contrast, Irf2 was required to prevent NK-cell apoptosis and keep immature NK cells alive, thus promoting NK-cell maturation and their supply to peripheral blood.
Saito et al. (2006) observed increased bacterial growth in lungs of Il15 -/- mice following intraperitoneal infection with the Mycobacterium bovis attenuated vaccine strain (BCG). CD8-positive but not CD4-positive T-cell production of Ifng was impaired, and the CD8-positive cells were more susceptible to apoptosis in infected Il15 -/- mice than in infected wildtype mice. Saito et al. (2006) concluded that IL15 is important in the development of long-lasting protective immunity to BCG infection.
Using flow cytometry, Dubois et al. (2006) found that Il15 -/- mice lacked Cd44-hi/Cd122-hi memory phenotype Cd8-positive T cells in both the periphery and thymus, whereas Itk (186973) -/- mice lacked Cd44-lo/Cd122-lo naive Cd8-positive T cells in the periphery and thymus. Mice lacking both Itk and Il15 had a severe reduction of all CD8-positive T cells. Dubois et al. (2006) proposed that there are 2 distinct populations of CD8-positive T cells dependent on ITK or IL15, and that the IL15-dependent CD44-hi/CD122-hi memory phenotype CD8-positive T cells have functions in both innate and adaptive immunity.
In CD4-depleted mice, Oh et al. (2008) showed that vaccines codelivered with Il15 can promote the longevity of CD8+ T cells and the avoidance of Trail (TNFSF10; 603598)-mediated apoptosis through downregulation of Bax (600040) and upregulation of Bclxl (BCL2L1; 600039) in CD8+ T cells. CD4+ T cells induced dendritic cell production of Il15, and Il15 -/- dendritic cells were unable to mediate optimal helper responses. Oh et al. (2008) proposed that IL15 codelivered with vaccines can overcome CD4+ T cell deficiency to induce CD8+ T cells with maintained cytotoxic lymphocyte function against infection and cancer.
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