Existing Annotations Review

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 “IL-15-presenting” cell displays a membrane IL-15/IL-15Rα 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.

Core Functions

IL15 binds IL15RA with high affinity and is commonly delivered as an IL15:IL15RA complex to adjacent IL2RB/IL2RG-expressing cells, initiating IL15-mediated JAK-STAT signaling.

Molecular Function:

interleukin-15 receptor binding

Directly Involved In:

interleukin-15-mediated signaling pathway cell surface receptor signaling pathway via JAK-STAT cell-cell signaling

Cellular Locations:

extracellular region cell surface

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.
Reactome:R-HSA-8983307
IL15 binds IL15RA

IL15 cytokine activity promotes proliferation, activation and maintenance of specific lymphocyte populations, especially NK cells, T cells and activated B cells, rather than indiscriminate cell population proliferation.

Molecular Function:

cytokine activity

Directly Involved In:

positive regulation of natural killer cell proliferation positive regulation of natural killer cell activation positive regulation of T cell proliferation positive regulation of B cell proliferation positive regulation of immunoglobulin production

Cellular Locations:

extracellular region

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.
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.

IL15 also acts on innate immune cells, supporting neutrophil activation, phagocytosis, cytokine/chemokine production and recruitment.

Molecular Function:

cytokine activity

Directly Involved In:

neutrophil activation positive regulation of phagocytosis positive regulation of neutrophil chemotaxis positive regulation of cytokine production

Cellular Locations:

extracellular region

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.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10627470

Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma.

IL15 promotes myeloma cell survival through autocrine signaling

PMID:10851076

Altered natural killer cell differentiation in CD34+ progenitors from chronic myeloid leukemia patients.

PMID:12244150

IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response.

Study on IL-21 showing STAT3 activation; IL15 cited for comparison

PMID:14718574

The human plasma proteome: a nonredundant list developed by combination of four separate sources.

PMID:15123770

Interleukin-15 enhances human neutrophil phagocytosis by a Syk-dependent mechanism: importance of the IL-15Ralpha chain.

IL15 enhances neutrophil phagocytosis
Mechanism involves Syk kinase and requires IL-15Ralpha

PMID:16284400

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 x IL-15R alpha fusion proteins.

PMID:16482511

Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells.

IL15 contributes to IL-17 production regulation

PMID:23104097

Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15.

Crystal structure of IL15 reveals signaling mechanism
IL15 and IL2 have distinct receptor engagement modes

PMID:24942581

CD4 ligation on human blood monocytes triggers macrophage differentiation and enhances HIV infection.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:27684068

Deficiency of Interleukin-15 Confers Resistance to Obesity by Diminishing Inflammation and Enhancing the Thermogenic Function of Adipose Tissues.

IL15 deficiency enhances thermogenesis - pleiotropic effect

PMID:7759105

Chromosomal assignment and genomic structure of Il15.

PMID:8178155

Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor.

Original identification of IL15 as T cell growth factor
IL15 signals through IL2RB (shared with IL-2)

PMID:9097905

Role of IL-15 in HIV-1-associated hypergammaglobulinaemia.

Reactome:R-HSA-449115

IL15:IL15RA binds IL2RB:JAK1 and IL2RG:JAK3

Reactome:R-HSA-8983298

IL15 binds IL2RB:JAK1 and IL2RG:JAK3

Reactome:R-HSA-8983300

IL15RA:IL15:IL2RB:JAK1:IL2RG:JAK3 phosphorylates JAK3 and JAK1

Reactome:R-HSA-8983307

IL15 binds IL15RA

Reactome:R-HSA-8983335

IL15:IL15RA:IL2RB:JAK1:IL2RG:JAK3 translocates from the plasma membrane to the endosome

Reactome:R-HSA-8983371

IL15:IL15RA:p-Y-IL2RB:p-Y-JAK1:p-Y-IL2RG:p-Y-JAK3 phosphorylates STAT3 and STAT5

Reactome:R-HSA-8983374

p-Y-STAT3 and p-STAT5 dissociates from IL15:IL15RA:IL2RB:p-JAK1:IL2RG:p-JAK3:p-Y-STAT3:p-STAT5

Reactome:R-HSA-8983378

IL15:IL15RA:p-Y-IL2RB:p-Y-JAK1:p-Y-IL2RG:p-Y-JAK3 binds STAT3 and STAT5

Reactome:R-HSA-8983384

IL15:IL15RA:p-Y-IL2RB:p-Y-JAK1:p-Y-IL2RG:p-Y-JAK3:p-Y-SHC1:GRB2 binds SOS1,SOS2

file:human/IL15/IL15-deep-research-falcon.md

Falcon deep research on IL15 GO-relevant functions

IL15 functions primarily as an IL15RA-bound cytokine delivered by trans-presentation or as soluble IL15/IL15RA heterodimer, rather than only as free soluble cytokine.

"A central concept for GO curation is that IL-15 is not best modeled as a freely diffusing cytokine under physiologic conditions. Instead, IL-15 is commonly delivered by **trans-presentation**: an “IL-15-presenting” cell displays a **membrane IL-15/IL-15Rα complex** that stimulates neighboring lymphocytes through **IL2RB/IL2RG**."
Specific receptor-binding terms and cell-type-specific immune process terms are preferable to generic protein binding or broad proliferation annotations.

"Prefer specific terms supported by direct assays (cytokine activity, IL15RA binding, trans-presentation, NK/CD8/B/neutrophil processes, JAK/STAT signaling, isoform-localization) and avoid generic “protein binding,” broad “cell population proliferation,” or over-broad immune/developmental annotations unless directly tested in the relevant lineage/context."
IL15 receptor signaling activates JAK1/JAK3 and STAT3/STAT5 downstream of IL2RB/IL2RG.

"IL-15 receptor signaling activates JAK1/JAK3 and predominantly STAT5, with STAT3 also activated in some T-cell/IEL contexts downstream of IL2RB/IL2RG."
IL15 isoforms support both secretory/extracellular localization and intracellular cytoplasm/nucleus localization depending on the signal peptide.

"The 21-aa short signal peptide isoform is largely nonsecreted and localizes to cytoplasmic and nuclear compartments, supporting isoform-specific intracellular annotations."

Deep Research

Falcon

(IL15-deep-research-falcon.md)

Question: You are an expert researcher providing comprehensive, well-cited information. Falcon Edison Scientific Literature 45 citations 2026-05-12T14:59:10.727578

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Concise GO annotation research for human IL15 / UniProt P40933. Focus only on GO-relevant evidence: IL15 cytokine activity; high-affinity binding to IL15RA and signaling through IL2RB/IL2RG; IL15 trans-presentation by IL15RA versus soluble/secreted cytokine activity; NK cell, CD8 T cell, T cell, B cell and neutrophil proliferation/activation/survival; positive regulation of cytokine production and immune response; JAK1/JAK3, STAT3/STAT5 signaling; isoform-specific localization of secreted IL15-S48AA versus intracellular IL15-S21AA cytoplasm/nucleus; caveats for generic protein binding, broad cell population proliferation, and over-broad immune/developmental process annotations. Include PMID/DOI citations and keep under 1500 words.

Concise GO annotation research report: Human IL15 (UniProt P40933)

Scope and approach

This report summarizes GO-relevant mechanistic evidence for human IL-15 (IL15; UniProt P40933) focusing on (i) cytokine activity, (ii) high-affinity IL15RA binding and signaling via IL2RB/IL2RG, (iii) IL-15 trans-presentation versus soluble IL-15/IL-15Rα activity, (iv) downstream JAK1/JAK3 → STAT3/STAT5 signaling, (v) leukocyte functional outcomes (NK, CD8 T, T, B, neutrophils), and (vi) isoform-specific localization determined by alternative signal peptides (48-aa vs 21-aa). Evidence is prioritized for 2023–2024 where possible; however, key GO assertions rely on foundational mechanistic studies.

1) Key concepts and definitions (current understanding)

IL-15 as a cytokine and receptor system

IL-15 is a common γ-chain (γc) cytokine that signals through a heterotrimeric receptor system: a private IL-15Rα (IL15RA/CD215) chain and shared signaling chains IL-2Rβ (IL2RB/CD122) and γc (IL2RG/CD132). (skariah2024signallingmechanismsdriving pages 2-3)

A central concept for GO curation is that IL-15 is not best modeled as a freely diffusing cytokine under physiologic conditions. Instead, IL-15 is commonly delivered by trans-presentation: an “IL-15-presenting” cell displays a membrane IL-15/IL-15Rα complex that stimulates neighboring lymphocytes through IL2RB/IL2RG. (skariah2024signallingmechanismsdriving pages 2-3, skariah2024signallingmechanismsdriving pages 3-3)

Trans-presentation vs soluble cytokine activity

Recent synthesis emphasizes that soluble IL-15 is rarely detected as ‘free’ IL-15 in serum; rather, it is found complexed with soluble IL-15Rα (heterodimeric IL-15/IL-15Rα), which can also stimulate IL2RB/IL2RG on lymphocytes. (skariah2024signallingmechanismsdriving pages 2-3, skariah2024signallingmechanismsdriving pages 10-11)

2) Recent developments and latest research (prioritize 2023–2024)

A 2024 mechanistic review integrates current understanding that IL-15 is controlled at multiple levels (mRNA translation, trafficking, receptor chaperoning), and that IL-15Rα serves as both a high-affinity binding partner and a chaperone that stabilizes IL-15 and supports surface display and trans-presentation. (Skariah et al., 2024-01, Discovery Immunology, DOI: 10.1093/discim/kyae002, URL: https://doi.org/10.1093/discim/kyae002) (skariah2024signallingmechanismsdriving pages 4-5, skariah2024signallingmechanismsdriving pages 2-3)

This review also highlights downstream signaling branches relevant to GO BP terms (JAK/STAT; PI3K/AKT/mTOR; MAPK) and connects IL-15 to tissue lymphocyte homeostasis and inflammation. (skariah2024signallingmechanismsdriving pages 7-8, skariah2024signallingmechanismsdriving pages 8-8)

3) Molecular function evidence (GO: Molecular Function)

High-affinity binding to IL15RA and recruitment of IL2RB/IL2RG

A definitive biochemical mapping study identified IL-15 residues required for IL-15Rα binding and implicated additional residues in IL-2Rβ recruitment (thus supporting specific receptor-binding MF annotations rather than generic “protein binding”). (Bernard et al., 2004-06, J Biol Chem, DOI: 10.1074/jbc.M312458200, URL: https://doi.org/10.1074/jbc.M312458200) (bernard2004identificationofan pages 1-2, bernard2004identificationofan pages 8-9)

Quantitatively, this study reports tight IL-15:IL-15Rα binding (Kd ≈ 0.05 nM) and provides mutational effects on affinity and bioactivity (e.g., V49D ~13-fold affinity drop with near WT bioactivity; certain mutations preserve IL-15Rα binding but abrogate activity, consistent with disrupted signaling-chain recruitment). (bernard2004identificationofan pages 1-2, bernard2004identificationofan pages 8-9)

Independent receptor framework evidence (including transfection responsiveness requiring IL-2Rβ and γc) is summarized in a highly cited receptor review. (Waldmann et al., 1998-01, Int Rev Immunol, DOI: 10.3109/08830189809042995, URL: https://doi.org/10.3109/08830189809042995) (waldmann1998interleukin2interleukin15and pages 8-11)

4) Signaling evidence (GO: Biological Process—cytokine-mediated signaling; JAK-STAT)

JAK1/JAK3 and STAT3/STAT5 activation

Quantitative phosphoproteomics in T-cell lines showed IL-15 induces tyrosine-phosphorylation/activation of JAK1 and JAK3 and downstream STAT5 phosphorylation. JAK1 and JAK3 were highly enriched in phosphotyrosine immunocomplexes (reported ratios ~13 and 20, respectively), and JAK3 phosphopeptides including Y980/Y981 were strongly enriched (up to ratio 75). STAT5 phosphorylation (e.g., STAT5 Y694/Y699 depending on isoform/assay) was validated. (Osinalde et al., 2015-01, PROTEOMICS, DOI: 10.1002/pmic.201400194, URL: https://doi.org/10.1002/pmic.201400194) (osinalde2015simultaneousdissectionand pages 6-7, osinalde2015simultaneousdissectionand pages 7-8)

In immune contexts, IL-15-driven expansion and effector programs are frequently described as JAK/STAT-dependent, and JAK1→STAT3 and JAK3/STAT5 dependencies are emphasized in disease-relevant models (e.g., IL-15-induced STAT3 phosphorylation increased with activating JAK1 mutations and abolished by JAK1 inhibition; JAK3/STAT5 inhibition abolishes NK proliferation). (skariah2024signallingmechanismsdriving pages 7-8)

5) Presentation mode and IL-15Rα chaperoning (GO-relevant for trans-presentation and soluble complex activity)

IL-15Rα as chaperone and soluble heterodimer

In vivo evidence demonstrates that IL-15Rα can chaperone IL-15 to yield secreted bioactive IL-15/IL-15Rα heterodimers, particularly enabling secretion/activity of the SSP isoform when co-expressed with IL-15Rα. (Bergamaschi et al., 2009-09, J Immunol, DOI: 10.4049/jimmunol.0900693, URL: https://doi.org/10.4049/jimmunol.0900693) (bergamaschi2009secretionandbiological pages 1-2, bergamaschi2009secretionandbiological pages 8-9)

A conceptual and mechanistic review additionally supports that soluble IL-15Rα can extend IL-15 half-life and modulate activity, and provides approximate sizes for soluble receptor species (human ~42 kDa). (Bulfone-Paus et al., 2006-04, BioEssays, DOI: 10.1002/bies.20380, URL: https://doi.org/10.1002/bies.20380) (bulfone‐paus2006theinterleukin‐15interleukin‐15receptor pages 6-8)

6) Isoform-specific localization (GO: Cellular Component)

Two human IL-15 precursor isoforms are generated by alternate signal peptides, with identical mature cytokine sequences.

48-aa long signal peptide (LSP) isoform: ER localization and secretion competence. In COS cells, LSP-GFP showed ER staining in the majority of fluorescent cells (~85%) and LSP-IL-15 was described as largely secreted (though translation/trafficking can be limiting). (Tagaya et al., 1997-12, PNAS, DOI: 10.1073/pnas.94.26.14444, URL: https://doi.org/10.1073/pnas.94.26.14444) (tagaya1997generationofsecretable pages 4-5)
21-aa short signal peptide (SSP) isoform: not secreted in COS-cell experiments and instead localizes to cytoplasm and nucleus, supporting isoform-specific intracellular/nuclear CC annotations. (Tagaya et al., 1997) (tagaya1997generationofsecretable pages 1-2)

Follow-up trafficking work showed LSP-IL-15 has multiple fates (ER entry with glycosylation and secretion vs cytosolic unglycosylated proteasome-targeted species), while SSP-IL-15 does not enter ER and can enter the nucleus. (Kurys et al., 2000-09, J Biol Chem, DOI: 10.1074/jbc.M002373200, URL: https://doi.org/10.1074/jbc.M002373200) (kurys2000thelongsignal pages 4-5, kurys2000thelongsignal pages 1-1)

7) Functional outcomes relevant to GO Biological Process annotations

NK cells and CD8 T cells (proliferation/activation/survival)

IL-15 supports homeostatic and inflammatory programs in tissue lymphocytes, promoting proliferation and effector differentiation (e.g., NK metabolic activation via mTORC1 to support cytotoxic effector functions). (skariah2024signallingmechanismsdriving pages 8-8, skariah2024signallingmechanismsdriving pages 7-8)

The 2024 synthesis emphasizes IL-15-dependent maintenance of specific lymphocyte populations and effector molecules, supporting BP annotations such as positive regulation of NK cell proliferation/activation and positive regulation of CD8 T cell homeostasis/trafficking. (skariah2024signallingmechanismsdriving pages 8-8, skariah2024signallingmechanismsdriving pages 10-11)

B cells (proliferation, differentiation, immunoglobulin production)

Primary data show IL-15 costimulates activated human B cell proliferation (but not resting B cells) and, in combination with CD40L, induces polyclonal Ig secretion (IgM, IgG1, IgA). Blocking studies demonstrate IL-15 signaling in B cells requires IL-2Rβ (IL2RB) but not IL-2Rα, supporting a receptor-signaling GO link that is specific and experimentally tested. (Armitage et al., 1995-01, J Immunol, DOI: 10.4049/jimmunol.154.2.483, URL: https://doi.org/10.4049/jimmunol.154.2.483) (armitage1995il15hasstimulatory pages 1-2, armitage1995il15hasstimulatory pages 4-5)

FDC-derived IL-15 presented in membrane-bound form enhances germinal center B cell proliferation, consistent with a trans-presentation-like delivery mode in B cell zones. (Park et al., 2004-12, J Immunol, DOI: 10.4049/jimmunol.173.11.6676, URL: https://doi.org/10.4049/jimmunol.173.11.6676) (park2004folliculardendriticcells pages 1-2)

Neutrophils (activation, phagocytosis, adhesion, chemotaxis, survival)

A focused neutrophil review summarizes direct IL-15 effects including cytoskeletal rearrangements, enhanced phagocytosis, IL-8 production (via NF-κB/AP-1 activation), and delayed apoptosis, supporting specific neutrophil-focused BP terms. (Cassatella & McDonald, 2000-05, Curr Opin Hematol, DOI: 10.1097/00062752-200005000-00008, URL: https://doi.org/10.1097/00062752-200005000-00008) (cassatella2000interleukin15andits pages 1-2, cassatella2000interleukin15andits pages 3-4)

IL-15 increases neutrophil adhesion onto respiratory epithelial cells and attracts neutrophils in vivo, and is associated with increased CXCL2/MIP-2 and IL-6 production, supporting neutrophil chemotaxis/recruitment and adhesion processes. (Pelletier & Girard, 2005-08, Clin Exp Immunol, DOI: 10.1111/j.1365-2249.2005.02861.x, URL: https://doi.org/10.1111/j.1365-2249.2005.02861.x) (pelletier2005interleukin‐15increasesneutrophil pages 9-11)

8) Curation caveats (avoid over-broad GO annotations)

Avoid generic “protein binding” when IL15RA binding is experimentally supported with affinity/mutational mapping (use specific receptor-binding terms). (bernard2004identificationofan pages 1-2)
Avoid over-broad “cell population proliferation” unless the cell type is explicitly assayed; IL-15 effects are lineage- and context-dependent (e.g., strong evidence in NK/CD8 T, activated B cells, neutrophils), and often depend on trans-presentation. (skariah2024signallingmechanismsdriving pages 2-3, armitage1995il15hasstimulatory pages 1-2)
Avoid overly broad immune/developmental process terms not directly supported in the experimental system (e.g., do not infer organism-wide developmental roles from in vitro proliferation or from tumor cell contexts). (bulfone‐paus2006theinterleukin‐15interleukin‐15receptor pages 6-8)
For cellular component, consider isoform-specific annotations: SSP (21 aa) cytoplasm/nucleus vs LSP (48 aa) ER/Golgi/secreted—do not collapse into a single “secreted cytokine” localization if annotating isoforms. (tagaya1997generationofsecretable pages 1-2, kurys2000thelongsignal pages 4-5)

Evidence-to-GO mapping table

GO aspect	Suggested GO term name	Evidence summary (1 sentence)	Key experimental system	Key citation details
MF	cytokine activity	IL-15 is a γc-family cytokine that exerts pleiotropic immune-enhancing activity on lymphocytes and other leukocytes, supporting a specific cytokine-function annotation rather than generic binding alone.	Human cells; review integrating primary studies	Skariah et al. 2024, Discovery Immunology, doi:10.1093/discim/kyae002; Fehniger & Caligiuri 2001, Blood, doi:10.1182/blood.v97.1.14 (skariah2024signallingmechanismsdriving pages 2-3, skariah2024signallingmechanismsdriving pages 4-5)
MF	interleukin-15 receptor alpha chain binding	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.	In vitro biochem; peptide scanning; mutagenesis	Bernard et al. 2004, J Biol Chem, doi:10.1074/jbc.M312458200; IL-15:IL15RA Kd ≈ 0.05 nM; alternative affinity notation Ka ~10^11 M^-1 in reviews (bernard2004identificationofan pages 1-2, djaafar2008effectsofil15 pages 21-25)
MF	cytokine receptor binding involved in IL2RB/IL2RG signaling	After IL15RA engagement, IL-15 recruits the signaling receptor chains IL2RB/IL2RG, with peptide-2 residues contributing to IL-2Rβ/γ recruitment and signaling-competent complex assembly.	In vitro biochem; receptor mapping; transfection	Bernard et al. 2004, J Biol Chem, doi:10.1074/jbc.M312458200; Waldmann et al. 1998, Int Rev Immunol, doi:10.3109/08830189809042995 (bernard2004identificationofan pages 1-2, waldmann1998interleukin2interleukin15and pages 8-11)
BP	cytokine-mediated signaling pathway via trans-presentation	Physiologic IL-15 delivery is dominated by IL15RA-dependent trans-presentation, where membrane IL-15/IL15RA on one cell stimulates IL2RB/IL2RG on adjacent lymphocytes.	Human/mouse immune cells; review with primary support	Skariah et al. 2024, Discovery Immunology, doi:10.1093/discim/kyae002; Cloutier et al. 2024, Front Immunol, doi:10.3389/fimmu.2024.1404891 (skariah2024signallingmechanismsdriving pages 2-3, skariah2024signallingmechanismsdriving pages 3-3)
MF/BP	soluble IL-15/IL-15Rα complex activity	Circulating soluble IL-15 is typically found as IL-15/IL15RA heterodimer, and soluble IL15RA can chaperone/stabilize IL-15 and enhance or modulate activity through IL2RB/IL2RG-bearing cells.	Human/mouse serum; in vivo plasmid expression; review	Bergamaschi et al. 2009, J Immunol, doi:10.4049/jimmunol.0900693; Bulfone-Paus et al. 2006, BioEssays, doi:10.1002/bies.20380; soluble IL15RA species ~30 kDa mouse/~42 kDa human (bergamaschi2009secretionandbiological pages 1-2, bulfone‐paus2006theinterleukin‐15interleukin‐15receptor pages 6-8)
BP	JAK-STAT cascade downstream of IL-15 receptor	IL-15 receptor signaling activates JAK1/JAK3 and predominantly STAT5, with STAT3 also activated in some T-cell/IEL contexts downstream of IL2RB/IL2RG.	Human T cells; T-cell lines; phosphoproteomics; NK review	Osinalde et al. 2015, PROTEOMICS, doi:10.1002/pmic.201400194; JAK1/JAK3 phospho-enrichment ratios ~13/~20 and JAK3 Y980/Y981 ratios up to 75; Marzec et al. 2008, Cancer Res, doi:10.1158/0008-5472.CAN-07-2403; Nielsen et al. 1998, Cytokine, doi:10.1006/cyto.1998.0356 (osinalde2015simultaneousdissectionand pages 6-7, marzec2008differentialeffectsof pages 4-5)
BP	positive regulation of natural killer cell proliferation / activation / cytotoxicity	IL-15 is essential for NK-cell development and potently promotes NK proliferation, activation, granzyme/perforin expression, degranulation, and inflammatory cytotoxicity.	Mouse genetics; human/mouse NK cells; recent review	Skariah et al. 2024, Discovery Immunology, doi:10.1093/discim/kyae002; Wang & Zhao 2021, Front Immunol, doi:10.3389/fimmu.2021.610789; JAK3/STAT5 inhibition abolishes NK proliferation (skariah2024signallingmechanismsdriving pages 7-8, wang2021transcriptionfactorsassociated pages 7-8)
BP	positive regulation of CD8-positive alpha-beta T cell homeostasis / survival / trafficking	IL-15 supports memory and tissue CD8 T-cell homeostasis, survival, and tissue trafficking/residency, including induction of CD69 and maintenance of intestinal/tissue-resident CD8 populations.	Mouse genetics; tissue lymphocyte studies; review	Skariah et al. 2024, Discovery Immunology, doi:10.1093/discim/kyae002; Berard et al. 2003, J Immunol, doi:10.4049/jimmunol.170.10.5018 (skariah2024signallingmechanismsdriving pages 8-8, skariah2024signallingmechanismsdriving pages 10-11)
BP	positive regulation of T cell proliferation / activation	IL-15 drives proliferation and activation-marker expression in T cells and can sustain TH1/CD8 programs without the IL-2-associated death phenotype.	Human T cells; cell lines; primary studies/reviews	Djaafar 2008 review summarizing primary data; Campbell et al. 2001, J Immunol, doi:10.4049/jimmunol.167.1.553; Lowe et al. 2014, Genes Immun, doi:10.1038/gene.2014.3 (djaafar2008effectsofil15 pages 25-29, skariah2024signallingmechanismsdriving pages 4-5)
BP	positive regulation of B cell proliferation / differentiation / immunoglobulin production	IL-15 costimulates activated human B-cell proliferation and, with CD40L, induces IgM, IgG1, and IgA secretion via IL2RB-dependent signaling.	Purified human B cells; in vitro culture	Armitage et al. 1995, J Immunol, doi:10.4049/jimmunol.154.2.483; anti-IL-2Rβ blocks IL-15-driven B-cell proliferation; Park et al. 2004, J Immunol, doi:10.4049/jimmunol.173.11.6676 (armitage1995il15hasstimulatory pages 4-5, park2004folliculardendriticcells pages 1-2)
BP	positive regulation of neutrophil survival / phagocytosis / adhesion / chemotaxis	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.	Human neutrophils; in vivo recruitment models	Bouchard et al. 2004, J Leukoc Biol, doi:10.1189/jlb.1103585; Ratthé & Girard 2004, J Leukoc Biol, doi:10.1189/jlb.0605298; Pelletier & Girard 2005, Clin Exp Immunol, doi:10.1111/j.1365-2249.2005.02861.x (cassatella2000interleukin15andits pages 3-4, pelletier2005interleukin‐15increasesneutrophil pages 9-11)
CC	extracellular region / secretory pathway localization (48-aa isoform)	The 48-aa long signal peptide isoform enters ER/Golgi trafficking and is the major secretable form, although some molecules are inefficiently translocated and degraded.	COS cells; GFP chimeras; biochemical trafficking assays	Tagaya et al. 1997, PNAS, doi:10.1073/pnas.94.26.14444; ~85% of LSP-GFP fluorescent cells showed ER staining; Kurys et al. 2000, J Biol Chem, doi:10.1074/jbc.M002373200 (tagaya1997generationofsecretable pages 4-5, kurys2000thelongsignal pages 4-5)
CC	cytoplasm / nucleus localization (21-aa isoform)	The 21-aa short signal peptide isoform is largely nonsecreted and localizes to cytoplasmic and nuclear compartments, supporting isoform-specific intracellular annotations.	COS cells; confocal microscopy; fusion constructs	Tagaya et al. 1997, PNAS, doi:10.1073/pnas.94.26.14444; Kurys et al. 2000, J Biol Chem, doi:10.1074/jbc.M002373200; Bergamaschi et al. 2009, J Immunol, doi:10.4049/jimmunol.0900693 (tagaya1997generationofsecretable pages 1-2, kurys2000thelongsignal pages 1-1)
Curation note	caveats for GO curation	Prefer specific terms supported by direct assays (cytokine activity, IL15RA binding, trans-presentation, NK/CD8/B/neutrophil processes, JAK/STAT signaling, isoform-localization) and avoid generic “protein binding,” broad “cell population proliferation,” or over-broad immune/developmental annotations unless directly tested in the relevant lineage/context.	GO curation synthesis from evidence above	Specific receptor/functional evidence comes from Bernard 2004, Tagaya 1997, Kurys 2000, Armitage 1995, Skariah 2024, and neutrophil/NK studies above; broad claims should not be inferred beyond assayed cell types or delivery modes (bernard2004identificationofan pages 1-2, tagaya1997generationofsecretable pages 4-5)

Table: This table summarizes GO-relevant evidence for human IL15 (UniProt P40933), linking molecular function, biological process, and cellular component annotations to primary mechanistic studies and a recent 2024 review. It is designed to support concise, evidence-based curation and highlight important annotation caveats.

References

(skariah2024signallingmechanismsdriving pages 2-3): Neema Skariah, Olivia J James, and Mahima Swamy. Signalling mechanisms driving homeostatic and inflammatory effects of interleukin-15 on tissue lymphocytes. Discovery Immunology, Jan 2024. URL: https://doi.org/10.1093/discim/kyae002, doi:10.1093/discim/kyae002. This article has 29 citations.
(skariah2024signallingmechanismsdriving pages 3-3): Neema Skariah, Olivia J James, and Mahima Swamy. Signalling mechanisms driving homeostatic and inflammatory effects of interleukin-15 on tissue lymphocytes. Discovery Immunology, Jan 2024. URL: https://doi.org/10.1093/discim/kyae002, doi:10.1093/discim/kyae002. This article has 29 citations.
(skariah2024signallingmechanismsdriving pages 10-11): Neema Skariah, Olivia J James, and Mahima Swamy. Signalling mechanisms driving homeostatic and inflammatory effects of interleukin-15 on tissue lymphocytes. Discovery Immunology, Jan 2024. URL: https://doi.org/10.1093/discim/kyae002, doi:10.1093/discim/kyae002. This article has 29 citations.
(skariah2024signallingmechanismsdriving pages 4-5): Neema Skariah, Olivia J James, and Mahima Swamy. Signalling mechanisms driving homeostatic and inflammatory effects of interleukin-15 on tissue lymphocytes. Discovery Immunology, Jan 2024. URL: https://doi.org/10.1093/discim/kyae002, doi:10.1093/discim/kyae002. This article has 29 citations.
(skariah2024signallingmechanismsdriving pages 7-8): Neema Skariah, Olivia J James, and Mahima Swamy. Signalling mechanisms driving homeostatic and inflammatory effects of interleukin-15 on tissue lymphocytes. Discovery Immunology, Jan 2024. URL: https://doi.org/10.1093/discim/kyae002, doi:10.1093/discim/kyae002. This article has 29 citations.
(skariah2024signallingmechanismsdriving pages 8-8): Neema Skariah, Olivia J James, and Mahima Swamy. Signalling mechanisms driving homeostatic and inflammatory effects of interleukin-15 on tissue lymphocytes. Discovery Immunology, Jan 2024. URL: https://doi.org/10.1093/discim/kyae002, doi:10.1093/discim/kyae002. This article has 29 citations.
(bernard2004identificationofan pages 1-2): Jérôme Bernard, Catherine Harb, Erwan Mortier, Agnès Quéméner, Rob H. Meloen, Claudine Vermot-Desroches, John Wijdeness, Peter van Dijken, Joachim Grötzinger, Jerry W. Slootstra, Ariane Plet, and Yannick Jacques. Identification of an interleukin-15α receptor-binding site on human interleukin-15*. Journal of Biological Chemistry, 279:24313-24322, Jun 2004. URL: https://doi.org/10.1074/jbc.m312458200, doi:10.1074/jbc.m312458200. This article has 104 citations and is from a domain leading peer-reviewed journal.
(bernard2004identificationofan pages 8-9): Jérôme Bernard, Catherine Harb, Erwan Mortier, Agnès Quéméner, Rob H. Meloen, Claudine Vermot-Desroches, John Wijdeness, Peter van Dijken, Joachim Grötzinger, Jerry W. Slootstra, Ariane Plet, and Yannick Jacques. Identification of an interleukin-15α receptor-binding site on human interleukin-15*. Journal of Biological Chemistry, 279:24313-24322, Jun 2004. URL: https://doi.org/10.1074/jbc.m312458200, doi:10.1074/jbc.m312458200. This article has 104 citations and is from a domain leading peer-reviewed journal.
(waldmann1998interleukin2interleukin15and pages 8-11): Thomas Waldmann, Yutaka Tagaya, and Richard Bamford. Interleukin-2, interleukin-15, and their receptors. International reviews of immunology, 16 3-4:205-26, Jan 1998. URL: https://doi.org/10.3109/08830189809042995, doi:10.3109/08830189809042995. This article has 254 citations and is from a peer-reviewed journal.
(osinalde2015simultaneousdissectionand pages 6-7): Nerea Osinalde, Virginia Sanchez‐Quiles, Vyacheslav Akimov, Barbara Guerra, Blagoy Blagoev, and Irina Kratchmarova. Simultaneous dissection and comparison of il‐2 and il‐15 signaling pathways by global quantitative phosphoproteomics. PROTEOMICS, 15:520-531, Jan 2015. URL: https://doi.org/10.1002/pmic.201400194, doi:10.1002/pmic.201400194. This article has 34 citations and is from a peer-reviewed journal.
(osinalde2015simultaneousdissectionand pages 7-8): Nerea Osinalde, Virginia Sanchez‐Quiles, Vyacheslav Akimov, Barbara Guerra, Blagoy Blagoev, and Irina Kratchmarova. Simultaneous dissection and comparison of il‐2 and il‐15 signaling pathways by global quantitative phosphoproteomics. PROTEOMICS, 15:520-531, Jan 2015. URL: https://doi.org/10.1002/pmic.201400194, doi:10.1002/pmic.201400194. This article has 34 citations and is from a peer-reviewed journal.
(bergamaschi2009secretionandbiological pages 1-2): Cristina Bergamaschi, Rashmi Jalah, Viraj Kulkarni, Margherita Rosati, Gen-Mu Zhang, Candido Alicea, Andrei S. Zolotukhin, Barbara K. Felber, and George N. Pavlakis. Secretion and biological activity of short signal peptide il-15 is chaperoned by il-15 receptor alpha in vivo1. The Journal of Immunology, 183:3064-3072, Sep 2009. URL: https://doi.org/10.4049/jimmunol.0900693, doi:10.4049/jimmunol.0900693. This article has 81 citations.
(bergamaschi2009secretionandbiological pages 8-9): Cristina Bergamaschi, Rashmi Jalah, Viraj Kulkarni, Margherita Rosati, Gen-Mu Zhang, Candido Alicea, Andrei S. Zolotukhin, Barbara K. Felber, and George N. Pavlakis. Secretion and biological activity of short signal peptide il-15 is chaperoned by il-15 receptor alpha in vivo1. The Journal of Immunology, 183:3064-3072, Sep 2009. URL: https://doi.org/10.4049/jimmunol.0900693, doi:10.4049/jimmunol.0900693. This article has 81 citations.
(bulfone‐paus2006theinterleukin‐15interleukin‐15receptor pages 6-8): Silvia Bulfone‐Paus, Elena Bulanova, Vadim Budagian, and Ralf Paus. The interleukin‐15/interleukin‐15 receptor system as a model for juxtacrine and reverse signaling. BioEssays, 28:362-377, Apr 2006. URL: https://doi.org/10.1002/bies.20380, doi:10.1002/bies.20380. This article has 91 citations and is from a peer-reviewed journal.
(tagaya1997generationofsecretable pages 4-5): Yutaka Tagaya, Gloria Kurys, Tiffany A. Thies, Jacqueline M. Losi, Nazli Azimi, John A. Hanover, Richard N. Bamford, and Thomas A. Waldmann. Generation of secretable and nonsecretable interleukin 15 isoforms through alternate usage of signal peptides. Proceedings of the National Academy of Sciences of the United States of America, 94 26:14444-9, Dec 1997. URL: https://doi.org/10.1073/pnas.94.26.14444, doi:10.1073/pnas.94.26.14444. This article has 277 citations and is from a highest quality peer-reviewed journal.
(tagaya1997generationofsecretable pages 1-2): Yutaka Tagaya, Gloria Kurys, Tiffany A. Thies, Jacqueline M. Losi, Nazli Azimi, John A. Hanover, Richard N. Bamford, and Thomas A. Waldmann. Generation of secretable and nonsecretable interleukin 15 isoforms through alternate usage of signal peptides. Proceedings of the National Academy of Sciences of the United States of America, 94 26:14444-9, Dec 1997. URL: https://doi.org/10.1073/pnas.94.26.14444, doi:10.1073/pnas.94.26.14444. This article has 277 citations and is from a highest quality peer-reviewed journal.
(kurys2000thelongsignal pages 4-5): Gloria Kurys, Yutaka Tagaya, Richard Bamford, John A. Hanover, and Thomas A. Waldmann. The long signal peptide isoform and its alternative processing direct the intracellular trafficking of interleukin-15*. The Journal of Biological Chemistry, 275:30653-30659, Sep 2000. URL: https://doi.org/10.1074/jbc.m002373200, doi:10.1074/jbc.m002373200. This article has 143 citations.
(kurys2000thelongsignal pages 1-1): Gloria Kurys, Yutaka Tagaya, Richard Bamford, John A. Hanover, and Thomas A. Waldmann. The long signal peptide isoform and its alternative processing direct the intracellular trafficking of interleukin-15*. The Journal of Biological Chemistry, 275:30653-30659, Sep 2000. URL: https://doi.org/10.1074/jbc.m002373200, doi:10.1074/jbc.m002373200. This article has 143 citations.
(armitage1995il15hasstimulatory pages 1-2): R J Armitage, B M Macduff, J Eisenman, R Paxton, and K H Grabstein. Il-15 has stimulatory activity for the induction of b cell proliferation and differentiation. Journal of immunology, 154 2:483-90, Jan 1995. URL: https://doi.org/10.4049/jimmunol.154.2.483, doi:10.4049/jimmunol.154.2.483. This article has 598 citations and is from a domain leading peer-reviewed journal.
(armitage1995il15hasstimulatory pages 4-5): R J Armitage, B M Macduff, J Eisenman, R Paxton, and K H Grabstein. Il-15 has stimulatory activity for the induction of b cell proliferation and differentiation. Journal of immunology, 154 2:483-90, Jan 1995. URL: https://doi.org/10.4049/jimmunol.154.2.483, doi:10.4049/jimmunol.154.2.483. This article has 598 citations and is from a domain leading peer-reviewed journal.
(park2004folliculardendriticcells pages 1-2): Chan-Sik Park, Sun-Ok Yoon, Richard J. Armitage, and Yong Sung Choi. Follicular dendritic cells produce il-15 that enhances germinal center b cell proliferation in membrane-bound form1. The Journal of Immunology, 173:6676-6683, Dec 2004. URL: https://doi.org/10.4049/jimmunol.173.11.6676, doi:10.4049/jimmunol.173.11.6676. This article has 162 citations.
(cassatella2000interleukin15andits pages 1-2): Marco A. Cassatella and Patrick P. McDonald. Interleukin-15 and its impact on neutrophil function. Current Opinion in Hematology, 7:174-177, May 2000. URL: https://doi.org/10.1097/00062752-200005000-00008, doi:10.1097/00062752-200005000-00008. This article has 72 citations and is from a peer-reviewed journal.
(cassatella2000interleukin15andits pages 3-4): Marco A. Cassatella and Patrick P. McDonald. Interleukin-15 and its impact on neutrophil function. Current Opinion in Hematology, 7:174-177, May 2000. URL: https://doi.org/10.1097/00062752-200005000-00008, doi:10.1097/00062752-200005000-00008. This article has 72 citations and is from a peer-reviewed journal.
(pelletier2005interleukin‐15increasesneutrophil pages 9-11): Martin Pelletier and Denis Girard. Interleukin‐15 increases neutrophil adhesion onto human respiratory epithelial a549 cells and attracts neutrophils in vivo. Clinical & Experimental Immunology, Aug 2005. URL: https://doi.org/10.1111/j.1365-2249.2005.02861.x, doi:10.1111/j.1365-2249.2005.02861.x. This article has 42 citations and is from a peer-reviewed journal.
(djaafar2008effectsofil15 pages 21-25): S Djaafar. Effects of il-15 and its specific inhibitor, the mutant il-15/fcγ2a protein, on bone turnover: new players in osteoimmunology. Unknown journal, 2008.
(marzec2008differentialeffectsof pages 4-5): Michal Marzec, Krzysztof Halasa, Monika Kasprzycka, Maria Wysocka, Xiaobin Liu, John W. Tobias, Donald Baldwin, Qian Zhang, Niels Odum, Alain H. Rook, and Mariusz A. Wasik. Differential effects of interleukin-2 and interleukin-15 versus interleukin-21 on cd4+ cutaneous t-cell lymphoma cells. Cancer research, 68 4:1083-91, Feb 2008. URL: https://doi.org/10.1158/0008-5472.can-07-2403, doi:10.1158/0008-5472.can-07-2403. This article has 104 citations and is from a highest quality peer-reviewed journal.
(wang2021transcriptionfactorsassociated pages 7-8): Xiang Wang and Xiang-Yu Zhao. Transcription factors associated with il-15 cytokine signaling during nk cell development. Frontiers in Immunology, Mar 2021. URL: https://doi.org/10.3389/fimmu.2021.610789, doi:10.3389/fimmu.2021.610789. This article has 144 citations and is from a peer-reviewed journal.
(djaafar2008effectsofil15 pages 25-29): S Djaafar. Effects of il-15 and its specific inhibitor, the mutant il-15/fcγ2a protein, on bone turnover: new players in osteoimmunology. Unknown journal, 2008.

Citations

skariah2024signallingmechanismsdriving pages 2-3
skariah2024signallingmechanismsdriving pages 7-8
tagaya1997generationofsecretable pages 4-5
tagaya1997generationofsecretable pages 1-2
park2004folliculardendriticcells pages 1-2
bernard2004identificationofan pages 1-2
skariah2024signallingmechanismsdriving pages 3-3
skariah2024signallingmechanismsdriving pages 10-11
skariah2024signallingmechanismsdriving pages 4-5
skariah2024signallingmechanismsdriving pages 8-8
bernard2004identificationofan pages 8-9
osinalde2015simultaneousdissectionand pages 6-7
osinalde2015simultaneousdissectionand pages 7-8
bergamaschi2009secretionandbiological pages 1-2
bergamaschi2009secretionandbiological pages 8-9
kurys2000thelongsignal pages 4-5
kurys2000thelongsignal pages 1-1
marzec2008differentialeffectsof pages 4-5
wang2021transcriptionfactorsassociated pages 7-8
https://doi.org/10.1093/discim/kyae002
https://doi.org/10.1074/jbc.M312458200
https://doi.org/10.3109/08830189809042995
https://doi.org/10.1002/pmic.201400194
https://doi.org/10.4049/jimmunol.0900693
https://doi.org/10.1002/bies.20380
https://doi.org/10.1073/pnas.94.26.14444
https://doi.org/10.1074/jbc.M002373200
https://doi.org/10.4049/jimmunol.154.2.483
https://doi.org/10.4049/jimmunol.173.11.6676
https://doi.org/10.1097/00062752-200005000-00008
https://doi.org/10.1111/j.1365-2249.2005.02861.x
https://doi.org/10.1093/discim/kyae002,
https://doi.org/10.1074/jbc.m312458200,
https://doi.org/10.3109/08830189809042995,
https://doi.org/10.1002/pmic.201400194,
https://doi.org/10.4049/jimmunol.0900693,
https://doi.org/10.1002/bies.20380,
https://doi.org/10.1073/pnas.94.26.14444,
https://doi.org/10.1074/jbc.m002373200,
https://doi.org/10.4049/jimmunol.154.2.483,
https://doi.org/10.4049/jimmunol.173.11.6676,
https://doi.org/10.1097/00062752-200005000-00008,
https://doi.org/10.1111/j.1365-2249.2005.02861.x,
https://doi.org/10.1158/0008-5472.can-07-2403,
https://doi.org/10.3389/fimmu.2021.610789,

📚 Additional Documentation

Notes

(IL15-notes.md)

IL15 notes

Falcon integration, 2026-05-12

Falcon deep research frames IL15 as a common gamma-chain cytokine that is usually delivered by IL15RA-dependent trans-presentation rather than only as freely soluble cytokine: "an IL-15-presenting cell displays a membrane IL-15/IL-15Ralpha complex that stimulates neighboring lymphocytes through IL2RB/IL2RG" [file:human/IL15/IL15-deep-research-falcon.md].
The most informative MF term beyond generic cytokine activity is interleukin-15 receptor binding. Generic protein binding annotations remain over-annotated because the curated biology is IL15RA binding plus recruitment of IL2RB/IL2RG [file:human/IL15/IL15-deep-research-falcon.md].
Added NEW BP terms for NK-cell proliferation/activation, B-cell proliferation/immunoglobulin production, and neutrophil chemotaxis because the existing broad cell proliferation and immune response annotations obscure these assayed cell-type-specific functions [file:human/IL15/IL15-deep-research-falcon.md].
Retained isoform-specific cellular component interpretation: IL15-S48AA is the secreted form, while IL15-S21AA is intracellular with cytoplasm/nucleus localization, matching the existing UniProt-based review text [UniProtKB:P40933; file:human/IL15/IL15-deep-research-falcon.md].

📄 View Raw YAML

id: P40933
gene_symbol: IL15
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
aliases:
  - IL-15
description: >-
  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).
existing_annotations:
# === IBA (Phylogenetic) Annotations ===
  - term:
      id: GO:0001819
      label: positive regulation of cytokine production
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
  - term:
      id: GO:0050778
      label: positive regulation of immune response
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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."
      action: ACCEPT
  - term:
      id: GO:0005125
      label: cytokine activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ACCEPT: IL15 is definitively a cytokine. UniProt RecName is "Interleukin-15"
        and function description begins "Cytokine that plays a major role..."
      action: ACCEPT
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ACCEPT: IL15 (isoform S48AA) is secreted. UniProt SUBCELLULAR LOCATION
        states "Isoform IL15-S48AA: Secreted."
      action: ACCEPT
  - term:
      id: GO:0042102
      label: positive regulation of T cell proliferation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ACCEPT: IL15 stimulates T cell proliferation. UniProt: "Stimulates the
        proliferation of natural killer cells, T-cells and B-cells."
      action: ACCEPT
  - term:
      id: GO:0042119
      label: neutrophil activation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ACCEPT: IL15 activates neutrophils. PMID:15123770 cited in UniProt shows
        IL15 enhances neutrophil phagocytosis.
      action: ACCEPT
# === IEA (Electronic) Annotations ===
  - term:
      id: GO:0005125
      label: cytokine activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        ACCEPT: Redundant with IBA annotation but correct. IL15 has cytokine activity.
      action: ACCEPT
  - term:
      id: GO:0005126
      label: cytokine receptor binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        ACCEPT: IL15 binds cytokine receptors. UniProt INTERACTION section shows
        IL15 binds IL15RA and IL2RB. This is core to its function.
      action: ACCEPT
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        ACCEPT: IL15 is found in extracellular region when secreted (isoform S48AA).
      action: ACCEPT
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        ACCEPT: Redundant but correct. Secreted isoform found in extracellular space.
      action: ACCEPT
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        ACCEPT: UniProt states "Isoform IL15-S21AA: Cytoplasm. Nucleus." The
        intracellular isoform localizes to the nucleus.
      action: ACCEPT
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        ACCEPT: UniProt states "Isoform IL15-S21AA: Cytoplasm." The intracellular
        isoform localizes to cytoplasm.
      action: ACCEPT
  - term:
      id: GO:0006955
      label: immune response
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        ACCEPT: IL15 functions in immune response. UniProt: "plays a major role in
        the development of inflammatory and protective immune responses."
      action: ACCEPT
  - term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      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.
      action: KEEP_AS_NON_CORE
# === IPI (Physical Interaction) Annotations ===
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16284400
    review:
      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."
      action: MARK_AS_OVER_ANNOTATED
      supported_by:
        - reference_id: PMID:16284400
          supporting_text: 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.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23104097
    review:
      summary: >-
        MARK_AS_OVER_ANNOTATED: Same as above - "protein binding" is uninformative.
        The IL15-receptor interaction is better captured by specific MF terms.
      action: MARK_AS_OVER_ANNOTATED
      supported_by:
        - reference_id: PMID:23104097
          supporting_text: Mechanistic and structural insight into the 
            functional dichotomy between IL-2 and IL-15.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25416956
    review:
      summary: >-
        MARK_AS_OVER_ANNOTATED: High-throughput interactome study. Generic protein
        binding is not informative for cytokine function annotation.
      action: MARK_AS_OVER_ANNOTATED
# === Ensembl/Mouse Orthologue Transfer ===
      supported_by:
        - reference_id: PMID:25416956
          supporting_text: A proteome-scale map of the human interactome 
            network.
  - term:
      id: GO:0120163
      label: negative regulation of cold-induced thermogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: KEEP_AS_NON_CORE
# === HPA Subcellular Localization ===
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        ACCEPT: HPA immunofluorescence data. Consistent with UniProt statement that
        isoform IL15-S21AA localizes to nucleus.
      action: ACCEPT
  - term:
      id: GO:0016607
      label: nuclear speck
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        ACCEPT: HPA immunofluorescence data showing nuclear speck localization.
        More specific than general nucleus annotation.
      action: ACCEPT
# === NAS (Non-traceable Author Statement) ===
  - term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    evidence_type: NAS
    original_reference_id: PMID:23104097
    review:
      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."
      action: ACCEPT
      supported_by:
        - reference_id: PMID:23104097
          supporting_text: Mechanistic and structural insight into the 
            functional dichotomy between IL-2 and IL-15.
  - term:
      id: GO:0035723
      label: interleukin-15-mediated signaling pathway
    evidence_type: NAS
    original_reference_id: PMID:23104097
    review:
      summary: >-
        ACCEPT: This IS the core signaling pathway for IL15. The gene product is
        literally the ligand that initiates this pathway.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:23104097
          supporting_text: Mechanistic and structural insight into the 
            functional dichotomy between IL-2 and IL-15.
  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: NAS
    original_reference_id: PMID:10627470
    review:
      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.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:10627470
          supporting_text: Expression of functional interleukin-15 receptor and 
            autocrine production of interleukin-15 as mechanisms of tumor 
            propagation in multiple myeloma.
  - term:
      id: GO:0043410
      label: positive regulation of MAPK cascade
    evidence_type: NAS
    original_reference_id: PMID:23104097
    review:
      summary: >-
        ACCEPT: IL15 activates MAPK in addition to JAK-STAT. This is part of its
        signaling mechanism.
      action: ACCEPT
# === IDA (Direct Assay) Annotations ===
      supported_by:
        - reference_id: PMID:23104097
          supporting_text: Mechanistic and structural insight into the 
            functional dichotomy between IL-2 and IL-15.
  - term:
      id: GO:0005125
      label: cytokine activity
    evidence_type: IDA
    original_reference_id: PMID:9097905
    review:
      summary: >-
        ACCEPT: Direct experimental evidence for cytokine activity. PMID:9097905
        demonstrates IL15 function in HIV context.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:9097905
          supporting_text: Role of IL-15 in HIV-1-associated 
            hypergammaglobulinaemia.
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IDA
    original_reference_id: PMID:9097905
    review:
      summary: >-
        ACCEPT: Direct evidence IL15 is secreted and found extracellularly.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:9097905
          supporting_text: Role of IL-15 in HIV-1-associated 
            hypergammaglobulinaemia.
  - term:
      id: GO:0035723
      label: interleukin-15-mediated signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:9097905
    review:
      summary: >-
        ACCEPT: Direct evidence for IL15-mediated signaling.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:9097905
          supporting_text: Role of IL-15 in HIV-1-associated 
            hypergammaglobulinaemia.
  - term:
      id: GO:0030225
      label: macrophage differentiation
    evidence_type: IDA
    original_reference_id: PMID:24942581
    review:
      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.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:24942581
          supporting_text: CD4 ligation on human blood monocytes triggers 
            macrophage differentiation and enhances HIV infection.
  - term:
      id: GO:0035723
      label: interleukin-15-mediated signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:15123770
    review:
      summary: >-
        ACCEPT: Direct evidence from study on IL15 signaling in neutrophils.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:15123770
          supporting_text: 'Interleukin-15 enhances human neutrophil phagocytosis
            by a Syk-dependent mechanism: importance of the IL-15Ralpha chain.'
  - term:
      id: GO:0050731
      label: positive regulation of peptidyl-tyrosine phosphorylation
    evidence_type: IDA
    original_reference_id: PMID:15123770
    review:
      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.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:15123770
          supporting_text: 'Interleukin-15 enhances human neutrophil phagocytosis
            by a Syk-dependent mechanism: importance of the IL-15Ralpha chain.'
  - term:
      id: GO:0050766
      label: positive regulation of phagocytosis
    evidence_type: IDA
    original_reference_id: PMID:15123770
    review:
      summary: >-
        ACCEPT: PMID:15123770 title is "Interleukin-15 enhances human neutrophil
        phagocytosis." Direct experimental evidence.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:15123770
          supporting_text: 'Interleukin-15 enhances human neutrophil phagocytosis
            by a Syk-dependent mechanism: importance of the IL-15Ralpha chain.'
  - term:
      id: GO:0042119
      label: neutrophil activation
    evidence_type: IDA
    original_reference_id: PMID:15123770
    review:
      summary: >-
        ACCEPT: PMID:15123770 demonstrates IL15 activates neutrophils (enhances
        phagocytosis). Consistent with IBA annotation.
      action: ACCEPT
# === ISS (Sequence Similarity) ===
      supported_by:
        - reference_id: PMID:15123770
          supporting_text: 'Interleukin-15 enhances human neutrophil phagocytosis
            by a Syk-dependent mechanism: importance of the IL-15Ralpha chain.'
  - term:
      id: GO:0120163
      label: negative regulation of cold-induced thermogenesis
    evidence_type: ISS
    original_reference_id: PMID:27684068
    review:
      summary: >-
        KEEP_AS_NON_CORE: Redundant with IEA annotation. Pleiotropic effect via
        adipose tissue regulation, not core cytokine function.
      action: KEEP_AS_NON_CORE
# === TAS/Reactome Annotations ===
      supported_by:
        - reference_id: PMID:27684068
          supporting_text: eCollection 2016. Deficiency of Interleukin-15 
            Confers Resistance to Obesity by Diminishing Inflammation and 
            Enhancing the Thermogenic Function of Adipose Tissues.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-449115
    review:
      summary: >-
        ACCEPT: Reactome pathway shows IL15:IL15RA complex formation. IL15 is
        found extracellularly.
      action: ACCEPT
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8983298
    review:
      summary: >-
        ACCEPT: Reactome pathway step. Redundant but correct.
      action: ACCEPT
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8983300
    review:
      summary: >-
        ACCEPT: Reactome pathway step.
      action: ACCEPT
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8983307
    review:
      summary: >-
        ACCEPT: Reactome pathway step.
      action: ACCEPT
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8983335
    review:
      summary: >-
        ACCEPT: Reactome pathway step showing receptor complex translocation.
      action: ACCEPT
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8983371
    review:
      summary: >-
        ACCEPT: Reactome pathway step.
      action: ACCEPT
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8983374
    review:
      summary: >-
        ACCEPT: Reactome pathway step.
      action: ACCEPT
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8983378
    review:
      summary: >-
        ACCEPT: Reactome pathway step.
      action: ACCEPT
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8983384
    review:
      summary: >-
        ACCEPT: Reactome pathway step.
      action: ACCEPT
  - term:
      id: GO:0005768
      label: endosome
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8983335
    review:
      summary: >-
        ACCEPT: Reactome shows IL15 receptor complex translocates to endosome
        during signaling.
      action: ACCEPT
  - term:
      id: GO:0035723
      label: interleukin-15-mediated signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:24942581
    review:
      summary: >-
        ACCEPT: Direct evidence for IL15-mediated signaling pathway.
      action: ACCEPT
# === GO:0007260 (Phosphorylation - Previously Reviewed) ===
      supported_by:
        - reference_id: PMID:24942581
          supporting_text: CD4 ligation on human blood monocytes triggers 
            macrophage differentiation and enhances HIV infection.
  - term:
      id: GO:0007260
      label: tyrosine phosphorylation of STAT protein
    evidence_type: IDA
    original_reference_id: PMID:12244150
    review:
      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".
      action: MODIFY
      proposed_replacement_terms:
        - id: GO:0042531
          label: positive regulation of tyrosine phosphorylation of STAT protein
# === Additional IDA Annotations ===
      supported_by:
        - reference_id: PMID:12244150
          supporting_text: IL-21 up-regulates the expression of genes associated
            with innate immunity and Th1 response.
  - term:
      id: GO:0032740
      label: positive regulation of interleukin-17 production
    evidence_type: IDA
    original_reference_id: PMID:16482511
    review:
      summary: >-
        ACCEPT: IL15 promotes IL-17 production. This is part of its cytokine
        production stimulation function.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:16482511
          supporting_text: Divergent effects of IL-12 and IL-23 on the 
            production of IL-17 by human T cells.
  - term:
      id: GO:0034105
      label: positive regulation of tissue remodeling
    evidence_type: IC
    original_reference_id: PMID:16482511
    review:
      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.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:16482511
          supporting_text: Divergent effects of IL-12 and IL-23 on the 
            production of IL-17 by human T cells.
  - term:
      id: GO:0050729
      label: positive regulation of inflammatory response
    evidence_type: IC
    original_reference_id: PMID:16482511
    review:
      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."
      action: ACCEPT
# === Additional Location Annotations ===
      supported_by:
        - reference_id: PMID:16482511
          supporting_text: Divergent effects of IL-12 and IL-23 on the 
            production of IL-17 by human T cells.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: NAS
    original_reference_id: PMID:14718574
    review:
      summary: >-
        ACCEPT: Human plasma proteome study detected IL15 extracellularly.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:14718574
          supporting_text: 'Epub 2004 Jan 12. The human plasma proteome: a nonredundant
            list developed by combination of four separate sources.'
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: TAS
    original_reference_id: PMID:10851076
    review:
      summary: >-
        ACCEPT: IL15 found in extracellular space.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:10851076
          supporting_text: Altered natural killer cell differentiation in CD34+ 
            progenitors from chronic myeloid leukemia patients.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: TAS
    original_reference_id: PMID:10851076
    review:
      summary: >-
        ACCEPT: IL15-S21AA isoform is cytoplasmic per UniProt.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:10851076
          supporting_text: Altered natural killer cell differentiation in CD34+ 
            progenitors from chronic myeloid leukemia patients.
  - term:
      id: GO:0005768
      label: endosome
    evidence_type: TAS
    original_reference_id: PMID:10851076
    review:
      summary: >-
        ACCEPT: IL15 traffics through endosomal pathway.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:10851076
          supporting_text: Altered natural killer cell differentiation in CD34+ 
            progenitors from chronic myeloid leukemia patients.
  - term:
      id: GO:0005794
      label: Golgi apparatus
    evidence_type: TAS
    original_reference_id: PMID:10851076
    review:
      summary: >-
        ACCEPT: IL15 transits through Golgi during secretory pathway.
      action: ACCEPT
# === Additional Process Annotations ===
      supported_by:
        - reference_id: PMID:10851076
          supporting_text: Altered natural killer cell differentiation in CD34+ 
            progenitors from chronic myeloid leukemia patients.
  - term:
      id: GO:0006955
      label: immune response
    evidence_type: TAS
    original_reference_id: PMID:8178155
    review:
      summary: >-
        ACCEPT: Original cloning paper. IL15 functions in immune response.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:8178155
          supporting_text: Cloning of a T cell growth factor that interacts with
            the beta chain of the interleukin-2 receptor.
  - term:
      id: GO:0007165
      label: signal transduction
    evidence_type: TAS
    original_reference_id: PMID:8178155
    review:
      summary: >-
        KEEP_AS_NON_CORE: Very general term. IL15 does participate in signal
        transduction but more specific pathway terms are preferred.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:8178155
          supporting_text: Cloning of a T cell growth factor that interacts with
            the beta chain of the interleukin-2 receptor.
  - term:
      id: GO:0007267
      label: cell-cell signaling
    evidence_type: TAS
    original_reference_id: PMID:7759105
    review:
      summary: >-
        ACCEPT: IL15 mediates cell-cell signaling via trans-presentation (IL15
        on one cell presents to receptors on another cell).
      action: ACCEPT
      supported_by:
        - reference_id: PMID:7759105
          supporting_text: Chromosomal assignment and genomic structure of Il15.
  - term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
    evidence_type: TAS
    original_reference_id: PMID:10851076
    review:
      summary: >-
        KEEP_AS_NON_CORE: True but overly general. IL15 stimulates specific
        immune cell proliferation. More specific terms preferred.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:10851076
          supporting_text: Altered natural killer cell differentiation in CD34+ 
            progenitors from chronic myeloid leukemia patients.
# === Falcon-supported new annotations ===
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: NAS
    review:
      summary: >-
        NEW: IL15 is presented at the cell surface as an IL15:IL15RA complex
        during trans-presentation to IL2RB/IL2RG-bearing neighboring cells.
      action: NEW
      reason: >-
        Core function synthesis includes cell-surface trans-presentation, but
        the current GOA-derived cellular component annotations do not include
        cell surface.
      supported_by:
        - reference_id: file:human/IL15/IL15-deep-research-falcon.md
          supporting_text: >-
            IL-15 is commonly delivered by **trans-presentation**: an
            “IL-15-presenting” cell displays a **membrane IL-15/IL-15Rα complex**
            that stimulates neighboring lymphocytes through **IL2RB/IL2RG**.
  - term:
      id: GO:0016170
      label: interleukin-15 receptor binding
    evidence_type: NAS
    review:
      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.
      action: NEW
      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.
      supported_by:
        - reference_id: file:human/IL15/IL15-deep-research-falcon.md
          supporting_text: >-
            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.
  - term:
      id: GO:0032819
      label: positive regulation of natural killer cell proliferation
    evidence_type: NAS
    review:
      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.
      action: NEW
      reason: >-
        Existing annotations include only broad proliferation terms and miss the
        key NK-cell-specific proliferative activity.
      supported_by:
        - reference_id: file:human/IL15/IL15-deep-research-falcon.md
          supporting_text: >-
            IL-15 is essential for NK-cell development and potently promotes NK
            proliferation, activation, granzyme/perforin expression,
            degranulation, and inflammatory cytotoxicity.
  - term:
      id: GO:0032816
      label: positive regulation of natural killer cell activation
    evidence_type: NAS
    review:
      summary: >-
        NEW: IL15 positively regulates NK-cell activation, including effector
        programs linked to cytotoxicity.
      action: NEW
      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.
      supported_by:
        - reference_id: file:human/IL15/IL15-deep-research-falcon.md
          supporting_text: >-
            IL-15 is essential for NK-cell development and potently promotes NK
            proliferation, activation, granzyme/perforin expression,
            degranulation, and inflammatory cytotoxicity.
  - term:
      id: GO:0030890
      label: positive regulation of B cell proliferation
    evidence_type: NAS
    review:
      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.
      action: NEW
      reason: >-
        The review currently notes B-cell proliferation only in summaries and
        broad proliferation annotations; a specific B-cell BP term is warranted.
      supported_by:
        - reference_id: file:human/IL15/IL15-deep-research-falcon.md
          supporting_text: >-
            IL-15 costimulates activated human B-cell proliferation and, with
            CD40L, induces IgM, IgG1, and IgA secretion via IL2RB-dependent
            signaling.
  - term:
      id: GO:0002639
      label: positive regulation of immunoglobulin production
    evidence_type: NAS
    review:
      summary: >-
        NEW: In activated B cells, IL15 can promote immunoglobulin secretion in
        the appropriate costimulatory context.
      action: NEW
      reason: >-
        Falcon research identified direct B-cell evidence for immunoglobulin
        production that is absent from the current annotation set.
      supported_by:
        - reference_id: file:human/IL15/IL15-deep-research-falcon.md
          supporting_text: >-
            IL-15 costimulates activated human B-cell proliferation and, with
            CD40L, induces IgM, IgG1, and IgA secretion via IL2RB-dependent
            signaling.
  - term:
      id: GO:0090023
      label: positive regulation of neutrophil chemotaxis
    evidence_type: NAS
    review:
      summary: >-
        NEW: IL15 promotes neutrophil recruitment/chemotaxis in addition to the
        already accepted neutrophil activation and phagocytosis annotations.
      action: NEW
      reason: >-
        The current annotation set captures neutrophil activation and
        phagocytosis but misses the more specific neutrophil recruitment
        phenotype supported by the literature synthesis.
      supported_by:
        - reference_id: file:human/IL15/IL15-deep-research-falcon.md
          supporting_text: >-
            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.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10627470
    title: Expression of functional interleukin-15 receptor and autocrine 
      production of interleukin-15 as mechanisms of tumor propagation in 
      multiple myeloma.
    findings:
      - statement: IL15 promotes myeloma cell survival through autocrine 
          signaling
  - id: PMID:10851076
    title: Altered natural killer cell differentiation in CD34+ progenitors from
      chronic myeloid leukemia patients.
    findings: []
  - id: PMID:12244150
    title: IL-21 up-regulates the expression of genes associated with innate 
      immunity and Th1 response.
    findings:
      - statement: Study on IL-21 showing STAT3 activation; IL15 cited for 
          comparison
  - id: PMID:14718574
    title: 'The human plasma proteome: a nonredundant list developed by combination
      of four separate sources.'
    findings: []
  - id: PMID:15123770
    title: 'Interleukin-15 enhances human neutrophil phagocytosis by a Syk-dependent
      mechanism: importance of the IL-15Ralpha chain.'
    findings:
      - statement: IL15 enhances neutrophil phagocytosis
      - statement: Mechanism involves Syk kinase and requires IL-15Ralpha
  - id: PMID:16284400
    title: "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 x IL-15R alpha fusion proteins."
    findings: []
  - id: PMID:16482511
    title: Divergent effects of IL-12 and IL-23 on the production of IL-17 by 
      human T cells.
    findings:
      - statement: IL15 contributes to IL-17 production regulation
  - id: PMID:23104097
    title: Mechanistic and structural insight into the functional dichotomy 
      between IL-2 and IL-15.
    findings:
      - statement: Crystal structure of IL15 reveals signaling mechanism
      - statement: IL15 and IL2 have distinct receptor engagement modes
  - id: PMID:24942581
    title: CD4 ligation on human blood monocytes triggers macrophage 
      differentiation and enhances HIV infection.
    findings: []
  - id: PMID:25416956
    title: A proteome-scale map of the human interactome network.
    findings: []
  - id: PMID:27684068
    title: Deficiency of Interleukin-15 Confers Resistance to Obesity by 
      Diminishing Inflammation and Enhancing the Thermogenic Function of Adipose
      Tissues.
    findings:
      - statement: IL15 deficiency enhances thermogenesis - pleiotropic effect
  - id: PMID:7759105
    title: Chromosomal assignment and genomic structure of Il15.
    findings: []
  - id: PMID:8178155
    title: Cloning of a T cell growth factor that interacts with the beta chain 
      of the interleukin-2 receptor.
    findings:
      - statement: Original identification of IL15 as T cell growth factor
      - statement: IL15 signals through IL2RB (shared with IL-2)
  - id: PMID:9097905
    title: Role of IL-15 in HIV-1-associated hypergammaglobulinaemia.
    findings: []
  - id: Reactome:R-HSA-449115
    title: IL15:IL15RA binds IL2RB:JAK1 and IL2RG:JAK3
    findings: []
  - id: Reactome:R-HSA-8983298
    title: IL15 binds IL2RB:JAK1 and IL2RG:JAK3
    findings: []
  - id: Reactome:R-HSA-8983300
    title: IL15RA:IL15:IL2RB:JAK1:IL2RG:JAK3 phosphorylates JAK3 and JAK1
    findings: []
  - id: Reactome:R-HSA-8983307
    title: IL15 binds IL15RA
    findings: []
  - id: Reactome:R-HSA-8983335
    title: IL15:IL15RA:IL2RB:JAK1:IL2RG:JAK3 translocates from the plasma 
      membrane to the endosome
    findings: []
  - id: Reactome:R-HSA-8983371
    title: IL15:IL15RA:p-Y-IL2RB:p-Y-JAK1:p-Y-IL2RG:p-Y-JAK3 phosphorylates 
      STAT3 and STAT5
    findings: []
  - id: Reactome:R-HSA-8983374
    title: p-Y-STAT3 and p-STAT5 dissociates from 
      IL15:IL15RA:IL2RB:p-JAK1:IL2RG:p-JAK3:p-Y-STAT3:p-STAT5
    findings: []
  - id: Reactome:R-HSA-8983378
    title: IL15:IL15RA:p-Y-IL2RB:p-Y-JAK1:p-Y-IL2RG:p-Y-JAK3 binds STAT3 and 
      STAT5
    findings: []
  - id: Reactome:R-HSA-8983384
    title: IL15:IL15RA:p-Y-IL2RB:p-Y-JAK1:p-Y-IL2RG:p-Y-JAK3:p-Y-SHC1:GRB2 binds
      SOS1,SOS2
    findings: []
  - id: file:human/IL15/IL15-deep-research-falcon.md
    title: Falcon deep research on IL15 GO-relevant functions
    findings:
      - statement: >-
          IL15 functions primarily as an IL15RA-bound cytokine delivered by
          trans-presentation or as soluble IL15/IL15RA heterodimer, rather than
          only as free soluble cytokine.
        supporting_text: >-
          A central concept for GO curation is that IL-15 is not best modeled as
          a freely diffusing cytokine under physiologic conditions. Instead,
          IL-15 is commonly delivered by **trans-presentation**: an
          “IL-15-presenting” cell displays a **membrane IL-15/IL-15Rα complex**
          that stimulates neighboring lymphocytes through **IL2RB/IL2RG**.
      - statement: >-
          Specific receptor-binding terms and cell-type-specific immune process
          terms are preferable to generic protein binding or broad proliferation
          annotations.
        supporting_text: >-
          Prefer specific terms supported by direct assays (cytokine activity,
          IL15RA binding, trans-presentation, NK/CD8/B/neutrophil processes,
          JAK/STAT signaling, isoform-localization) and avoid generic “protein
          binding,” broad “cell population proliferation,” or over-broad
          immune/developmental annotations unless directly tested in the relevant
          lineage/context.
      - statement: >-
          IL15 receptor signaling activates JAK1/JAK3 and STAT3/STAT5 downstream
          of IL2RB/IL2RG.
        supporting_text: >-
          IL-15 receptor signaling activates JAK1/JAK3 and predominantly STAT5,
          with STAT3 also activated in some T-cell/IEL contexts downstream of
          IL2RB/IL2RG.
      - statement: >-
          IL15 isoforms support both secretory/extracellular localization and
          intracellular cytoplasm/nucleus localization depending on the signal
          peptide.
        supporting_text: >-
          The 21-aa short signal peptide isoform is largely nonsecreted and
          localizes to cytoplasmic and nuclear compartments, supporting
          isoform-specific intracellular annotations.
core_functions:
  - molecular_function:
      id: GO:0016170
      label: interleukin-15 receptor binding
    description: >-
      IL15 binds IL15RA with high affinity and is commonly delivered as an
      IL15:IL15RA complex to adjacent IL2RB/IL2RG-expressing cells, initiating
      IL15-mediated JAK-STAT signaling.
    supported_by:
      - reference_id: file:human/IL15/IL15-deep-research-falcon.md
        supporting_text: >-
          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.
      - reference_id: Reactome:R-HSA-8983307
        supporting_text: IL15 binds IL15RA
    directly_involved_in:
      - id: GO:0035723
        label: interleukin-15-mediated signaling pathway
      - id: GO:0007259
        label: cell surface receptor signaling pathway via JAK-STAT
      - id: GO:0007267
        label: cell-cell signaling
    locations:
      - id: GO:0005576
        label: extracellular region
      - id: GO:0009986
        label: cell surface
  - molecular_function:
      id: GO:0005125
      label: cytokine activity
    description: >-
      IL15 cytokine activity promotes proliferation, activation and maintenance
      of specific lymphocyte populations, especially NK cells, T cells and
      activated B cells, rather than indiscriminate cell population
      proliferation.
    supported_by:
      - reference_id: file:human/IL15/IL15-deep-research-falcon.md
        supporting_text: >-
          IL-15 is essential for NK-cell development and potently promotes NK
          proliferation, activation, granzyme/perforin expression, degranulation,
          and inflammatory cytotoxicity.
      - reference_id: file:human/IL15/IL15-deep-research-falcon.md
        supporting_text: >-
          IL-15 costimulates activated human B-cell proliferation and, with
          CD40L, induces IgM, IgG1, and IgA secretion via IL2RB-dependent
          signaling.
    directly_involved_in:
      - id: GO:0032819
        label: positive regulation of natural killer cell proliferation
      - id: GO:0032816
        label: positive regulation of natural killer cell activation
      - id: GO:0042102
        label: positive regulation of T cell proliferation
      - id: GO:0030890
        label: positive regulation of B cell proliferation
      - id: GO:0002639
        label: positive regulation of immunoglobulin production
    locations:
      - id: GO:0005576
        label: extracellular region
  - molecular_function:
      id: GO:0005125
      label: cytokine activity
    description: >-
      IL15 also acts on innate immune cells, supporting neutrophil activation,
      phagocytosis, cytokine/chemokine production and recruitment.
    supported_by:
      - reference_id: file:human/IL15/IL15-deep-research-falcon.md
        supporting_text: >-
          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.
    directly_involved_in:
      - id: GO:0042119
        label: neutrophil activation
      - id: GO:0050766
        label: positive regulation of phagocytosis
      - id: GO:0090023
        label: positive regulation of neutrophil chemotaxis
      - id: GO:0001819
        label: positive regulation of cytokine production
    locations:
      - id: GO:0005576
        label: extracellular region

IL15

Gene Description

Existing Annotations Review

Core Functions

IL15 binds IL15RA with high affinity and is commonly delivered as an IL15:IL15RA complex to adjacent IL2RB/IL2RG-expressing cells, initiating IL15-mediated JAK-STAT signaling.

IL15 cytokine activity promotes proliferation, activation and maintenance of specific lymphocyte populations, especially NK cells, T cells and activated B cells, rather than indiscriminate cell population proliferation.

IL15 also acts on innate immune cells, supporting neutrophil activation, phagocytosis, cytokine/chemokine production and recruitment.

References

Deep Research

Falcon

Concise GO annotation research report: Human IL15 (UniProt P40933)

Scope and approach

1) Key concepts and definitions (current understanding)

IL-15 as a cytokine and receptor system

Trans-presentation vs soluble cytokine activity

2) Recent developments and latest research (prioritize 2023–2024)

3) Molecular function evidence (GO: Molecular Function)

High-affinity binding to IL15RA and recruitment of IL2RB/IL2RG

4) Signaling evidence (GO: Biological Process—cytokine-mediated signaling; JAK-STAT)

JAK1/JAK3 and STAT3/STAT5 activation

5) Presentation mode and IL-15Rα chaperoning (GO-relevant for trans-presentation and soluble complex activity)

IL-15Rα as chaperone and soluble heterodimer

6) Isoform-specific localization (GO: Cellular Component)

7) Functional outcomes relevant to GO Biological Process annotations

NK cells and CD8 T cells (proliferation/activation/survival)

B cells (proliferation, differentiation, immunoglobulin production)

Neutrophils (activation, phagocytosis, adhesion, chemotaxis, survival)

8) Curation caveats (avoid over-broad GO annotations)

Evidence-to-GO mapping table

Citations

📚 Additional Documentation

Notes

IL15 notes

Falcon integration, 2026-05-12

📄 View Raw YAML