Interleukin-15 is a cytokine that plays a major role in the development of inflammatory and protective immune responses. It stimulates proliferation of natural killer cells, T-cells, and B-cells, and promotes secretion of cytokines. Unlike most cytokines, IL15 is expressed in association with its high affinity receptor IL15RA on the cell surface (trans-presentation) and signals through the IL2RB/IL2RG receptor complex, triggering JAK1/JAK3 phosphorylation and STAT3/STAT5 activation. Two isoforms exist: IL15-S48AA (secreted) and IL15-S21AA (intracellular, localized to cytoplasm and nucleus).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001819 positive regulation of cytokine production | IBA GO_REF:0000033 | ACCEPT | Summary: ACCEPT: IL15 stimulates cytokine production. UniProt states IL15 "promotes the secretion of several cytokines" and "induces the production of IL8 and monocyte chemotactic protein 1/CCL2" in monocytes. |
| GO:0050778 positive regulation of immune response | IBA GO_REF:0000033 | ACCEPT | Summary: ACCEPT: IL15 positively regulates immune responses by stimulating NK cells, T-cells, and B-cells. UniProt: "plays a major role in the development of inflammatory and protective immune responses to microbial invaders and parasites." |
| GO:0005125 cytokine activity | IBA GO_REF:0000033 | ACCEPT | Summary: ACCEPT: IL15 is definitively a cytokine. UniProt RecName is "Interleukin-15" and function description begins "Cytokine that plays a major role..." |
| GO:0005615 extracellular space | IBA GO_REF:0000033 | ACCEPT | Summary: ACCEPT: IL15 (isoform S48AA) is secreted. UniProt SUBCELLULAR LOCATION states "Isoform IL15-S48AA: Secreted." |
| GO:0042102 positive regulation of T cell proliferation | IBA GO_REF:0000033 | ACCEPT | Summary: ACCEPT: IL15 stimulates T cell proliferation. UniProt: "Stimulates the proliferation of natural killer cells, T-cells and B-cells." |
| GO:0042119 neutrophil activation | IBA GO_REF:0000033 | ACCEPT | Summary: ACCEPT: IL15 activates neutrophils. PMID:15123770 cited in UniProt shows IL15 enhances neutrophil phagocytosis. |
| GO:0005125 cytokine activity | IEA GO_REF:0000120 | ACCEPT | Summary: ACCEPT: Redundant with IBA annotation but correct. IL15 has cytokine activity. |
| GO:0005126 cytokine receptor binding | IEA GO_REF:0000002 | ACCEPT | Summary: ACCEPT: IL15 binds cytokine receptors. UniProt INTERACTION section shows IL15 binds IL15RA and IL2RB. This is core to its function. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: ACCEPT: IL15 is found in extracellular region when secreted (isoform S48AA). |
| GO:0005615 extracellular space | IEA GO_REF:0000043 | ACCEPT | Summary: ACCEPT: Redundant but correct. Secreted isoform found in extracellular space. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: ACCEPT: UniProt states "Isoform IL15-S21AA: Cytoplasm. Nucleus." The intracellular isoform localizes to the nucleus. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: ACCEPT: UniProt states "Isoform IL15-S21AA: Cytoplasm." The intracellular isoform localizes to cytoplasm. |
| GO:0006955 immune response | IEA GO_REF:0000002 | ACCEPT | Summary: ACCEPT: IL15 functions in immune response. UniProt: "plays a major role in the development of inflammatory and protective immune responses." |
| GO:0008284 positive regulation of cell population proliferation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: This is true but overly general. IL15 stimulates proliferation of specific immune cell types (NK, T, B cells), not general cell proliferation. More specific terms are preferred. |
| GO:0005515 protein binding | IPI PMID:16284400 Soluble interleukin-15 receptor alpha (IL-15R alpha)-sushi a... | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: "Protein binding" is uninformative. The specific interaction (IL15 binds IL15RA) is better captured by "cytokine receptor binding" (GO:0005126). Per curation guidelines, avoid generic "protein binding." Supporting Evidence: PMID:16284400 Nov 11. Soluble interleukin-15 receptor alpha (IL-15R alpha)-sushi as a selective and potent agonist of IL-15 action through IL-15R beta/gamma. |
| GO:0005515 protein binding | IPI PMID:23104097 Mechanistic and structural insight into the functional dicho... | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: Same as above - "protein binding" is uninformative. The IL15-receptor interaction is better captured by specific MF terms. Supporting Evidence: PMID:23104097 Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED: High-throughput interactome study. Generic protein binding is not informative for cytokine function annotation. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0120163 negative regulation of cold-induced thermogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: Transferred from mouse. PMID:27684068 shows IL15 deficiency enhances thermogenic function of adipose tissue. This is a secondary/pleiotropic effect, not a core function of IL15 as a cytokine. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: ACCEPT: HPA immunofluorescence data. Consistent with UniProt statement that isoform IL15-S21AA localizes to nucleus. |
| GO:0016607 nuclear speck | IDA GO_REF:0000052 | ACCEPT | Summary: ACCEPT: HPA immunofluorescence data showing nuclear speck localization. More specific than general nucleus annotation. |
| GO:0007259 cell surface receptor signaling pathway via JAK-STAT | NAS PMID:23104097 Mechanistic and structural insight into the functional dicho... | ACCEPT | Summary: ACCEPT: Core pathway for IL15 signaling. UniProt explicitly states IL15 "triggers the phosphorylation of JAK1 and JAK3 and the recruitment and subsequent phosphorylation of...STAT3 and STAT5." Supporting Evidence: PMID:23104097 Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. |
| GO:0035723 interleukin-15-mediated signaling pathway | NAS PMID:23104097 Mechanistic and structural insight into the functional dicho... | ACCEPT | Summary: ACCEPT: This IS the core signaling pathway for IL15. The gene product is literally the ligand that initiates this pathway. Supporting Evidence: PMID:23104097 Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. |
| GO:0043066 negative regulation of apoptotic process | NAS PMID:10627470 Expression of functional interleukin-15 receptor and autocri... | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: PMID:10627470 shows IL15 promotes multiple myeloma cell survival. Anti-apoptotic effects are downstream of cytokine signaling, not a core function. May be context-dependent. Supporting Evidence: PMID:10627470 Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma. |
| GO:0043410 positive regulation of MAPK cascade | NAS PMID:23104097 Mechanistic and structural insight into the functional dicho... | ACCEPT | Summary: ACCEPT: IL15 activates MAPK in addition to JAK-STAT. This is part of its signaling mechanism. Supporting Evidence: PMID:23104097 Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. |
| GO:0005125 cytokine activity | IDA PMID:9097905 Role of IL-15 in HIV-1-associated hypergammaglobulinaemia. | ACCEPT | Summary: ACCEPT: Direct experimental evidence for cytokine activity. PMID:9097905 demonstrates IL15 function in HIV context. Supporting Evidence: PMID:9097905 Role of IL-15 in HIV-1-associated hypergammaglobulinaemia. |
| GO:0005615 extracellular space | IDA PMID:9097905 Role of IL-15 in HIV-1-associated hypergammaglobulinaemia. | ACCEPT | Summary: ACCEPT: Direct evidence IL15 is secreted and found extracellularly. Supporting Evidence: PMID:9097905 Role of IL-15 in HIV-1-associated hypergammaglobulinaemia. |
| GO:0035723 interleukin-15-mediated signaling pathway | IDA PMID:9097905 Role of IL-15 in HIV-1-associated hypergammaglobulinaemia. | ACCEPT | Summary: ACCEPT: Direct evidence for IL15-mediated signaling. Supporting Evidence: PMID:9097905 Role of IL-15 in HIV-1-associated hypergammaglobulinaemia. |
| GO:0030225 macrophage differentiation | IDA PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage di... | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: PMID:24942581 shows CD4 ligation on monocytes triggers macrophage differentiation enhanced by IL15. This is a downstream effect of IL15 signaling, not a core function. Supporting Evidence: PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage differentiation and enhances HIV infection. |
| GO:0035723 interleukin-15-mediated signaling pathway | IDA PMID:15123770 Interleukin-15 enhances human neutrophil phagocytosis by a S... | ACCEPT | Summary: ACCEPT: Direct evidence from study on IL15 signaling in neutrophils. Supporting Evidence: PMID:15123770 Interleukin-15 enhances human neutrophil phagocytosis by a Syk-dependent mechanism: importance of the IL-15Ralpha chain. |
| GO:0050731 positive regulation of peptidyl-tyrosine phosphorylation | IDA PMID:15123770 Interleukin-15 enhances human neutrophil phagocytosis by a S... | ACCEPT | Summary: ACCEPT: IL15 positively regulates tyrosine phosphorylation through JAK-STAT pathway activation. This is mechanistically correct - IL15 binding triggers JAK kinase activation which phosphorylates STATs. Supporting Evidence: PMID:15123770 Interleukin-15 enhances human neutrophil phagocytosis by a Syk-dependent mechanism: importance of the IL-15Ralpha chain. |
| GO:0050766 positive regulation of phagocytosis | IDA PMID:15123770 Interleukin-15 enhances human neutrophil phagocytosis by a S... | ACCEPT | Summary: ACCEPT: PMID:15123770 title is "Interleukin-15 enhances human neutrophil phagocytosis." Direct experimental evidence. Supporting Evidence: PMID:15123770 Interleukin-15 enhances human neutrophil phagocytosis by a Syk-dependent mechanism: importance of the IL-15Ralpha chain. |
| GO:0042119 neutrophil activation | IDA PMID:15123770 Interleukin-15 enhances human neutrophil phagocytosis by a S... | ACCEPT | Summary: ACCEPT: PMID:15123770 demonstrates IL15 activates neutrophils (enhances phagocytosis). Consistent with IBA annotation. Supporting Evidence: PMID:15123770 Interleukin-15 enhances human neutrophil phagocytosis by a Syk-dependent mechanism: importance of the IL-15Ralpha chain. |
| GO:0120163 negative regulation of cold-induced thermogenesis | ISS PMID:27684068 Deficiency of Interleukin-15 Confers Resistance to Obesity b... | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: Redundant with IEA annotation. Pleiotropic effect via adipose tissue regulation, not core cytokine function. Supporting Evidence: PMID:27684068 eCollection 2016. Deficiency of Interleukin-15 Confers Resistance to Obesity by Diminishing Inflammation and Enhancing the Thermogenic Function of Adipose Tissues. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-449115 | ACCEPT | Summary: ACCEPT: Reactome pathway shows IL15:IL15RA complex formation. IL15 is found extracellularly. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8983298 | ACCEPT | Summary: ACCEPT: Reactome pathway step. Redundant but correct. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8983300 | ACCEPT | Summary: ACCEPT: Reactome pathway step. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8983307 | ACCEPT | Summary: ACCEPT: Reactome pathway step. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8983335 | ACCEPT | Summary: ACCEPT: Reactome pathway step showing receptor complex translocation. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8983371 | ACCEPT | Summary: ACCEPT: Reactome pathway step. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8983374 | ACCEPT | Summary: ACCEPT: Reactome pathway step. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8983378 | ACCEPT | Summary: ACCEPT: Reactome pathway step. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8983384 | ACCEPT | Summary: ACCEPT: Reactome pathway step. |
| GO:0005768 endosome | TAS Reactome:R-HSA-8983335 | ACCEPT | Summary: ACCEPT: Reactome shows IL15 receptor complex translocates to endosome during signaling. |
| GO:0035723 interleukin-15-mediated signaling pathway | IDA PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage di... | ACCEPT | Summary: ACCEPT: Direct evidence for IL15-mediated signaling pathway. Supporting Evidence: PMID:24942581 CD4 ligation on human blood monocytes triggers macrophage differentiation and enhances HIV infection. |
| GO:0007260 tyrosine phosphorylation of STAT protein | IDA PMID:12244150 IL-21 up-regulates the expression of genes associated with i... | MODIFY | Summary: OVER-ANNOTATION: IL15 is a cytokine that INDUCES STAT phosphorylation via the JAK-STAT signaling pathway, but does NOT catalyze the phosphorylation reaction itself. Cytokines are signaling ligands that trigger downstream JAK kinases to phosphorylate STAT proteins. IL15 has no kinase activity. The appropriate term is GO:0042531 "positive regulation of tyrosine phosphorylation of STAT protein". Proposed replacements: positive regulation of tyrosine phosphorylation of STAT protein Supporting Evidence: PMID:12244150 IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response. |
| GO:0032740 positive regulation of interleukin-17 production | IDA PMID:16482511 Divergent effects of IL-12 and IL-23 on the production of IL... | ACCEPT | Summary: ACCEPT: IL15 promotes IL-17 production. This is part of its cytokine production stimulation function. Supporting Evidence: PMID:16482511 Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. |
| GO:0034105 positive regulation of tissue remodeling | IC PMID:16482511 Divergent effects of IL-12 and IL-23 on the production of IL... | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: Inferred from GO:0032740 (IL-17 production). Tissue remodeling is a downstream consequence of cytokine signaling, several steps removed from IL15's direct activity. Supporting Evidence: PMID:16482511 Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. |
| GO:0050729 positive regulation of inflammatory response | IC PMID:16482511 Divergent effects of IL-12 and IL-23 on the production of IL... | ACCEPT | Summary: ACCEPT: Inferred from IL-17 production. IL15 promotes inflammation through multiple mechanisms including cytokine induction. UniProt states IL15 is involved in "inflammatory...immune responses." Supporting Evidence: PMID:16482511 Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. |
| GO:0005576 extracellular region | NAS PMID:14718574 The human plasma proteome: a nonredundant list developed by ... | ACCEPT | Summary: ACCEPT: Human plasma proteome study detected IL15 extracellularly. Supporting Evidence: PMID:14718574 Epub 2004 Jan 12. The human plasma proteome: a nonredundant list developed by combination of four separate sources. |
| GO:0005615 extracellular space | TAS PMID:10851076 Altered natural killer cell differentiation in CD34+ progeni... | ACCEPT | Summary: ACCEPT: IL15 found in extracellular space. Supporting Evidence: PMID:10851076 Altered natural killer cell differentiation in CD34+ progenitors from chronic myeloid leukemia patients. |
| GO:0005737 cytoplasm | TAS PMID:10851076 Altered natural killer cell differentiation in CD34+ progeni... | ACCEPT | Summary: ACCEPT: IL15-S21AA isoform is cytoplasmic per UniProt. Supporting Evidence: PMID:10851076 Altered natural killer cell differentiation in CD34+ progenitors from chronic myeloid leukemia patients. |
| GO:0005768 endosome | TAS PMID:10851076 Altered natural killer cell differentiation in CD34+ progeni... | ACCEPT | Summary: ACCEPT: IL15 traffics through endosomal pathway. Supporting Evidence: PMID:10851076 Altered natural killer cell differentiation in CD34+ progenitors from chronic myeloid leukemia patients. |
| GO:0005794 Golgi apparatus | TAS PMID:10851076 Altered natural killer cell differentiation in CD34+ progeni... | ACCEPT | Summary: ACCEPT: IL15 transits through Golgi during secretory pathway. Supporting Evidence: PMID:10851076 Altered natural killer cell differentiation in CD34+ progenitors from chronic myeloid leukemia patients. |
| GO:0006955 immune response | TAS PMID:8178155 Cloning of a T cell growth factor that interacts with the be... | ACCEPT | Summary: ACCEPT: Original cloning paper. IL15 functions in immune response. Supporting Evidence: PMID:8178155 Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. |
| GO:0007165 signal transduction | TAS PMID:8178155 Cloning of a T cell growth factor that interacts with the be... | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: Very general term. IL15 does participate in signal transduction but more specific pathway terms are preferred. Supporting Evidence: PMID:8178155 Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. |
| GO:0007267 cell-cell signaling | TAS PMID:7759105 Chromosomal assignment and genomic structure of Il15. | ACCEPT | Summary: ACCEPT: IL15 mediates cell-cell signaling via trans-presentation (IL15 on one cell presents to receptors on another cell). Supporting Evidence: PMID:7759105 Chromosomal assignment and genomic structure of Il15. |
| GO:0008284 positive regulation of cell population proliferation | TAS PMID:10851076 Altered natural killer cell differentiation in CD34+ progeni... | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE: True but overly general. IL15 stimulates specific immune cell proliferation. More specific terms preferred. Supporting Evidence: PMID:10851076 Altered natural killer cell differentiation in CD34+ progenitors from chronic myeloid leukemia patients. |
| GO:0009986 cell surface | NAS | NEW | Summary: NEW: IL15 is presented at the cell surface as an IL15:IL15RA complex during trans-presentation to IL2RB/IL2RG-bearing neighboring cells. Reason: Core function synthesis includes cell-surface trans-presentation, but the current GOA-derived cellular component annotations do not include cell surface. Supporting Evidence: file:human/IL15/IL15-deep-research-falcon.md IL-15 is commonly delivered by **trans-presentation**: an βIL-15-presentingβ cell displays a **membrane IL-15/IL-15RΞ± complex** that stimulates neighboring lymphocytes through **IL2RB/IL2RG**. |
| GO:0016170 interleukin-15 receptor binding | NAS | NEW | Summary: NEW: IL15 binds its private high-affinity receptor chain IL15RA and then recruits IL2RB/IL2RG for signaling. This is more informative than generic protein binding and more specific than the existing cytokine receptor binding annotation. Reason: Specific IL15 receptor binding is a core molecular function supported by biochemical, structural and trans-presentation literature but is absent from the current GOA-derived annotations. Supporting Evidence: file:human/IL15/IL15-deep-research-falcon.md Human IL-15 binds IL15RA with very high affinity and mutational mapping identified key IL-15 residues in helices B/C required for IL15RA engagement. |
| GO:0032819 positive regulation of natural killer cell proliferation | NAS | NEW | Summary: NEW: IL15 is a central positive regulator of NK-cell proliferation, activation and maintenance. This more specific term should complement the broad cell population proliferation annotations kept as non-core. Reason: Existing annotations include only broad proliferation terms and miss the key NK-cell-specific proliferative activity. Supporting Evidence: file:human/IL15/IL15-deep-research-falcon.md IL-15 is essential for NK-cell development and potently promotes NK proliferation, activation, granzyme/perforin expression, degranulation, and inflammatory cytotoxicity. |
| GO:0032816 positive regulation of natural killer cell activation | NAS | NEW | Summary: NEW: IL15 positively regulates NK-cell activation, including effector programs linked to cytotoxicity. Reason: NK activation is a specific, well-established immune-cell outcome of IL15 signaling that is not represented by the existing broad immune response annotations. Supporting Evidence: file:human/IL15/IL15-deep-research-falcon.md IL-15 is essential for NK-cell development and potently promotes NK proliferation, activation, granzyme/perforin expression, degranulation, and inflammatory cytotoxicity. |
| GO:0030890 positive regulation of B cell proliferation | NAS | NEW | Summary: NEW: IL15 costimulates activated B-cell proliferation, providing a specific B-cell term to replace overly broad cell population proliferation when B-cell evidence is intended. Reason: The review currently notes B-cell proliferation only in summaries and broad proliferation annotations; a specific B-cell BP term is warranted. Supporting Evidence: file:human/IL15/IL15-deep-research-falcon.md IL-15 costimulates activated human B-cell proliferation and, with CD40L, induces IgM, IgG1, and IgA secretion via IL2RB-dependent signaling. |
| GO:0002639 positive regulation of immunoglobulin production | NAS | NEW | Summary: NEW: In activated B cells, IL15 can promote immunoglobulin secretion in the appropriate costimulatory context. Reason: Falcon research identified direct B-cell evidence for immunoglobulin production that is absent from the current annotation set. Supporting Evidence: file:human/IL15/IL15-deep-research-falcon.md IL-15 costimulates activated human B-cell proliferation and, with CD40L, induces IgM, IgG1, and IgA secretion via IL2RB-dependent signaling. |
| GO:0090023 positive regulation of neutrophil chemotaxis | NAS | NEW | Summary: NEW: IL15 promotes neutrophil recruitment/chemotaxis in addition to the already accepted neutrophil activation and phagocytosis annotations. Reason: The current annotation set captures neutrophil activation and phagocytosis but misses the more specific neutrophil recruitment phenotype supported by the literature synthesis. Supporting Evidence: file:human/IL15/IL15-deep-research-falcon.md IL-15 directly delays neutrophil apoptosis and enhances phagocytosis, adhesion, IL-8 production, and in vivo recruitment, supporting specific neutrophil-focused process annotations rather than broad leukocyte proliferation terms. |
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