Affinage

IL15

Interleukin-15 · UniProt P40933

Round 2 corrected
Length
162 aa
Mass
18.1 kDa
Annotated
2026-04-28
130 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL-15 is a pleiotropic four-helix-bundle cytokine that signals through a trimeric receptor comprising a private high-affinity IL-15Rα chain and the shared IL-2Rβ/γc heterodimer, activating JAK1/JAK3–STAT3/STAT5 and PI3K–mTORC1 pathways to govern survival, proliferation, and differentiation of NK cells, NKT cells, and CD8⁺ memory T cells (PMID:8178155, PMID:7641685, PMID:7568001). IL-15Rα on dendritic cells and stromal cells trans-presents IL-15 to responding lymphocytes, with the sushi domain allosterically enhancing IL-15 affinity for IL-2Rβ; graded levels of trans-presented IL-15 specify distinct NK-cell developmental outcomes and CD8⁺ T cell homeostatic proliferation through quantitative differences in STAT5 phosphorylation (PMID:23104097, PMID:18812469, PMID:21715685, PMID:16284400). IL-15 promotes lymphocyte survival via Bcl-2 and Bcl-xL induction and drives antigen-independent memory CD8⁺ T cell cycling through mTORC1, while its expression is regulated post-transcriptionally by inhibitory upstream AUGs in the 5′ UTR and transcriptionally through the ATF4–IRF7 axis and Notch-dependent silencing during hematopoietic lineage commitment (PMID:16365444, PMID:22084435, PMID:26241055, PMID:8613692, PMID:29431743, PMID:23966624). Beyond canonical immune roles, intracellular IL-15 functions as a transcriptional repressor of mast cell chymase, and compartment-specific IL-15 overexpression in both gut epithelium and lamina propria drives villous atrophy in a coeliac disease model (PMID:17643110, PMID:32051586).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1994 High

    The discovery that IL-15 is a T cell growth factor that shares IL-2Rβ (CD122) and γc (CD132) but not IL-2Rα established it as a second cytokine exploiting the IL-2 receptor system, raising the question of how specificity is achieved.

    Evidence cDNA cloning, receptor competition binding, and neutralizing antibody inhibition in two independent studies

    PMID:8026467 PMID:8178155

    Open questions at the time
    • The IL-15-specific receptor component was not yet identified
    • Downstream signaling pathways were unknown
  2. 1995 High

    Cloning of IL-15Rα as a high-affinity private α chain structurally related to IL-2Rα resolved how IL-15 achieves receptor specificity and defined the complete trimeric receptor complex (IL-15Rα/IL-2Rβ/γc).

    Evidence Molecular cloning, reconstitution of trimeric complex, and direct binding quantification in myeloid cells

    PMID:7641685

    Open questions at the time
    • Whether IL-15Rα functions in cis or trans was unknown
    • Three-dimensional receptor architecture was unresolved
  3. 1995 High

    Identification of JAK1/JAK3 activation and STAT3/STAT5 induction downstream of IL-15 established the proximal signaling cascade, paralleling IL-2 but foreshadowing cell-type-specific differences.

    Evidence Immunoprecipitation, phosphotyrosine blotting, and EMSA in human T cells

    PMID:7568001

    Open questions at the time
    • Whether additional pathways (MAPK, PI3K) are engaged was not addressed
    • Cell-type-specific signaling differences were unexplored
  4. 1996 High

    Demonstration that 10 upstream AUGs in the IL-15 5′ UTR suppress translation revealed that IL-15 protein output is tightly controlled post-transcriptionally, explaining the discrepancy between widespread mRNA expression and limited protein detection.

    Evidence RT-PCR characterization and translational efficiency comparison of chimeric mRNAs with varying upstream AUG content

    PMID:8613692

    Open questions at the time
    • Which trans-acting factors relieve translational repression was unknown
    • In vivo relevance of individual upstream AUGs was not tested
  5. 2000 High

    Showing that CD8⁺ memory T cell homeostatic proliferation requires IL-15 while being opposed by IL-2 established IL-15 as the non-redundant survival cytokine for immunological memory, distinct from IL-2.

    Evidence In vivo proliferation in IL-15-deficient mice combined with IL-2 blockade; adoptive transfer system

    PMID:10784451

    Open questions at the time
    • The cellular source of IL-15 for memory T cell maintenance was unresolved
    • Downstream survival effectors were not identified
  6. 2003 High

    Concurrent studies defined IL-15 as the dominant NK cell survival signal via Bcl-2, showed that IL-15Rα enhances sensitivity but is dispensable on responding cells (β/γc are essential), identified SOCS1 as a negative regulator of IL-15–STAT5 signaling, and revealed alternative IL-15Rα splice variants in mast cells with distinct signaling profiles.

    Evidence Adoptive transfer into IL-15 KO hosts; receptor subunit KO cell assays; SOCS1 KO thymic organ culture; mast cell IL-15Rα isoform cloning with signaling reconstitution

    PMID:12586624 PMID:12734346 PMID:12734349 PMID:12907450

    Open questions at the time
    • Whether IL-15Rα on accessory cells trans-presents IL-15 in vivo was not directly demonstrated
    • Quantitative relationship between IL-15 dose and specific developmental outcomes was unknown
    • Mast cell IL-15Rα isoform findings from a single lab awaited independent confirmation
  7. 2005 High

    Dissection of the IL-15Rα sushi domain as an agonist versus the full ectodomain as an antagonist explained how soluble IL-15Rα fragments allosterically modulate IL-15 potency, enabling rational design of IL-15 superagonists (RLI).

    Evidence Recombinant domain fragments tested in binding, proliferation, apoptosis, and receptor internalization assays

    PMID:16284400

    Open questions at the time
    • Structural basis for the allosteric enhancement was not yet resolved at atomic level
    • In vivo pharmacokinetics of sushi-domain fusions were not characterized
  8. 2006 High

    A convergence of in vivo studies established that IL-15/IL-15Rα complexes potently expand memory CD8⁺ T cells and NK cells, that IL-15 protects effector CD8⁺ T cells from contraction-phase apoptosis via Bcl-2 (shown by Bcl-2 transgene rescue in IL-15 KO), and that IL-15 is required specifically for the CD44ʰⁱCD122ʰⁱ memory-phenotype CD8⁺ T cell subset.

    Evidence IL-15/sIL-15Rα complex injection; IL-15 KO and transgenic mice with Bcl-2 rescue; IL-15/ITK double-KO epistasis

    PMID:16365444 PMID:16757567 PMID:16880398

    Open questions at the time
    • Which accessory cell types are the physiological source of trans-presented IL-15 was still unresolved
    • Whether IL-15 supports CD8⁺ memory via Bcl-2 versus proliferative mechanisms was debated
  9. 2007 High

    Two studies revealed unexpected non-canonical IL-15 functions: intracellular IL-15 in mast cells acts as a transcriptional repressor of chymase, and extracellular IL-15 orchestrates neutrophil migration through a sequential IL-18→MIP-2/TNF-α/LTB4 cytokine cascade.

    Evidence IL-15 KO mice in CLP sepsis model with chymase activity assays; peritoneal neutrophil migration in multiple cytokine/receptor KO mice

    PMID:17643110 PMID:17979156

    Open questions at the time
    • Mechanism by which intracellular IL-15 represses chymase transcription was not defined
    • Whether the neutrophil-recruiting cascade operates in tissues beyond the peritoneum was unknown
  10. 2008 High

    Restricting IL-15Rα expression to dendritic cells proved sufficient for homeostatic memory CD8⁺ T cell proliferation, identifying DCs as a physiologically relevant trans-presenting cell type.

    Evidence IL-15Rα transgenic mouse model limiting expression to DCs; adoptive transfer with viral infection

    PMID:18812469

    Open questions at the time
    • Contribution of non-DC populations (macrophages, stromal cells) was not excluded
    • Whether DC trans-presentation is sufficient for NK cell homeostasis was not tested
  11. 2011 High

    Quantitative studies showed that graded IL-15 trans-presentation levels on accessory cells determine distinct NK cell developmental thresholds via proportional STAT5 phosphorylation, and that IL-15 controls NKT cell terminal differentiation through a Bcl-xL survival and T-bet transcriptional program.

    Evidence IL-15Rα knockin mice with titrated expression; NK-DC coculture with STAT5 readout; IL-15 KO NKT cell gene expression profiling

    PMID:21715685 PMID:22084435

    Open questions at the time
    • How specific STAT5 phosphorylation thresholds activate distinct gene programs was not mechanistically resolved
    • Whether T-bet is directly or indirectly regulated by STAT5 downstream of IL-15 was unclear
  12. 2012 High

    Crystal structures of the quaternary IL-15–IL-15Rα–IL-2Rβ–γc complex revealed near-identical receptor engagement geometry to the IL-2 quaternary complex, demonstrating that IL-15Rα allosterically increases IL-15 affinity for IL-2Rβ and that functional differences between IL-2 and IL-15 arise from differential receptor affinities rather than distinct signaling geometries.

    Evidence X-ray crystallography of the quaternary complex; surface plasmon resonance; functional signaling assays

    PMID:23104097

    Open questions at the time
    • How identical β/γc engagement produces differential STAT activation kinetics between IL-2 and IL-15 remained unexplained
    • Structural basis for IL-15Rα's allosteric effect on IL-2Rβ binding was not fully delineated
  13. 2015 High

    Type I IFN-driven IL-15 was shown to push memory CD8⁺ T cells into rapid mTORC1-dependent cell-cycle entry independently of antigen, establishing mTORC1 as a key downstream effector of IL-15 in bystander activation of memory T cells.

    Evidence IL-15 KO mice during viral infection; rapamycin treatment; BrdU incorporation

    PMID:26241055

    Open questions at the time
    • How IL-15 activates mTORC1 (via PI3K–Akt or alternative route) in memory T cells was not resolved
    • Whether mTORC1-independent IL-15 effects contribute to bystander activation was not tested
  14. 2018 High

    Two mechanistic advances emerged: NKG2D ligation by ULBP2 induces nanoscale co-clustering of NKG2D with IL-2/IL-15Rβ to enable cooperative signaling in NK cells, and the ATF4–IRF7 transcriptional axis was identified as a regulator of IL-15 expression in AML cells.

    Evidence Super-resolution dSTORM imaging on primary NK cells with functional validation; siRNA/overexpression of IRF7/ATF4 in AML cells with chromatin analysis

    PMID:29431743 PMID:29636390

    Open questions at the time
    • Whether NKG2D–IL-15Rβ co-clustering occurs with other NKG2D ligands beyond ULBP2 was unknown
    • Generalizability of ATF4–IRF7–IL-15 axis beyond FLT3-ITD+ AML was not tested
  15. 2019 High

    IL-15 was shown to preserve stem cell memory (Tscm) phenotype in CAR-T cells through mTORC1 suppression and metabolic reprogramming toward mitochondrial fitness, and a de novo designed protein (Neo-2/15) that binds IL-2Rβγc without engaging α chains confirmed that β/γc engagement alone is sufficient for downstream signaling.

    Evidence CAR-T expansion with IL-15 versus IL-2 plus rapamycin phenocopy; metabolic profiling; crystal structure of Neo-2/15 in complex with IL-2Rβγc

    PMID:30626941 PMID:30890531

    Open questions at the time
    • Whether IL-15-mediated mTORC1 suppression in CAR-T cells is dose-dependent or context-dependent was not determined
    • Neo-2/15 structure did not address IL-15Rα allosteric mechanism
  16. 2020 High

    A compartment-specific transgenic model demonstrated that IL-15 overexpression must occur simultaneously in both gut epithelium and lamina propria to drive coeliac-like villous atrophy, placing IL-15 as a central pathogenic mediator linking innate and adaptive intestinal immunity.

    Evidence Transgenic mice with compartment-restricted IL-15 overexpression; HLA-DQ8; gluten feeding; T cell depletion; IFN-γ KO

    PMID:32051586

    Open questions at the time
    • Whether epithelial versus lamina propria IL-15 engages distinct receptor configurations or cell types was not resolved
    • Applicability to human coeliac disease pathogenesis requires clinical confirmation
  17. 2025 High

    Identification of CREM as an IL-15-induced negative regulator of CAR-NK cell function via PKA–CREB signaling and epigenetic reprogramming revealed a previously unknown feedback restraint downstream of IL-15 in engineered NK cells.

    Evidence CREM deletion in CAR-NK cells; PKA/CREB pathway inhibition; epigenomic profiling; in vivo tumor models

    PMID:40468083

    Open questions at the time
    • Whether CREM-mediated restraint operates in endogenous NK cells or is specific to CAR-NK expansion conditions is unknown
    • The specific epigenetic targets of CREM in NK cells were not fully catalogued

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how identical IL-2Rβ/γc engagement geometry by IL-2 and IL-15 produces distinct signaling kinetics and biological outcomes, the structural mechanism of IL-15Rα's allosteric enhancement of IL-15 affinity for IL-2Rβ, how intracellular IL-15 represses chymase transcription in mast cells, and whether quantitative STAT5 thresholds downstream of trans-presented IL-15 specify gene programs through distinct transcription factor assemblies.
  • No structural model for IL-15Rα allosteric transmission to the IL-2Rβ binding interface
  • Mechanism of intracellular IL-15 transcriptional repression in mast cells is undefined
  • How STAT5 dose-response translates into binary developmental decisions in NK/NKT cells remains unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0098772 molecular function regulator activity 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-168256 Immune System 15 R-HSA-162582 Signal Transduction 9 R-HSA-1266738 Developmental Biology 3 R-HSA-5357801 Programmed Cell Death 3
Partners
IL15RAIL2RBIL2RGJAK1JAK3STAT3STAT5A

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 IL-15 was cloned as a novel T cell growth factor that interacts with the β chain of the IL-2 receptor (CD122); monoclonal antibodies to the IL-2R β chain inhibited IL-15 biological activity, and IL-15 competed for IL-2 binding, establishing that IL-15 uses components of the IL-2 receptor complex. cDNA cloning, receptor competition binding assay, neutralizing monoclonal antibody inhibition Science High 8178155
1994 IL-15 utilizes both the β chain (CD122) and γc chain (CD132) of the IL-2 receptor for high-affinity binding and signaling; the IL-2Rα subunit is not involved in IL-15 binding, implying the existence of a distinct IL-15-specific receptor component. Transfection of IL-2R subunits into cells, direct binding assays, signaling assays The EMBO journal High 8026467
1995 A high-affinity IL-15-specific receptor α chain (IL-15Rα) was identified and cloned; IL-15Rα alone binds IL-15 with affinity equivalent to the full heterotrimeric IL-2R for IL-2, and together with IL-2Rβ and γc forms a functional trimeric IL-15 receptor complex. IL-15Rα is structurally related to IL-2Rα, defining a new cytokine receptor subfamily. Molecular cloning, direct binding assays, reconstitution of receptor complex in myeloid cell line The EMBO journal High 7641685
1995 IL-15 rapidly induces tyrosine phosphorylation and activation of JAK1 and JAK3, and activates STAT3 and STAT5 transcription factors in human T cells, similar to IL-2; IL-4 activates STAT3 but not STAT5, distinguishing the downstream signaling of these cytokines. Immunoprecipitation, Western blot for phosphotyrosine, EMSA (DNA-binding assays for STAT complexes) Proceedings of the National Academy of Sciences of the United States of America High 7568001
1996 The IL-15 mRNA contains 10 upstream AUGs in its 5′ UTR that function as negative regulators of translation. An HTLV-I R-region/IL-15 chimeric mRNA that lacks most upstream AUGs is translated much more efficiently, demonstrating that IL-15 protein expression is regulated post-transcriptionally at the level of mRNA translation. RT-PCR characterization of mRNA isoforms, translational analysis comparing upstream AUG content, analysis of HTLV-I fusion transcript Journal of leukocyte biology High 8613692
2000 CD8+ memory-phenotype T cells undergo slow homeostatic division in vivo that requires IL-15; this division is markedly increased by inhibition of IL-2, showing that IL-15 and IL-2 exert opposing control over CD8+ memory T cell homeostasis. In vivo proliferation assays in IL-15-deficient mice and IL-2 inhibition experiments; adoptive transfer system Science High 10784451
2003 IL-15Rα is not required for IL-15-induced proliferation or pro-survival effects on CD8+ T cells, but greatly enhances sensitivity to low concentrations of IL-15; the β and γ chains of IL-15R are absolutely required for both proliferative and pro-survival effects. IL-15 promotes survival of both naive and memory CD8+ T cells via upregulation of Bcl-2. In vitro survival and proliferation assays with IL-15Rα-deficient and β/γ-chain-deficient cells; Bcl-2 and Bcl-xL expression analysis Journal of immunology High 12734346
2003 IL-15 is the dominant survival signal for peripheral NK cells, maintaining them via upregulation of the anti-apoptotic factor Bcl-2. MHC class I molecules do not regulate NK cell survival or homeostatic expansion. Adoptive transfer of NK cells into IL-15-deficient hosts; Bcl-2 expression analysis; NK cell survival assays Blood High 12586624
2003 SOCS1 is an essential negative regulator of IL-15 receptor signaling in CD8+ thymocytes. In SOCS1-deficient CD8+ thymocytes, IL-15 selectively induces sustained STAT5 phosphorylation, massive proliferation, and strong upregulation of Bcl-xL and CD44, demonstrating that SOCS1 attenuates IL-15 signaling in a cell-type-specific manner. SOCS1−/− and SOCS1−/−IFNγ−/− mouse models; fetal thymic organ culture; intrathymic transfer; STAT5 phosphorylation assays; proliferation assays Blood High 12907450
2003 Murine mast cells express three novel IL-15Rα isoforms generated by alternative splicing (lacking exon 4; exons 3 and 4; or exons 3, 4, and 5). These isoforms localize to the Golgi, ER, perinuclear space, and cell membrane, bind IL-15 with high affinity, and mediate signaling through phosphorylation of STAT3, STAT5, STAT6, JAK2, and Syk kinase. RT-PCR, sequencing, transient transfection in COS-7 cells, glycosylation analysis, IL-15 binding assay in BA/F3 transfectants, STAT/JAK phosphorylation analysis Journal of immunology Medium 12734349
2005 The sushi domain of soluble IL-15Rα acts as a potent agonist of IL-15 action through the IL-15Rβ/γ heterodimer by enhancing IL-15 binding and biological effects, whereas the full extracellular domain acts as an antagonist. Fusion proteins (RLI) linking IL-15 to the sushi domain are hyperagonists that bind IL-15Rβ/γ, are internalized, and induce potent lymphocyte proliferation and survival. Recombinant protein production, binding assays, cell proliferation assays, apoptosis assays, receptor internalization studies The Journal of biological chemistry High 16284400
2006 Binding of soluble IL-15Rα to IL-15 markedly enhances biological activity, rapidly inducing strong expansion of memory-phenotype CD8+ T cells and NK cells in vivo. This suggests that IL-15Rα binding induces a conformational change that potentiates IL-15 recognition by the βγc receptor. In contrast, IL-2 function is inhibited by binding to soluble IL-2Rα. In vivo injection of IL-15/IL-15Rα complexes in mice; flow cytometry of lymphocyte populations Proceedings of the National Academy of Sciences of the United States of America High 16757567
2006 IL-15 plays a critical role in protecting effector CD8+ T cells from apoptosis during the contraction phase following microbial infection, via induction of Bcl-2 expression. Enforced Bcl-2 expression rescues effector T cells from death in IL-15-KO mice, placing Bcl-2 downstream of IL-15 signaling. Adoptive transfer into IL-15 KO and IL-15 transgenic mice, in vivo rIL-15 administration, Bcl-2 transgenic rescue experiment Journal of immunology High 16365444
2006 IL-15 mediates mechanical hypernociception through a sequential pathway: IL-15 → IFN-γ → endothelin-1 (ET-1) via ETA receptor → prostaglandin E2 (PGE2). IL-15 failed to induce hypernociception in IFN-γ−/− mice, and IL-15 induced ET-1 production in an IFN-γ-dependent manner. Mouse peritoneal injection models; IFN-γ−/− mice; pharmacological inhibitors (ETA/ETB antagonists, COX inhibitors); cytokine measurement Proceedings of the National Academy of Sciences of the United States of America Medium 16766656
2006 IL-15-deficient mice lack the CD44hiCD122hi memory-phenotype CD8+ T cell subset, while ITK-deficient mice lack the CD44loCD122lo conventional CD8+ T cell subset; double-KO mice have severe depletion of all CD8+ T cells. These findings establish that IL-15 specifically supports a CD8+ T cell subset with both adaptive and innate immune functions. IL-15−/−, ITK−/−, and IL-15−/−ITK−/− double-KO mouse analysis; flow cytometry; functional assays (TCR and NK receptor stimulation) Proceedings of the National Academy of Sciences of the United States of America High 16880398
2007 Intracellular IL-15 stored in mast cells acts as a specific negative transcriptional regulator of the mast cell chymase MCP-2 gene. Deletion of IL-15 markedly increases chymase activity and neutrophil-recruiting chemokine processing, leading to increased bactericidal responses and survival in murine septic peritonitis. Il15 KO mouse model; cecal ligation and puncture (CLP) sepsis model; chymase activity assays; chemokine processing assays; transcriptional analysis Nature medicine High 17643110
2007 IL-15 mediates antigen-induced neutrophil migration by triggering a sequential cytokine cascade: IL-15 induces IL-18 production, which then drives MIP-2, MIP-1α, TNF-α, and leukotriene B4 release to promote neutrophil migration. IL-18−/−, MIP-1α−/−, TNFR1−/−, and 5-LOX−/− mice are resistant to IL-15-induced neutrophil migration. Mouse peritoneal model; IL-18−/−, MIP-1α−/−, TNFR1−/−, 5-LOX−/− KO mice; neutralizing antibodies; cytokine measurement European journal of immunology High 17979156
2008 Dendritic cells (DCs) transpresent IL-15 to memory CD8+ T cells, driving their homeostatic proliferation. A transgenic model restricting IL-15 transpresentation to DCs shows that DC-mediated transpresentation is largely sufficient for normal homeostatic proliferation of established memory CD8+ T cells, preferentially supporting a KLRG-1+CD27− subset. IL-15Rα transgenic mouse model limiting transpresentation to DCs; adoptive transfer; flow cytometry; viral infection model Blood High 18812469
2011 IL-15 regulates NKT cell survival through Bcl-xL (but not other Bcl-2 family members), and controls thymic stage 2 to stage 3 lineage progression and terminal NKT cell differentiation by regulating T-bet (Tbx21) expression, which in turn controls IFN-γ, granzyme A/C, and NK receptor expression. IL-15 KO mouse analysis; in vitro IL-15 stimulation; global gene expression profiling; validation by RT-PCR and flow cytometry; Bcl-xL-specific dependency assessment Journal of immunology High 22084435
2011 Different developmental events of NK cells (homeostasis, mature differentiation, Ly49 acquisition, and effector function) require quantitatively different levels of IL-15 trans-presentation. The level of IL-15Rα on accessory cells (both bone marrow-derived DCs and radiation-resistant stromal cells) directly determines the level of STAT5 phosphorylation in NK cells and the degree of each developmental outcome; the IL-15Rα on NK cells themselves is not required. IL-15Rα knockin/transgenic mice with graded IL-15Rα expression; STAT5 phosphorylation assays in NK cells cocultured with DCs; in vivo NK cell development analysis Journal of immunology High 21715685
2012 Crystal structures of the IL-15–IL-15Rα–IL-2Rβ–γc quaternary complex show that IL-15 binds IL-2Rβ and γc in a geometry nearly indistinguishable from IL-2 in the IL-2–IL-2Rα–IL-2Rβ–γc complex. IL-15Rα substantially increases the affinity of IL-15 for IL-2Rβ (allosteric effect required for IL-15 trans-signaling). The functional differences between IL-2 and IL-15 in lymphocytes result from disparate receptor affinities rather than distinct signaling geometries. X-ray crystallography of quaternary receptor complex; surface plasmon resonance for affinity measurements; functional signaling assays in lymphocytes Nature immunology High 23104097
2013 IL-15 promoter activity is restricted to myeloid lineages during hematopoiesis; lymphoid cells extinguish IL-15 expression in a stepwise, Notch-dependent manner during development. Hematopoietic stem cells (LSK) express high IL-15. IL-15 expression is regulated at the pre-DC branch point, generating IL-15+CD8+ and IL-15−/lowCD8− DC subsets. IL-15 reporter transgenic mouse; flow cytometry of defined hematopoietic populations; Notch inhibition experiments Journal of immunology Medium 23966624
2015 Type I IFN-driven IL-15 expression during viral infection drives memory CD8+ T cells into rapid cell-cycle progression via mTORC1 (independently of antigen re-exposure), providing a proliferative advantage. IL-15 prepares memory cells for faster division upon subsequent antigen encounter. Murine viral infection and peptide immunization models; IL-15 KO mice; mTORC1 inhibitor (rapamycin) treatment; BrdU incorporation cell-cycle analysis The Journal of clinical investigation High 26241055
2016 IL-15 activates the JAK3/STAT3 signaling pathway in skeletal muscle cells to stimulate glucose uptake and GLUT4 translocation to the plasma membrane. IL-15 does not activate Akt, AMPK, JAK1, or STAT5 in this context. STAT3 inhibition abolishes IL-15-induced glucose uptake, and HIF1α expression is dependent on IL-15-induced STAT3 activation. C2C12 differentiated myotube treatment with IL-15; phosphorylation assays (Western blot); co-immunoprecipitation of JAK3/STAT3; STAT3 nuclear translocation imaging; GLUT4 translocation assay; STAT3 inhibitor rescue experiments Frontiers in physiology Medium 28066259
2018 Ligation of NKG2D by ULBP2 (but not MICA) induces enlargement of NKG2D nanoclusters at the NK cell surface and causes the cytokine receptor subunit IL-2/IL-15Rβ to coalesce into these nanoclusters, enabling cooperative signaling between NKG2D and the IL-15 receptor. This nanoscale receptor co-organization amplifies NK cell responses to ULBP2 + IL-15. Superresolution (dSTORM) microscopy on primary human NK cells; functional NK cell activation assays; IL-15Rα-coated surface trans-presentation experiments Science signaling High 29636390
2018 Sorafenib reduces expression of the transcription factor ATF4 in FLT3-ITD+ AML cells, thereby relieving ATF4-mediated negative regulation of IRF7, which enhances IL-15 transcription. IRF7 knockdown or ATF4 overexpression abolishes sorafenib-induced IL-15 production, defining the ATF4–IRF7–IL-15 transcriptional axis. siRNA knockdown of IRF7; ATF4 overexpression; Western blot; chromatin state analysis; IL-15 ELISA; in vitro and in vivo mouse AML models Nature medicine High 29431743
2019 IL-15 expansion of CAR-T cells reduces mTORC1 activity, decreases glycolytic enzyme expression, and improves mitochondrial fitness, preserving a stem cell memory (Tscm; CD62L+CD45RA+CCR7+) phenotype. Culturing CAR-T cells in rapamycin (mTORC1 inhibitor) recapitulates the IL-15 effect, demonstrating that IL-15-mediated mTORC1 suppression is responsible for maintaining the Tscm phenotype. In vitro CAR-T expansion with IL-15 vs IL-2; rapamycin treatment; mTORC1 activity assays; metabolic profiling; phenotypic flow cytometry; in vivo xenograft tumor model Cancer immunology research High 30890531
2019 De novo designed protein Neo-2/15 mimics IL-2 and IL-15 by binding to IL-2Rβγc but lacking binding sites for IL-2Rα or IL-15Rα. Crystal structures of Neo-2/15 alone and in complex with IL-2Rβγc confirm the designed model and show the protein elicits downstream cell signaling independently of the private α chains. Computational de novo protein design; X-ray crystallography of Neo-2/15 alone and in IL-2Rβγc complex; cell signaling assays; in vivo mouse tumor models Nature High 30626941
2020 In a mouse model of coeliac disease, overexpression of IL-15 is required simultaneously in both the gut epithelium and lamina propria to drive villous atrophy. CD4+ T cells and HLA-DQ8 license cytotoxic CD8+ T cells to mediate intestinal epithelial cell lysis; IFN-γ and TG2 contribute to tissue destruction downstream of IL-15. Transgenic mouse model with compartment-specific IL-15 overexpression (epithelium and/or lamina propria); HLA-DQ8 expression; gluten feeding; histopathology; T cell depletion studies; IFN-γ KO Nature High 32051586
2025 CREM (cyclic AMP response element modulator) is induced in CAR-NK cells by both CAR activation and IL-15 signaling via the PKA–CREB pathway (downstream of ITAM signaling or IL-15). CREM deletion enhances CAR-NK cell effector function in vitro and in vivo and increases resistance to immunosuppression. CREM exerts its regulatory functions through epigenetic reprogramming of CAR-NK cells. Transcriptomic analysis; CREM deletion (genetic KO); PKA/CREB pathway inhibition; epigenetic profiling; in vivo tumor mouse model; CAR-NK rechallenge assays Nature High 40468083

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1994 Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science (New York, N.Y.) 1271 8178155
1994 Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. The EMBO journal 992 8026467
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2004 The human plasma proteome: a nonredundant list developed by combination of four separate sources. Molecular & cellular proteomics : MCP 658 14718574
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2000 Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science (New York, N.Y.) 615 10784451
1995 Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor. The EMBO journal 580 7641685
2012 IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood 526 23160470
2011 Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 510 21300928
2004 IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proceedings of the National Academy of Sciences of the United States of America 490 14762166
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2004 Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs. Proceedings of the National Academy of Sciences of the United States of America 427 15536127
2019 De novo design of potent and selective mimics of IL-2 and IL-15. Nature 412 30626941
2019 IL15 Enhances CAR-T Cell Antitumor Activity by Reducing mTORC1 Activity and Preserving Their Stem Cell Memory Phenotype. Cancer immunology research 379 30890531
2006 Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. Proceedings of the National Academy of Sciences of the United States of America 341 16757567
1995 Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15. Proceedings of the National Academy of Sciences of the United States of America 316 7568001
2016 IL15 Trispecific Killer Engagers (TriKE) Make Natural Killer Cells Specific to CD33+ Targets While Also Inducing Persistence, In Vivo Expansion, and Enhanced Function. Clinical cancer research : an official journal of the American Association for Cancer Research 314 26847056
2003 IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells. Journal of immunology (Baltimore, Md. : 1950) 302 12759422
2017 Transgenic Expression of IL15 Improves Antiglioma Activity of IL13Rα2-CAR T Cells but Results in Antigen Loss Variants. Cancer immunology research 277 28550091
2003 IL-15 promotes the survival of naive and memory phenotype CD8+ T cells. Journal of immunology (Baltimore, Md. : 1950) 276 12734346
2015 Hair follicle-derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma. Nature medicine 274 26479922
2003 IL-15 is an essential mediator of peripheral NK-cell homeostasis. Blood 271 12586624
2010 IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors. The Journal of experimental medicine 260 20142427
2005 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. The Journal of biological chemistry 259 16284400
2015 IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction. Nature reviews. Immunology 251 26567920
2018 Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells. Nature medicine 243 29431743
2017 CD56bright NK cells exhibit potent antitumor responses following IL-15 priming. The Journal of clinical investigation 243 28972539
2007 Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. The Journal of infectious diseases 223 17703412
2018 Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect. JCI insight 214 29415897
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2018 Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo. Science translational medicine 205 30021889
2001 Interleukin 15 skews monocyte differentiation into dendritic cells with features of Langerhans cells. The Journal of experimental medicine 200 11581322
2002 IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response. Journal of immunology (Baltimore, Md. : 1950) 199 12244150
2015 The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. Cancer immunology research 197 25736261
2009 Safety and immunologic effects of IL-15 administration in nonhuman primates. Blood 196 19605850
2020 IL-15 in the Combination Immunotherapy of Cancer. Frontiers in immunology 194 32508818
2012 Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. Nature immunology 194 23104097
2010 IL-7 and IL-21 are superior to IL-2 and IL-15 in promoting human T cell-mediated rejection of systemic lymphoma in immunodeficient mice. Blood 187 20190192
2009 Trans-presentation: a novel mechanism regulating IL-15 delivery and responses. Immunology letters 178 19818367
2020 IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease. Nature 169 32051586
2022 Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy. Trends in immunology 163 36058806
2020 Immunomodulatory Effects of IL-2 and IL-15; Implications for Cancer Immunotherapy. Cancers 157 33266177
2014 Characterization of the IL-15 niche in primary and secondary lymphoid organs in vivo. Proceedings of the National Academy of Sciences of the United States of America 145 24449915
2011 IL-15 regulates homeostasis and terminal maturation of NKT cells. Journal of immunology (Baltimore, Md. : 1950) 144 22084435
2021 Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities. Journal for immunotherapy of cancer 142 34896980
2021 Optimized gene engineering of murine CAR-T cells reveals the beneficial effects of IL-15 coexpression. The Journal of experimental medicine 139 33156338
2012 IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity. The Journal of clinical investigation 137 22565311
2017 IL-15 super-agonist (ALT-803) enhances natural killer (NK) cell function against ovarian cancer. Gynecologic oncology 111 28236454
1996 Human herpesvirus-6 enhances natural killer cell cytotoxicity via IL-15. The Journal of clinical investigation 108 8617868
2016 IL-15 promotes activation and expansion of CD8+ T cells in HIV-1 infection. The Journal of clinical investigation 103 27322062
2016 IL-15 signaling in NK cell cancer immunotherapy. Current opinion in immunology 100 27835762
2021 Transcription Factors Associated With IL-15 Cytokine Signaling During NK Cell Development. Frontiers in immunology 99 33815365
2006 IL-15 regulates CD8+ T cell contraction during primary infection. Journal of immunology (Baltimore, Md. : 1950) 99 16365444
2010 Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates. Blood 97 20631381
1997 IL-15, an immunomodulator of T cell responses in intracellular infection. Journal of immunology (Baltimore, Md. : 1950) 95 8992997
1996 Intragraft IL-15 transcripts are increased in human renal allograft rejection. Transplantation 95 8781624
2019 Mechanisms involved in IL-15 superagonist enhancement of anti-PD-L1 therapy. Journal for immunotherapy of cancer 91 30898149
2008 Dendritic cells drive memory CD8 T-cell homeostasis via IL-15 transpresentation. Blood 91 18812469
2015 Inflammatory IL-15 is required for optimal memory T cell responses. The Journal of clinical investigation 90 26241055
2012 Regulating the immune system via IL-15 transpresentation. Cytokine 89 22795955
2007 IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities. Nature medicine 89 17643110
2013 The biology of IL-15: implications for cancer therapy and the treatment of autoimmune disorders. The journal of investigative dermatology. Symposium proceedings 87 24326545
2015 IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ. Journal of immunology (Baltimore, Md. : 1950) 86 26216888
1995 Ultraviolet B radiation up-regulates the expression of IL-15 in human skin. Journal of immunology (Baltimore, Md. : 1950) 84 7594612
2018 IL-15 Overcomes Hepatocellular Carcinoma-Induced NK Cell Dysfunction. Frontiers in immunology 82 29867983
2002 IL-15, a survival factor for kidney epithelial cells, counteracts apoptosis and inflammation during nephritis. The Journal of clinical investigation 82 11927622
1997 IL-15 is chemotactic for natural killer cells and stimulates their adhesion to vascular endothelium. Journal of leukocyte biology 81 9201264
2016 IL-15 Activates the Jak3/STAT3 Signaling Pathway to Mediate Glucose Uptake in Skeletal Muscle Cells. Frontiers in physiology 80 28066259
2012 Functions of IL-15 in anti-viral immunity: multiplicity and variety. Cytokine 80 22704694
2006 ULBPs, human ligands of the NKG2D receptor, stimulate tumor immunity with enhancement by IL-15. Blood 80 16621962
2010 IL-15 induces CD8+ T cells to acquire functional NK receptors capable of modulating cytotoxicity and cytokine secretion. Immunobiology 79 20956026
2021 Tumor-conditional IL-15 pro-cytokine reactivates anti-tumor immunity with limited toxicity. Cell research 74 34376814
2010 Role of IL-15 in immune-mediated and infectious diseases. Cytokine & growth factor reviews 74 21074481
2002 IL-15 is a growth factor and an activator of CD8 memory T cells. Annals of the New York Academy of Sciences 74 12538153
2006 ITK and IL-15 support two distinct subsets of CD8+ T cells. Proceedings of the National Academy of Sciences of the United States of America 72 16880398
2017 IL-15 promotes human myogenesis and mitigates the detrimental effects of TNFα on myotube development. Scientific reports 70 29021612
2001 Expression of IL-15 in inflammatory pulmonary diseases. The Journal of allergy and clinical immunology 69 11742275
2012 IL-15 positively regulates IL-21 production in celiac disease mucosa. Mucosal immunology 68 22785229
2015 Oncolytic virus expressing RANTES and IL-15 enhances function of CAR-modified T cells in solid tumors. Oncoimmunology 67 25949885
2020 Efficient Colorectal Cancer Gene Therapy with IL-15 mRNA Nanoformulation. Molecular pharmaceutics 66 32787272
2020 Biological effects of IL-15 on immune cells and its potential for the treatment of cancer. International immunopharmacology 66 33383444
2007 IL-15 mediates antigen-induced neutrophil migration by triggering IL-18 production. European journal of immunology 63 17979156
2020 Inducible MyD88/CD40 synergizes with IL-15 to enhance antitumor efficacy of CAR-NK cells. Blood advances 60 32384544
2006 IL-15 mediates immune inflammatory hypernociception by triggering a sequential release of IFN-gamma, endothelin, and prostaglandin. Proceedings of the National Academy of Sciences of the United States of America 60 16766656
2009 A programmed switch from IL-15- to IL-2-dependent activation in human NK cells. Journal of immunology (Baltimore, Md. : 1950) 58 19414780
2023 Biomimetic nanovaccine-mediated multivalent IL-15 self-transpresentation (MIST) for potent and safe cancer immunotherapy. Nature communications 57 37875481
2002 Increased IL-15 production of muscle cells in polymyositis and dermatomyositis. International immunology 55 12147628
1996 IL-15: the role of translational regulation in their expression. Journal of leukocyte biology 55 8613692
2007 IL-15 is required for sustained lymphopenia-driven proliferation and accumulation of CD8 T cells. Journal of immunology (Baltimore, Md. : 1950) 53 17579029
2013 Transcriptional regulation of IL-15 expression during hematopoiesis. Journal of immunology (Baltimore, Md. : 1950) 52 23966624
2020 Inflammescent CX3CR1+CD57+CD8+ T cells are generated and expanded by IL-15. JCI insight 51 32369455
2002 Critical role for IL-15 in innate immunity. Current molecular medicine 51 12108948
2006 EBV-associated mononucleosis leads to long-term global deficit in T-cell responsiveness to IL-15. Blood 50 16543467
2010 Monocytes differentiated with IL-15 support Th17 and Th1 responses to wheat gliadin: implications for celiac disease. Clinical immunology (Orlando, Fla.) 48 20153259
2007 Airway epithelial IL-15 transforms monocytes into dendritic cells. American journal of respiratory cell and molecular biology 47 17363780
2005 Two interleukin (IL)-15 homologues in fish from two distinct origins. Molecular immunology 47 16055191
2018 Tissue maintenance of CMV-specific inflationary memory T cells by IL-15. PLoS pathogens 46 29652930
2011 IL-15 delays suppression and fails to promote immune reconstitution in virally suppressed chronically SIV-infected macaques. Blood 44 21757617
2012 An antibody fusion protein for cancer immunotherapy mimicking IL-15 trans-presentation at the tumor site. Molecular cancer therapeutics 42 22491823
2021 Heterodimeric IL-15 in Cancer Immunotherapy. Cancers 41 33671252
2008 Effects of IL-15 on rat brown adipose tissue: uncoupling proteins and PPARs. Obesity (Silver Spring, Md.) 41 18239634
2018 Epithelial IL-15 Is a Critical Regulator of γδ Intraepithelial Lymphocyte Motility within the Intestinal Mucosa. Journal of immunology (Baltimore, Md. : 1950) 40 29884699
2024 IL-15 in T-Cell Responses and Immunopathogenesis. Immune network 39 38455459
2011 Different NK cell developmental events require different levels of IL-15 trans-presentation. Journal of immunology (Baltimore, Md. : 1950) 38 21715685
1999 Molecular and functional characterization of chicken IL-15. Developmental and comparative immunology 38 10227483
2018 IL-15 regulates fibrosis and inflammation in a mouse model of chronic pancreatitis. American journal of physiology. Gastrointestinal and liver physiology 37 30212254
2011 RSV infection modulates IL-15 production and MICA levels in respiratory epithelial cells. The European respiratory journal 37 21852331
2010 Characterization and IL-15 dependence of NK cells in humanized mice. Immunobiology 37 20627447
2003 Suppressor of cytokine signaling 1 attenuates IL-15 receptor signaling in CD8+ thymocytes. Blood 37 12907450
2014 Protective effect of myokine IL-15 against H2O2-mediated oxidative stress in skeletal muscle cells. Molecular biology reports 36 25103021
2003 Mast cells express novel functional IL-15 receptor alpha isoforms. Journal of immunology (Baltimore, Md. : 1950) 36 12734349
2011 IL-15 promotes osteoclastogenesis via the PLD pathway in rheumatoid arthritis. Immunology letters 34 21620893
2008 IL-15 as memory T-cell adjuvant for topical HIV-1 DermaVir vaccine. Vaccine 34 18462844
2020 IL-15 Improves Aging-Induced Persistent T Cell Exhaustion in Mouse Models of Repeated Sepsis. Shock (Augusta, Ga.) 33 31935201
2013 IL-15 is required for postexercise induction of the pro-oxidative mediators PPARδ and SIRT1 in male mice. Endocrinology 33 24169546
2006 IL-15 an immunoregulatory and anti-cancer cytokine. Recent advances. Journal of experimental & clinical cancer research : CR 33 17310844
2022 IL-15 blockade and rapamycin rescue multifactorial loss of factor VIII from AAV-transduced hepatocytes in hemophilia A mice. Molecular therapy : the journal of the American Society of Gene Therapy 32 35821634
2017 IL-2 and IL-15 dependent thymic development of Foxp3-expressing regulatory T lymphocytes. Protein & cell 32 28540653
2018 A nanoscale reorganization of the IL-15 receptor is triggered by NKG2D in a ligand-dependent manner. Science signaling 31 29636390
2017 Regulatory effects of IL-15 on allergen-induced airway obstruction. The Journal of allergy and clinical immunology 31 28606589
2010 Aggravated experimental autoimmune encephalomyelitis in IL-15 knockout mice. Experimental neurology 30 20070942
2002 Decreased IL-15 may contribute to elevated IgE and acute inflammation in atopic dermatitis. Journal of immunology (Baltimore, Md. : 1950) 30 11751999
2001 CD40 ligation enhances IL-15 production by tubular epithelial cells. Journal of the American Society of Nephrology : JASN 30 11134253
2012 Immunotherapeutic applications of IL-15. Immunotherapy 29 23046239
2025 CREM is a regulatory checkpoint of CAR and IL-15 signalling in NK cells. Nature 28 40468083
2022 A very long-acting IL-15: implications for the immunotherapy of cancer. Journal for immunotherapy of cancer 28 35101947
2011 The role of IL-15 in central nervous system disorders. Acta neurologica Scandinavica 28 21615353