Affinage

IL2

Interleukin-2 · UniProt P60568

Round 2 corrected
Length
153 aa
Mass
17.6 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-2 is a secreted cytokine that orchestrates peripheral immune homeostasis by driving T-cell proliferation, directing helper T-cell fate decisions, sustaining regulatory T-cell function, and bridging adaptive and innate immunity through NK cell activation. IL-2 signals through a trimeric receptor (IL-2Rα/β/γc), where γc is essential for receptor internalization and high-affinity binding (PMID:1631559); ligand engagement activates Jak1 (via the IL-2Rβ serine-rich region) and Jak3 (via γc) to phosphorylate STAT5a/b redundantly, which in turn modulates cytokine receptor expression (IL-12Rβ2, IL-4Rα, gp130) to broadly regulate Th1, Th2, and Th17 lineage commitment (PMID:7973659, PMID:10072077, PMID:21516110). IL-2 also activates PI3K/AKT signaling, negatively regulated by PTEN and SOCS/CIS family proteins, and signal strength is tuned by PGE2-mediated downregulation of γc on tumor-infiltrating lymphocytes, linking prostaglandin metabolism to IL-2 sensing and ferroptotic vulnerability (PMID:10851055, PMID:16917540, PMID:38658764). IL-2-deficient mice are not impaired in thymic T-cell development but develop inflammatory bowel disease resembling ulcerative colitis, establishing IL-2 as essential for peripheral tolerance rather than lymphocyte ontogeny (PMID:1830926, PMID:8402910).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1983 High

    Molecular cloning of the human IL-2 cDNA established the primary structure of the protein and proved that the cloned sequence was sufficient for biological activity, enabling all subsequent structure–function work.

    Evidence cDNA cloning, sequencing, and functional expression in COS cells

    PMID:6403867

    Open questions at the time
    • post-translational modifications not characterized
    • receptor identity unknown at this point
  2. 1988 High

    Identification of distinct antigen receptor response elements (sites A, D, E) and their cognate transcription factors in the IL-2 enhancer revealed how TCR engagement transcriptionally activates IL-2 independently of PKC, establishing the promoter architecture governing inducible IL-2 expression.

    Evidence Deletion mutant analysis, gel-shift assays, and reporter gene assays in T cells

    PMID:3260003

    Open questions at the time
    • identity of all trans-acting factors not resolved
    • chromatin-level regulation not addressed
  3. 1991 High

    IL-2 knockout mice demonstrated that IL-2 is dispensable for thymic T-cell development but essential for peripheral immune homeostasis, reframing IL-2 from a T-cell growth factor to a tolerance regulator.

    Evidence Gene-targeted IL-2-null mice with flow cytometry, proliferation assays, and immunoglobulin measurements

    PMID:1830926

    Open questions at the time
    • mechanism of peripheral tolerance breakdown not defined
    • contribution of Tregs not yet recognized
  4. 1992 High

    Discovery of γc as the third IL-2R subunit resolved how high-affinity and intermediate-affinity receptor forms assemble and showed that γc is required for ligand-induced receptor internalization, completing the receptor architecture.

    Evidence cDNA cloning, receptor reconstitution in fibroblastoid cells, binding and internalization assays

    PMID:1631559

    Open questions at the time
    • signaling events downstream of γc not yet mapped
    • shared use of γc by other cytokines not explored here
  5. 1993 High

    Mapping of IL-2Rβ cytoplasmic domains identified a serine-rich region for mitogenic signaling and an acidic region that recruits p56lck, linking IL-2R to Src-family kinase activation and immediate-early gene induction, while IL-2-null mice developed ulcerative colitis-like disease, cementing IL-2's role in mucosal tolerance.

    Evidence IL-2Rβ deletion mutants with co-IP and kinase assays; IL-2 KO mice with histopathology and autoantibody detection

    PMID:8402910 PMID:8476561

    Open questions at the time
    • identity of kinases directly activated by the serine-rich region not yet known
    • Treg mechanism of tolerance not established
  6. 1994 High

    Demonstrating that Jak1 binds IL-2Rβ and Jak3 binds γc—and that Jak3 reconstitution restores IL-2 responsiveness—established the proximal kinase pair that initiates IL-2 signaling cascades.

    Evidence Co-IP domain mapping plus reconstitution of Jak3 in Jak3-deficient fibroblasts

    PMID:7973659

    Open questions at the time
    • temporal dynamics of Jak1 vs Jak3 activation unclear
    • downstream substrate hierarchy not defined
  7. 1998 Medium

    Identification of ZEB as a repressor of IL-2 transcription in Th2 cells via the NRE-A element revealed a lineage-specific negative regulatory mechanism silencing IL-2 during T-helper differentiation.

    Evidence Promoter deletion analysis, gel-shift assays, reporter assays in differentiated Th cells

    PMID:9574548

    Open questions at the time
    • in vivo relevance of ZEB-mediated repression not confirmed with knockout
    • interaction with other promoter-bound factors not mapped
  8. 1999 High

    Stat5a/b double-knockout mice proved that STAT5 is the essential, redundant downstream effector of IL-2-induced T-cell proliferation and cell-cycle entry, phenocopying IL-2Rβ deficiency.

    Evidence Stat5a/b double-KO mice with proliferation assays, gene expression analysis, and flow cytometry

    PMID:10072077

    Open questions at the time
    • STAT5-independent IL-2 signaling outputs not fully cataloged
    • direct STAT5 transcriptional targets in T cells not genome-wide mapped at this point
  9. 2000 High

    Integration of biochemical and genetic data consolidated the JAK-STAT5 and PI3K/AKT axes as the principal IL-2 signaling pathways, with CIS/SOCS proteins identified as negative feedback regulators of STAT5 activation.

    Evidence Biochemical signaling assays, gene-targeting analyses, cytokine dose-response studies

    PMID:10851055

    Open questions at the time
    • relative contribution of each SOCS family member not individually resolved
    • metabolic consequences of PI3K/AKT activation downstream of IL-2 not yet defined
  10. 2006 High

    PTEN was established as a key negative regulator of IL-2R-driven PI3K signaling in Tregs, with its deletion enabling IL-2-alone-driven Treg expansion, revealing a tunable brake on the IL-2/PI3K/AKT axis that governs Treg homeostasis.

    Evidence Conditional PTEN KO in Tregs with reciprocal gain/loss-of-function experiments, PI3K signaling, and in vivo colitis model

    PMID:16917540

    Open questions at the time
    • PTEN interaction with SOCS-mediated STAT5 regulation not addressed
    • Treg-specific vs pan-T-cell PTEN effects not fully delineated
  11. 2011 High

    IL-2 was shown to broadly control helper T-cell fate by STAT5-dependent modulation of cytokine receptor chains (IL-12Rβ2, IL-4Rα, gp130), promoting Th1 and Th2 while suppressing Th17 differentiation—redefining IL-2 as a master regulator of T-helper lineage commitment.

    Evidence IL-2 KO T cells, retroviral transduction rescue, cytokine receptor expression profiling, human T-cell IL-2 blockade

    PMID:21516110

    Open questions at the time
    • epigenetic mechanisms linking STAT5 to receptor gene regulation not resolved
    • quantitative thresholds of IL-2 needed for each lineage decision unknown
  12. 2012 High

    Structural and functional characterization of 'super-2' (an engineered high-affinity IL-2Rβ binder) demonstrated that stabilizing the CD25-bound conformation of IL-2 eliminates CD25 dependence, biasing signaling toward CD8+ effector expansion over Treg expansion—establishing the principle of receptor-biased IL-2 engineering.

    Evidence Crystal structures of free and receptor-bound superkine, molecular dynamics, signaling and proliferation assays, in vivo tumor models

    PMID:22446627

    Open questions at the time
    • long-term immunological consequences of bypassing CD25 not assessed
    • toxicity mechanisms beyond pulmonary edema not explored
  13. 2016 High

    Chemical genetic dissection revealed two temporally distinct JAK3-dependent waves of STAT5 phosphorylation during IL-2-driven proliferation, with the second wave essential for cyclin expression and S-phase entry, refining the kinetic model of IL-2 signaling.

    Evidence Covalent JAK3 inhibitor with inhibitor-resistant C905S mutant rescue, time-resolved STAT5 phosphorylation, cell-cycle analysis

    PMID:27018889

    Open questions at the time
    • molecular basis for differential JAK3 sensitivity of the two waves unclear
    • whether this biphasic pattern applies to all T-cell subsets untested
  14. 2018 High

    In vivo fate-mapping showed that IL-2-producing CD4+ T cells receiving the strongest TCR signals become TFH cells, while non-producers receiving IL-2 in trans become non-TFH effectors, establishing a paracrine delivery model for IL-2-driven fate divergence.

    Evidence IL-2 reporter mice, fate-mapping, infection models, adoptive transfer

    PMID:30213884

    Open questions at the time
    • molecular mechanism of trans-delivery (synapse vs diffusion) not resolved
    • generalizability beyond infection models not tested
  15. 2019 High

    De novo computational design of Neo-2/15, a synthetic IL-2/IL-15 mimetic with no sequence or structural homology to natural cytokines, demonstrated that IL-2Rβγc engagement alone—without any IL-2Rα contact—suffices for potent signaling and superior antitumor activity with reduced toxicity.

    Evidence Crystal structures (free and receptor-bound), binding assays, cell signaling, mouse melanoma and colon cancer models

    PMID:30626941

    Open questions at the time
    • human clinical translation and immunogenicity not assessed
    • whether Neo-2/15 engages non-canonical IL-2 signaling pathways unknown
  16. 2021 High

    The IL-2 partial agonist H9T showed that attenuated STAT5 signaling preserves TCF-1 expression and mitochondrial fitness in CD8+ T cells, generating stem-cell-like effectors with enhanced antitumor activity—demonstrating that signal strength, not just pathway identity, determines T-cell differentiation outcome.

    Evidence Engineered IL-2 variant with STAT5 signaling, epigenetic profiling, metabolic assays, in vivo tumor models

    PMID:34526724

    Open questions at the time
    • epigenetic mechanisms linking attenuated STAT5 to TCF-1 maintenance not defined
    • durability of stem-like state after withdrawal of H9T not tested
  17. 2023 Medium

    Discovery of a non-canonical IL-2 signaling mode through CD25 and a chemokine receptor pathway—distinct from JAK1/3-STAT5—that specifically enhances Treg suppressive function revealed an unexpected layer of signaling complexity exploitable for selective immunomodulation.

    Evidence Biased anti-CD25 antibody, heparan sulfate treatment, engineered IL-2 immunocytokine, EAE model, Treg suppression assays

    PMID:37598341

    Open questions at the time
    • identity and mechanism of the chemokine receptor component not fully defined
    • whether this pathway operates in human Tregs in vivo not demonstrated
    • independent replication needed
  18. 2024 High

    PGE2 was shown to impair IL-2 sensing in tumor-infiltrating CD8+ T cells by EP2/EP4-mediated downregulation of γc, disrupting IL-2Rβ–γc dimer assembly and causing mTOR-PGC1α failure, oxidative stress, and ferroptosis—linking the tumor prostaglandin microenvironment directly to IL-2 signaling resistance.

    Evidence EP2/EP4 pharmacology, γc surface expression and dimer assembly assays, mTOR/PGC1α/ROS/ferroptosis assays, adoptive cell transfer models

    PMID:38658764

    Open questions at the time
    • whether PGE2-driven γc loss affects other γc-dependent cytokines in TILs not tested
    • mechanism of EP2/EP4-mediated γc transcriptional or post-translational downregulation not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: (1) the structural and kinetic basis for non-canonical IL-2 signaling through CD25/chemokine receptor pathways; (2) how IL-2 signal strength is decoded epigenetically to produce distinct T-cell differentiation and metabolic programs; and (3) whether therapeutic IL-2 variants can be designed to independently tune STAT5 vs PI3K/AKT vs non-canonical outputs for precision immunotherapy.
  • no structural model of the non-canonical signaling complex exists
  • genome-wide STAT5 target gene sets in specific T-cell subsets at defined IL-2 concentrations not available
  • clinical translation data for biased IL-2 variants remain limited

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 6 GO:0140110 transcription regulator activity 3
Partners
IL2RAIL2RBIL2RGJAK1JAK3PTENSTAT5ASTAT5B

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1983 The human IL-2 cDNA encodes a 153-amino-acid polypeptide including a putative signal sequence; expression of this cDNA in COS cells produced biologically active IL-2, establishing the primary structure of the protein. cDNA cloning, sequencing, and expression in COS cells Nature High 6403867
1988 The IL-2 enhancer contains distinct antigen receptor response elements (sites A, D, E) that are required for maximal IL-2 induction; site E binds an inducible nuclear factor (NF-IL-2E) and site A binds a constitutive T-cell factor (NF-IL-2A); these elements respond to antigen receptor signals independently of PKC stimulation. Deletion mutant analysis, gel-shift/DNA binding assays, reporter gene assays in T cells Molecular and cellular biology High 3260003
1991 IL-2-deficient mice generated by gene targeting develop normally with respect to thymocyte and peripheral T-cell subset composition, but exhibit reduced polyclonal in vitro T-cell responses and dramatic changes in serum immunoglobulin isotype levels, demonstrating that IL-2 is not required for T-cell development but is required for normal peripheral immune homeostasis. Gene targeting (knockout mice), flow cytometry, in vitro proliferation assays, immunoglobulin measurement Nature High 1830926
1992 The gamma chain (γc) of the IL-2 receptor was identified as a third subunit necessary for formation of high-affinity (αβγ heterotrimer) and intermediate-affinity (βγ heterodimer) IL-2 receptors; γc is required for IL-2-induced receptor internalization, as α and β chains alone are insufficient. cDNA cloning, receptor reconstitution in murine fibroblastoid cells, binding assays, internalization assays Science High 1631559
1993 The IL-2 receptor β chain (IL-2Rβ) contains at least two distinct cytoplasmic signaling regions: a 'serine-rich' region required for mitotic signaling and an 'acidic' region that physically associates with p56lck (a Src-family PTK) and activates it upon IL-2 stimulation, linking IL-2R to c-fos/c-jun and c-myc induction. IL-2Rβ cytoplasmic domain deletion mutants expressed in BAF-B03 cells, co-immunoprecipitation of p56lck, in vitro kinase assays Annual review of immunology High 8476561
1993 IL-2-deficient mice develop an inflammatory bowel disease with clinical and histological similarity to ulcerative colitis, characterized by activated T and B cells, elevated immunoglobulin secretion, and anti-colon antibodies, demonstrating a primary role of IL-2 in preventing aberrant immune responses to intestinal antigens. IL-2 knockout mice, histopathology, flow cytometry, immunoglobulin assays, autoantibody detection Cell High 8402910
1994 Jak1 and Jak3 kinases are selectively associated with IL-2 receptor subunits: Jak1 binds the serine-rich region of IL-2Rβ and Jak3 binds the C-terminal region of IL-2Rγ; both associations are required for IL-2 signaling, and Jak3-negative cells reconstituted with IL-2R components only become IL-2-responsive upon addition of Jak3 cDNA. Co-immunoprecipitation, domain-mapping with mutant receptor subunits, reconstitution in Jak3-deficient fibroblasts Science High 7973659
1999 Stat5a and Stat5b are essential, redundant mediators of IL-2-induced T-cell proliferation and cell cycle progression; Stat5a/b double-knockout mice have peripheral T cells that fail to proliferate or express cell-cycle genes in response to IL-2, and additionally lack NK cells and develop splenomegaly resembling IL-2Rβ-deficient mice. Stat5a/b double-knockout mice, proliferation assays, gene expression analysis, flow cytometry Immunity High 10072077
1998 ZEB, a zinc finger E-box binding transcription factor, represses IL-2 gene transcription in differentiated Th2 cells by binding to a negative regulatory element (NRE-A) in the IL-2 promoter. Promoter deletion analysis, gel-shift assays, reporter gene assays, Th cell differentiation experiments Journal of immunology Medium 9574548
2000 IL-2 signaling activates the JAK-STAT pathway (particularly Stat5a/Stat5b) and other pathways including PI3K/AKT; negative regulation of IL-2-induced Stat5 activation is mediated by CIS/SOCS/SSI family proteins. Biochemical in vitro studies, gene-targeting analyses of Stat5a/Stat5b, cytokine signaling assays Oncogene High 10851055
2000 IL-2 directly induces a unique signaling pattern in naive resting CD8+ T cells (TCR-independent): strong LCK/JAK3-dependent PI3K/AKT pathway activation with little involvement of STAT5, NF-κB, or calcineurin/NFAT, resulting in proliferation and selective expression of eomesodermin and differentiation into central memory cells. Purified naive CD8+ T cell culture with IL-2 in absence of Ag/APC, signaling pathway inhibitors, flow cytometry, adoptive transfer Journal of immunology Medium 24166977
2001 CD28 translocation to lipid rafts is required for costimulation of IL-2 production; all tyrosine-phosphorylated CD28 and CD28 associated with PI3K localize in lipid raft fractions, and targeting the CD28 cytoplasmic domain to lipid rafts is sufficient to induce its tyrosine phosphorylation; murine CD28 mutants defective in raft translocation lose the ability to costimulate IL-2. Lipid raft fractionation, co-immunoprecipitation, CD28 cytoplasmic domain targeting constructs, CD28 mutant analysis in Jurkat and peripheral T cells Proceedings of the National Academy of Sciences of the United States of America Medium 15280538
2004 IL-2 suppression of hepatic CYP3A activity in vivo is not a direct effect on hepatocytes but requires Kupffer cells; in hepatocyte/Kupffer cell co-cultures, IL-2 caused 50–70% concentration-dependent suppression of CYP3A activity, whereas hepatocytes alone showed no sustained suppression. Primary human hepatocyte/Kupffer cell co-culture at physiologic ratios, CYP3A activity assays, cytokine dose-response experiments Drug metabolism and disposition Medium 14977871
2006 PTEN is a negative regulator of IL-2 receptor signaling in regulatory T cells: targeted deletion of PTEN allows Treg expansion in response to IL-2 alone by de-repressing PI3K signaling downstream of the IL-2R, whereas PTEN re-expression in PTEN-deficient cells or in activated CD4+ T cells inhibits IL-2-dependent proliferation. Conditional PTEN knockout in Tregs, ex vivo IL-2-driven expansion assays, PI3K signaling measurement, suppression assays, colitis model The Journal of clinical investigation High 16917540
2006 NAB2 is induced by TCR engagement and acts as a co-activator of IL-2 transcription by binding Egr-1 at the IL-2 promoter; NAB2 overexpression enhances IL-2 production, siRNA knockdown markedly inhibits it, and ChIP confirms NAB2 recruitment to the Egr-1 binding site of the IL-2 promoter. siRNA knockdown, overexpression, chromatin immunoprecipitation (ChIP), reporter assays in T cells Journal of immunology Medium 17142725
2009 The crystal structure of the basiliximab Fab in complex with IL-2Rα ectodomain at 2.9 Å resolution reveals that basiliximab uses all six CDR loops to engage a discontinuous epitope spanning the D1 and D2 domains of IL-2Rα, overlapping with most IL-2 contact residues and thereby sterically blocking IL-2 binding to IL-2Rα. X-ray crystallography at 2.9 Å resolution, binding affinity measurements (Kd = 0.14 nM) Journal of immunology High 20032294
2011 IL-2 broadly regulates helper T cell differentiation by modulating cytokine receptor expression via STAT5: IL-2 induces STAT5-dependent expression of IL-12Rβ2 and T-bet to promote Th1 differentiation, regulates Il4ra to promote Th2 differentiation, and inhibits Th17 differentiation by downregulating Il6ra and Il6st (gp130); retroviral transduction of IL-12Rβ2 or Il6st can rescue or augment the respective Th subset differentiation even when IL-2 is present or absent. IL-2 knockout T cells, retroviral transduction, cytokine receptor expression assays, STAT5 reporter, human T cell IL-2 blockade, Th subset differentiation assays Nature immunology High 21516110
2012 The IL-2 'superkine' (super-2), engineered with increased IL-2Rβ binding affinity, structurally mimics the CD25-bound conformation of IL-2 by stabilizing a helix at the IL-2Rβ binding site, eliminating the functional requirement for CD25 while eliciting potent STAT5 phosphorylation, T-cell proliferation, superior CD8+ T-cell expansion, and reduced Treg expansion and pulmonary oedema compared to wild-type IL-2. In vitro evolution, crystal structures of free and receptor-bound superkine, molecular dynamics simulations, STAT5 phosphorylation assays, proliferation assays, in vivo mouse tumor models Nature High 22446627
2016 JAK3 kinase activity is required in two temporally distinct waves during IL-2-driven T cell proliferation: an early wave (sensitive to high JAK3 inhibitor concentrations) and a later, more JAK3-dependent second wave of STAT5 phosphorylation that is essential for cyclin expression and S-phase entry; an inhibitor-resistant JAK3 C905S mutant rescued all effects in isolated T cells and in mice. Selective covalent JAK3 inhibitor, chemical genetic rescue with JAK3 C905S mutant, STAT5 phosphorylation time-course in CD4+ T cells, cell cycle analysis Nature chemical biology High 27018889
2018 IL-2 drives CD4+ T follicular helper (TFH) versus non-TFH fate determination through differential IL-2 production at the single-cell level: IL-2 producers receiving the strongest TCR signals are fated to become TFH cells, and they deliver IL-2 in trans to nonproducer cells fated to become non-TFH cells. IL-2 reporter mice, fate-mapping, in vivo infection models, adoptive transfer experiments Science High 30213884
2018 IL-2 signals via the JAK1/3-STAT5 pathway to regulate T-cell metabolic programs in addition to transcriptional programs; global phosphoproteomic approaches revealed a diverse array of phosphoproteins influenced by IL-2 that shape T cell fate within each subset. Phosphoproteomics, JAK inhibitor studies, metabolic assays, T-cell subset analysis Annual review of immunology Medium 29677473
2019 De novo designed IL-2/IL-15 mimetics (Neoleukin-2/15, Neo-2/15) bind IL-2Rβγc with higher affinity than natural IL-2 and elicit downstream signaling without any IL-2Rα binding site; crystal structures of Neo-2/15 alone and in complex with IL-2Rβγc confirmed the designed topology, and Neo-2/15 showed superior antitumour activity in mouse models with reduced toxicity. Computational protein design, crystal structures (free and receptor-bound), binding assays, cell signaling assays, in vivo mouse melanoma and colon cancer models Nature High 30626941
2021 H9T, an engineered IL-2 partial agonist, promotes CD8+ T cell expansion without terminal differentiation by generating altered (attenuated) STAT5 signaling, sustaining TCF-1 expression, and promoting mitochondrial fitness, resulting in a stem-cell-like T cell state with enhanced antitumour activity in melanoma and ALL mouse models. Engineered IL-2 variant, STAT5 signaling assays, epigenetic profiling, metabolic assays, TCF-1 expression analysis, in vivo mouse tumor models Nature High 34526724
2023 IL-2 can signal through a non-canonical CD25–chemokine receptor pathway (alternative to the canonical JAK1/3-STAT5 axis) to promote the suppressive function of Tregs; biasing IL-2 signaling toward this alternative pathway using a specific anti-CD25 antibody, heparan sulfate, or an engineered IL-2 immunocytokine increases Treg suppressive activity and ameliorates EAE in mice. Biased anti-CD25 antibody, heparan sulfate treatment, engineered IL-2 immunocytokine, EAE mouse model, Treg suppression assays Cell reports Medium 37598341
2024 PGE2, via its receptors EP2 and EP4, inhibits IL-2 sensing in human CD8+ TILs by downregulating the IL-2Rγc chain, causing defective assembly of IL-2Rβ–IL-2Rγc membrane dimers; this impairs IL-2–mTOR adaptation, represses PGC1α transcription, causes oxidative stress and ferroptotic cell death in tumour-reactive TILs; blocking EP2/EP4 during TIL expansion restores IL-2 sensing and antitumour efficacy. PGE2/EP2/EP4 receptor pharmacology, IL-2Rγc surface expression measurement, IL-2Rβ–γc dimer assembly assays, mTOR signaling assays, PGC1α expression, ROS/ferroptosis assays, adoptive cell transfer mouse models Nature High 38658764
2008 IL-2Rβ chains can spontaneously form homodimers (IL-2Rβ/β) in the absence of γc, as demonstrated by co-immunoprecipitation of differentially tagged IL-2Rβ subunits and FRET between fluorescent reporter-fused IL-2Rβ chains at the cell surface; these homodimers bind IL-2 with Kd ~1 nM, similar to IL-2Rβ/γc heterodimers. Co-immunoprecipitation (HA/MYC-tagged co-transfection), FRET between ECFP/EYFP-fused IL-2Rβ, 125I-IL-2 binding assays European cytokine network Medium 18299274
2000 IL-2 signaling in human monocytes requires protein tyrosine kinase activity and specifically involves phosphorylation and activation of p59hck (Hck); herbimycin A (PTK inhibitor) abolishes IL-2-induced monocyte tumoricidal activity and cytokine production; IL-2 upregulates hck mRNA/protein and increases p59hck tyrosine phosphorylation and kinase activity in vitro. PTK inhibitor (herbimycin A), anti-phosphotyrosine immunoblotting, in vitro kinase assay, RT-PCR, cytotoxicity assay Journal of immunology Medium 10779760
2001 LFA-1 costimulation of IL-2 gene expression is mediated primarily through enhanced IL-2 transcription (not mRNA stabilization), as shown using an IL-2 promoter-luciferase transgenic reporter; in contrast, CD28 costimulation enhances both transcription and mRNA stability. IL-2 promoter-luciferase transgenic mice, real-time RT-PCR for mRNA stability, antigen-presenting cell lines with/without ICAM-1 or B7-1 Journal of immunology Medium 11673532
2017 PTEN drives Th17 cell differentiation by suppressing IL-2 production; Th17-specific Pten deletion increases IL-2 and STAT5 phosphorylation while reducing STAT3 phosphorylation, thereby inhibiting Th17 differentiation in vitro and ameliorating EAE; PTEN inhibitors phenocopy Th17 suppression. Conditional Th17-specific Pten knockout mice, IL-2 ELISA, STAT5/STAT3 phosphorylation assays, EAE model, PTEN inhibitor experiments The Journal of experimental medicine High 29018045
2002 CD56bright NK cells in human lymph nodes constitutively express the high-affinity IL-2 receptor and respond to endogenous T cell-derived IL-2 by secreting IFN-γ, establishing a direct mechanistic link between adaptive T cell-derived IL-2 and innate NK cell cytokine production. In situ hybridization, flow cytometry, lymph node NK cell isolation, IL-2 neutralization experiments, IFN-γ assays Blood Medium 12480696

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2013 Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 1778 24390342
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
1993 Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 1461 8402910
2009 Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nature genetics 1382 19430480
1983 Structure and expression of a cloned cDNA for human interleukin-2. Nature 1170 6403867
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2011 Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nature genetics 1078 21297633
2010 Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nature genetics 1018 20453842
2014 IL-2: the first effective immunotherapy for human cancer. Journal of immunology (Baltimore, Md. : 1950) 974 24907378
1992 Cloning of the gamma chain of the human IL-2 receptor. Science (New York, N.Y.) 879 1631559
2010 Multiple common variants for celiac disease influencing immune gene expression. Nature genetics 801 20190752
1993 Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science (New York, N.Y.) 772 8493579
1991 Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 756 1830926
2018 Signaling and Function of Interleukin-2 in T Lymphocytes. Annual review of immunology 746 29677473
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2002 CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. Blood 639 12480696
2004 Tolerance, not immunity, crucially depends on IL-2. Nature reviews. Immunology 632 15343366
2010 Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature 621 20596022
2008 Shared and distinct genetic variants in type 1 diabetes and celiac disease. The New England journal of medicine 566 19073967
1993 The IL-2 receptor complex: its structure, function, and target genes. Annual review of immunology 563 8476561
2011 IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Current opinion in immunology 550 21889323
1994 Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science (New York, N.Y.) 540 7973659
2008 Newly identified genetic risk variants for celiac disease related to the immune response. Nature genetics 519 18311140
2007 A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nature genetics 509 17558408
2004 Natural and induced CD4+CD25+ cells educate CD4+CD25- cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. Journal of immunology (Baltimore, Md. : 1950) 508 15100259
2018 Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nature reviews. Immunology 505 30089912
2018 Revisiting IL-2: Biology and therapeutic prospects. Science immunology 497 29980618
2011 Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nature genetics 467 21685912
2012 Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'. Nature 461 22446627
1988 Characterization of antigen receptor response elements within the interleukin-2 enhancer. Molecular and cellular biology 459 3260003
2008 Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. The Journal of infectious diseases 444 18275276
1995 Transcriptional regulation of the IL-2 gene. Current opinion in immunology 444 7546397
1999 Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 442 10072077
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2004 IL-2, regulatory T cells, and tolerance. Journal of immunology (Baltimore, Md. : 1950) 435 15034008
2019 De novo design of potent and selective mimics of IL-2 and IL-15. Nature 412 30626941
2016 Role of IL-2 in cancer immunotherapy. Oncoimmunology 401 27471638
2011 Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nature immunology 389 21516110
2022 Engineering IL-2 for immunotherapy of autoimmunity and cancer. Nature reviews. Immunology 280 35217787
2000 The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene 280 10851055
2014 The IL-2 cytokine family in cancer immunotherapy. Cytokine & growth factor reviews 217 25200249
2018 Differential IL-2 expression defines developmental fates of follicular versus nonfollicular helper T cells. Science (New York, N.Y.) 204 30213884
2006 IL-27 limits IL-2 production during Th1 differentiation. Journal of immunology (Baltimore, Md. : 1950) 174 16365415
1995 IL-2 knockout recipient mice reject islet cell allografts. Journal of immunology (Baltimore, Md. : 1950) 163 7602120
2020 Immunomodulatory Effects of IL-2 and IL-15; Implications for Cancer Immunotherapy. Cancers 157 33266177
2024 PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function. Nature 153 38658764
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