Affinage

IL2RA

Interleukin-2 receptor subunit alpha · UniProt P01589

Round 2 corrected
Length
272 aa
Mass
30.8 kDa
Annotated
2026-04-28
130 papers in source corpus 28 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL2RA (CD25) encodes the alpha chain of the interleukin-2 receptor, which assembles with IL-2Rβ and the common γ-chain to form the high-affinity IL-2 receptor quaternary complex; the 2.3 Å crystal structure shows that CD25 binding to IL-2 stabilizes a secondary surface for IL-2Rβ recruitment and subsequent γc docking, enabling Jak1/Jak3–STAT5 signaling (PMID:16293754, PMID:7973659). Transcription of IL2RA is activated in two phases—an early TCR/Src-kinase-dependent phase and a sustained JAK3/STAT5-dependent phase operating through non-redundant STAT5-bound superenhancer elements with chromatin looping—and is repressed by SATB1-recruited HDAC/nucleosome-remodeling complexes and by Bach2 (PMID:29078395, PMID:12374985, PMID:33979619, PMID:27936140). After internalization via a clathrin-independent pathway, CD25 recycles to the plasma membrane while the β and γ chains are ubiquitinated and degraded, and membrane CD25 can be proteolytically shed as soluble CD25 by MMP-9 (PMID:15645712, PMID:19878594). Homozygous loss-of-function IL2RA mutations in humans cause immune dysregulation with CD8+ T-cell lymphoproliferation and Treg dysfunction, and in AML, IL2RA cell-autonomously promotes proliferation, blocks differentiation, and sustains leukemic stem cell properties (PMID:23416241, PMID:32873636).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1984 High

    Molecular cloning of the IL2RA cDNA established that a single gene encodes the IL-2-binding α chain, resolving the molecular identity of the receptor subunit and revealing alternative splicing that abolishes ligand binding.

    Evidence cDNA cloning with expression in COS cells and IL-2 binding assay

    PMID:6090948 PMID:6090949

    Open questions at the time
    • No knowledge of additional receptor subunits required for high-affinity binding
    • Signaling mechanism unknown
    • No structural information
  2. 1989 High

    Co-expression of IL-2Rα with the newly cloned IL-2Rβ reconstituted high-affinity IL-2 binding, establishing that the high-affinity receptor is a multi-subunit complex and that CD25 alone forms only the low/intermediate-affinity state.

    Evidence Co-expression of IL-2Rα and IL-2Rβ cDNAs in T lymphoid cells with IL-2 binding assays

    PMID:2785715

    Open questions at the time
    • γc subunit not yet identified
    • No structural basis for cooperativity
    • Downstream signaling effectors unknown
  3. 1991 High

    Identification of κB enhancer and CArG box elements in the IL2RA promoter as essential cis-regulatory regions established the first transcriptional control mechanism, later extended by the finding that HTLV-I tat-I transactivates through the same region.

    Evidence Triplex oligonucleotide targeting of promoter combined with EMSA, nuclear run-on assays in lymphocytes, and promoter-CAT reporter deletion mapping

    PMID:2062658 PMID:3030566

    Open questions at the time
    • Trans-acting factors beyond NF-κB not identified
    • Chromatin-level regulation unknown
    • No in vivo validation of promoter elements
  4. 1994 High

    Demonstration that Jak1 associates with IL-2Rβ and Jak3 with γc, with both required for IL-2 signaling, defined the proximal kinase cascade downstream of the receptor complex that CD25 assembly enables.

    Evidence Co-immunoprecipitation and reconstitution in Jak3-negative fibroblasts bearing IL-2R subunits

    PMID:7973659

    Open questions at the time
    • Order of Jak activation unclear
    • STAT substrate specificity not fully delineated
    • How CD25 presence vs absence alters Jak activation not resolved
  5. 2002 High

    Discovery that SATB1 recruits NURD HDAC and ACF1/ISWI nucleosome-remodeling complexes to the IL2RA locus, with ectopic IL2RA expression in SATB1-null thymocytes, revealed that chromatin architecture actively represses IL2RA transcription in non-activated cells.

    Evidence ChIP for histone acetylation, nucleosome positioning assays, SATB1 knockout mice

    PMID:12374985

    Open questions at the time
    • Interplay between SATB1 repression and NF-κB activation not defined
    • Enhancer architecture not mapped
    • Whether other locus-specific repressors exist was unknown
  6. 2004 Medium

    Trafficking studies resolved that CD25 follows a clathrin-independent endocytic pathway and recycles to the surface, while IL-2Rβ/γc are ubiquitinated and degraded, explaining how CD25 is maintained for sustained IL-2 sensing even as signaling chains are turned over.

    Evidence Endocytosis assays, subcellular fractionation, ubiquitination analysis

    PMID:15645712

    Open questions at the time
    • Molecular sorting signals on CD25 that direct recycling not identified
    • Recycling kinetics not quantified in vivo
    • Relationship to lipid raft localization not established
  7. 2005 High

    The 2.3 Å crystal structure of the quaternary IL-2/IL-2Rα/IL-2Rβ/γc complex revealed that CD25 binding to IL-2 allosterically stabilizes the IL-2Rβ-binding surface and that γc docking uses degenerate contacts, providing the structural basis for high-affinity receptor assembly and explaining X-SCID mutations.

    Evidence X-ray crystallography of the full ectodomain quaternary complex

    PMID:16293754

    Open questions at the time
    • Transmembrane and intracellular domain organization unknown
    • How structural changes propagate to Jak activation not resolved
    • No dynamics information from static crystal
  8. 2009 High

    MMP-9 was identified as the protease responsible for shedding membrane CD25 as soluble CD25, validated by MMP-9 knockout, pharmacologic inhibition, and direct enzyme treatment, establishing a mechanism for the well-known soluble IL-2Rα found in serum.

    Evidence MMP-9 knockout mice, doxycycline inhibition, in situ zymography, Western blot of CD25 in corneal epithelial cells

    PMID:19878594

    Open questions at the time
    • Whether MMP-9 is the sole sheddase on immune cells not confirmed
    • Cleavage site on CD25 not mapped
    • Functional consequence of sCD25 on IL-2 signaling not defined
  9. 2009 High

    Disease-associated IL2RA polymorphisms were shown to regulate CD25 surface protein levels in a cell-type-specific manner (confirmed by allele-specific expression), mechanistically linking autoimmune risk variants to quantitative differences in IL-2 receptor expression rather than coding changes.

    Evidence Polychromatic flow cytometry for CD25 across immune subsets, genotype-stratified analysis, allele-specific expression

    PMID:19701192

    Open questions at the time
    • Causal regulatory variant not pinpointed
    • Epigenomic mechanism of cell-type specificity unknown
    • Whether variants alter enhancer–promoter contacts not tested
  10. 2013 High

    A homozygous IL2RA null patient demonstrated that CD25 is essential for immune homeostasis: its loss causes pronounced CD8+ T-cell lymphoproliferation with STAT5-activated tissue-infiltrating CD8+ cells and impaired antigen-specific responses, while Tregs retain residual IL-2 responsiveness.

    Evidence Immunological phenotyping of IL2RA-null patient with flow cytometry, STAT5 phosphorylation, antigen-specific assays, and tissue biopsy

    PMID:23416241

    Open questions at the time
    • Whether residual Treg function is mediated by intermediate-affinity IL-2R or alternative cytokines unclear
    • Only one patient studied at molecular depth
    • Mechanism of preferential CD8 hyperactivation not explained
  11. 2017 High

    CRISPR-Cas9 deletion of individual STAT5 binding sites within the Il2ra superenhancer each independently reduced IL-2-induced Il2ra expression, establishing that superenhancer elements are non-redundant and that STAT5-mediated chromatin looping is the sustained-phase transcriptional mechanism for IL2RA.

    Evidence ChIA-PET chromatin interaction mapping, CRISPR-Cas9 deletion of superenhancer elements in mice, ChIP-seq for STAT5

    PMID:29078395

    Open questions at the time
    • How superenhancer integrates with the early TCR/Src-dependent phase not resolved
    • Whether human IL2RA superenhancer has identical architecture not tested
    • Contribution of individual STAT5 sites to Treg vs effector T cell expression not defined
  12. 2020 High

    IL2RA was shown to cell-autonomously promote AML cell proliferation, block differentiation, and maintain leukemic stem cell properties—a non-immune function validated by genetic knockdown and antibody inhibition in two mouse AML models—expanding CD25's role beyond immune regulation.

    Evidence shRNA knockdown, overexpression, and anti-CD25 antibody in human AML cells, primary patient samples, and two mouse AML models

    PMID:32873636

    Open questions at the time
    • Downstream signaling pathway in AML cells not fully characterized
    • Whether AML CD25 signals through canonical Jak/STAT5 or alternative pathways unknown
    • Whether sCD25 shedding contributes to AML phenotype not tested
  13. 2021 High

    Bach2 was identified as a direct transcriptional repressor of CD25 in Tregs, with Bach2 deficiency upregulating CD25 and IL-2R signaling to partially compensate for poor Treg survival; this established a second chromatin-level repressive mechanism complementary to SATB1.

    Evidence Bach2 conditional knockout in Tregs, ChIP for Bach2 at Il2ra locus, flow cytometry, Tfr and GC analysis

    PMID:33979619

    Open questions at the time
    • Whether Bach2 and SATB1 operate on the same or distinct regulatory elements not determined
    • Molecular interplay between Bach2 repression and STAT5 superenhancer activation not resolved
  14. 2023 High

    Tumor-specific CD8+ T cells co-expressing CD25 and PD-1 depend on autocrine IL-2–CD25 signaling for anti-PD-1 responsiveness, and IL-2Rα-biased agonists synergize with checkpoint blockade, establishing CD25 as a critical node in antitumor immunity.

    Evidence Comparison of IL-2 variants (IL-2Rα-biased vs IL-2Rβγ-biased) in mouse tumor models, autocrine IL-2 blockade, anti-PD-1 combination, human patient correlation

    PMID:37550516

    Open questions at the time
    • Mechanism by which autocrine IL-2 is produced by TSTs not defined
    • Whether CD25-high TSTs represent a distinct differentiation state or activation state not resolved
    • Translation to human clinical anti-PD-1 settings not validated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for full-length receptor transmembrane signaling, the identity of sorting signals directing CD25 recycling, how disease-associated non-coding variants alter superenhancer architecture cell-type-specifically, and the signaling pathway through which CD25 drives AML stem cell properties.
  • No full-length IL-2R structural model including transmembrane/intracellular domains
  • CD25 recycling sorting signal not mapped
  • Causal autoimmune-risk variant–enhancer interactions not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4
Localization
GO:0005886 plasma membrane 4 GO:0005576 extracellular region 1 GO:0005768 endosome 1
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 4
Partners
BACH2IL2IL2RBIL2RGJAK1JAK3SATB1STAT5A
Complex memberships
IL-2 receptor (IL-2Rα/IL-2Rβ/γc)

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1984 Molecular cloning of the human IL-2 receptor alpha chain (IL2RA/CD25) cDNA revealed a single gene producing two mRNAs with different polyadenylation signals, and an alternatively spliced form lacking 216 bases that cannot bind IL-2; the encoded protein was expressed in COS cells and shown to bind IL-2. cDNA cloning, sequencing, expression in COS cells, IL-2 binding assay Nature High 6090948 6090949
1985 IL-2 itself upregulates cell-surface expression of its own receptor (Tac antigen/CD25) in an 8-10-fold enhancement of anti-Tac binding sites while simultaneously reducing high-affinity IL-2 binding sites; the magnitude of the proliferative response correlated with high-affinity IL-2 binding site density rather than CD25 (Tac) levels, demonstrating that IL-2–receptor interactions promote loss of IL-2 responsiveness. Radiolabeled monoclonal antibody binding assays, IL-2 binding competition, membrane proteolysis recovery assays, proliferation assays Proceedings of the National Academy of Sciences of the United States of America High 2983318
1987 The IL2RA promoter contains regulatory elements between −327 and −265 that drive constitutive expression in HTLV-I-infected T cells; the HTLV-I transactivator protein (tat-I) activates IL2RA promoter constructs through a specific region (−267 to −265) in a cell-type-specific manner requiring additional cellular factors. 5' deletion promoter-CAT reporter constructs, cotransfection with tat-I expression vector, cell-type specificity experiments Cell High 3030566
1989 The IL-2 receptor beta chain (IL-2Rβ, p70-75) was cloned; when co-expressed with IL-2Rα cDNA, the two chains together reconstitute a high-affinity IL-2 receptor, demonstrating that IL-2Rα and IL-2Rβ together form the high-affinity complex. cDNA cloning, co-expression of IL-2Rα and IL-2Rβ in T lymphoid cells, IL-2 binding assays Science High 2785715
1989 CD25 (IL-2Rα/Tac antigen) is detectable on 15–45% of circulating human T and B lymphocytes using a highly sensitive immunofluorescence procedure, revealing constitutive low-level CD25 expression on resting lymphocytes including CD4+ T cells, CD8+ T cells, and B cells. Highly sensitive indirect immunofluorescence with three different anti-CD25 antibodies, double-marker studies for lineage identification Immunology and cell biology Medium 2570038
1991 A triplex-forming oligonucleotide targeting the IL2RA promoter region (−273 to −246), spanning the κB enhancer and CArG box, selectively inhibited IL2RA mRNA transcription in intact lymphocytes for up to 12 hours after PHA stimulation, as confirmed by nuclear run-on assays, demonstrating that the κB and CArG elements are required for normal IL2RA transcriptional activation. Triplex oligonucleotide designed to IL2RA promoter, EMSA for binding specificity, restriction enzyme inhibition assay, nuclear run-on transcription assays in intact lymphocytes Nucleic acids research High 2062658
1993 CD25+ (activated) T cells are the principal producers of HIV in acutely infected PBMC cultures; elimination of the small CD25+ population (3–5%) before infection reduces p24 secretion by 99%, and killing CD25+ cells after infection virtually stops viral production and spread, while resting CD25− cells can be infected but only produce virus upon subsequent activation. Anti-CD25–ricin A chain immunotoxin (RFT5-dgA) selective depletion before/after HIV infection, p24 ELISA, coculture with H9 cells Journal of immunology High 8496611
1994 Jak1 and Jak3 are selectively and functionally associated with distinct IL-2R subunits: Jak1 associates with the serine-rich region of IL-2Rβ and Jak3 associates with the carboxyl-terminal region of IL-2Rγ; both associations are required for IL-2 signaling, and expression of Jak3 cDNA in Jak3-negative fibroblasts bearing reconstituted IL-2R conferred IL-2 responsiveness. Co-immunoprecipitation, reconstitution in Jak3-negative fibroblasts with IL-2R subunits and Jak3 cDNA, IL-2 stimulation and tyrosine phosphorylation assays Science High 7973659
1999 In the IL-2R signaling system, Jak3 can transphosphorylate a kinase-dead Jak1, but Jak1 cannot phosphorylate kinase-dead Jak3, suggesting Jak3 activation precedes Jak1; Jak3 phosphorylates both IL-2Rβ and IL-2Rγc, while Jak1 phosphorylates only IL-2Rβ; Jak3 activates STAT3 and STAT5 but not STAT1, whereas Jak1 activates STAT1, STAT3, and STAT5, revealing differential substrate specificity between the two kinases. Baculovirus-expressed recombinant Jak1, Jak3, and kinase-dead mutants; co-expression of IL-2R subunits; in vitro tyrosine phosphorylation assays; STAT phosphorylation analysis Leukemia & lymphoma Medium 10037026
2002 CD25 (IL-2Rα) suppressive function in human thymocytes is mediated by CTLA-4 and membrane TGF-β1 acting together to inhibit IL-2Rα chain (CD25) expression on target T cells; anti-CTLA-4 or anti-TGF-β1 alone partially inhibit suppression, but the combination completely blocks it and restores CD25 expression on target cells, thereby restoring IL-2 responsiveness. Mixed lymphocyte culture suppression assays with CD4+CD25+ human thymocytes, antibody blocking experiments (anti-CTLA-4, anti-TGF-β1), flow cytometry for CD25 expression on target cells The Journal of experimental medicine High 12163566
2002 CD25 (IL-2Rα) localization within membrane microdomains is proposed to switch IL-2R signaling: in the absence of CD25, IL-2R activation occurs in the soluble membrane fraction and promotes Jak3-independent, antiapoptotic signaling; when CD25 is induced by TCR signaling and localizes to microdomains with CD122, the high-affinity receptor complex activates Jak3 and shifts the balance toward proliferation versus activation-induced cell death. Review integrating published biochemical fractionation and signaling data; analysis of membrane microdomain distribution of CD25 and CD122 Immunology and cell biology Low 12121224
2002 SATB1 recruits the NURD histone deacetylase complex and the ACF1/ISWI nucleosome-remodeling complexes to a specific binding site in the IL-2Rα (IL2RA) locus, mediating deacetylation of histones over a large chromatin domain and regulating nucleosome positioning over 7 kilobases; in SATB1-null thymocytes, IL-2Rα is ectopically transcribed, demonstrating that SATB1 represses IL2RA through targeted chromatin remodeling. ChIP for histone acetylation, nucleosome positioning assays, SATB1 knockout mice (ectopic IL-2Rα transcription phenotype), co-recruitment of NURD/ACF1/ISWI complexes Nature High 12374985
2003 CD8+CD25+ human thymocytes suppress autologous CD25− T cell proliferation via a contact-dependent mechanism requiring CTLA-4 and membrane TGF-β1 acting together, and this suppression is mediated by inhibition of IL-2Rα (CD25) expression on target T cells—the same mechanism used by CD4+CD25+ regulatory thymocytes. Suppression assays with purified CD8+CD25+ thymocytes, antibody blocking (anti-CTLA-4 + anti-TGF-β1), flow cytometry for CD25 on target cells Blood High 12893750
2004 IL-2R α-chain (CD25) endocytic trafficking follows a clathrin-independent pathway; after internalization, CD25/IL-2Rα recycles to the plasma membrane while IL-2Rβ and IL-2Rγ are targeted to late endosomes/lysosomes for degradation via ubiquitination as a sorting signal. Endocytosis assays, subcellular fractionation, trafficking studies distinguishing clathrin-dependent vs. independent routes, ubiquitination analysis Current topics in microbiology and immunology Medium 15645712
2005 Crystal structure of the quaternary IL-2/IL-2Rα/IL-2Rβ/γc ectodomain complex at 2.3 Å resolution revealed that IL-2Rα binding to IL-2 stabilizes a secondary binding site that is presented to IL-2Rβ; γc is then recruited to the composite IL-2/IL-2Rβ surface through degenerate contacts consistent with its shared use by multiple cytokines; the structure provides a molecular rationale for X-SCID-associated loss-of-function mutations in γc. X-ray crystallography at 2.3 Å resolution of the quaternary ectodomain complex Science High 16293754
2009 CD25 (IL-2Rα) is expressed on corneal and conjunctival epithelial cells and is proteolytically cleaved to generate soluble CD25 in tears by matrix metalloproteinase 9 (MMP-9); desiccating stress increases MMP-9 activity and reduces membrane CD25 in the ocular surface epithelium; this cleavage is prevented by MMP-9 inhibition (doxycycline) and is absent in MMP-9 knockout mice, and confirmed by MMP-9 treatment of cultured corneal epithelial cells. MMP-9 knockout mice, topical MMP-9 inhibitor (doxycycline), in situ zymography, confocal immunofluorescence, Western blot of CD25 in epithelial lysates, immunobead assay for soluble CD25 in tears, MMP-9 treatment of human corneal epithelial cells Journal of inflammation High 19878594
2009 Differences in surface IL2RA (CD25) protein expression on specific immune cell types (but not others) correlate with haplotypes in the IL2RA region associated with type 1 diabetes and multiple sclerosis; this gene-phenotype correlation was confirmed at the RNA level by allele-specific expression, demonstrating that disease-associated IL2RA variants functionally regulate CD25 protein levels in a cell-type-specific manner. Polychromatic flow cytometry for CD25 surface expression across immune cell types, genotyping of IL2RA haplotypes, allele-specific expression (ASE) analysis at RNA level Nature genetics High 19701192
2012 In vitro evolution of IL-2 generated a 'superkine' (super-2) with increased affinity for IL-2Rβ that eliminates the functional requirement for CD25; crystal structures of the superkine in free and receptor-bound forms showed evolved mutations stabilize the IL-2Rβ binding helix into a CD25-bound-like conformation; the superkine recapitulates CD25 function by eliciting STAT5 phosphorylation and T cell proliferation independent of CD25 expression. In vitro evolution (yeast display), crystal structures of IL-2 superkine free and receptor-bound, molecular dynamics simulations, STAT5 phosphorylation assays, T cell proliferation assays, in vivo antitumor models Nature High 22446627
2013 A patient with a novel homozygous IL2RA null mutation exhibited pronounced CD8+ T cell lymphoproliferation with activated CD8+STAT5+ T cells infiltrating tissues, impaired antigen-specific responses, and FOXP3+ Tregs that retained higher capacity to respond to IL-2 compared to other T cell subsets, demonstrating that CD25/IL-2Rα is required for normal immune homeostasis and its loss leads to disproportionate CD8+ hyperactivation despite residual Treg IL-2 responsiveness. Analysis of IL2RA null patient: flow cytometry, STAT5 phosphorylation assays, in vitro/in vivo antigen-specific response assays, skin biopsy immunohistochemistry, serum cytokine measurement Clinical immunology High 23416241
2014 An MS-associated IL2RA polymorphism (rs2104286) specifically increases IL-2 responsiveness of naive TH cells, measured by GM-CSF production; the variant regulates the propensity of naive TH cells to develop into GM-CSF-producing memory TH cells, mechanistically linking the IL2RA risk allele to increased neuroinflammatory TH cell function. Genotype-stratified analysis of human donor T cells; IL-2 stimulation assays; intracellular cytokine staining for GM-CSF; ex vivo differentiation assays from naive to memory TH cells Nature communications High 25278028
2016 CD25 (IL-2Rα) expression on human peripheral blood T cells is regulated in two temporally distinct phases: an early Src kinase (TCR-associated)-dependent phase required for T cell competence and IL-2 responsiveness, and a later JAK3/STAT5-dependent phase that sustains high and prolonged CD25 expression to drive cell growth and proliferation; in competent CD25+ T cells bearing high-affinity IL-2R, IL-2 switches on a JAK3/STAT5 pathway that is constitutively JAK3-independent in quiescent cells. Selective kinase inhibitors (PP2 for Src, WHI-P131 for JAK3), flow cytometry for CD25 dynamics, STAT3/STAT5 phosphorylation assays (tyrosine phosphorylation), mitogen dose-response experiments in human peripheral blood lymphocytes PloS one Medium 27936140
2017 IL-2-activated STAT5 binds to a superenhancer at the Il2ra locus and induces new chromatin looping interactions; CRISPR-Cas9 editing of three individual STAT5 binding sites within the Il2ra superenhancer in mice each decreased STAT5 binding and reduced IL-2-induced Il2ra expression, demonstrating that superenhancer elements are non-redundant and all required for normal IL2RA gene expression; STAT5-mediated chromatin looping preferentially regulates highly IL-2-inducible genes. ChIA-PET chromatin interaction sequencing, CRISPR-Cas9 deletion of superenhancer elements in mice, ChIP-seq for STAT5 binding, quantitative Il2ra mRNA expression analysis Proceedings of the National Academy of Sciences of the United States of America High 29078395
2018 In a mouse model of hemophagocytic lymphohistiocytosis (HLH), CD25 expression on hyperactivated CD8+ T cells drives the immunological (but not hematologic) features of disease through excessive IL-2 consumption; genetic elimination of CD25 substantially corrected immunologic HLH features, while hematologic features were completely dependent on IFN-γ, revealing a dichotomous pathogenic mechanism. Prf1-knockout mouse model of HLH with genetic elimination of IFN-γ production or CD25 expression; assessment of hematologic, immunologic, and physiologic disease parameters The Journal of allergy and clinical immunology High 30578871
2019 High-affinity TCR signaling sustains IL-2R (CD25) expression longer on naive T cells than low-affinity TCR interactions, directing them toward Th1/Th17 rather than Tfh differentiation; this TCR affinity effect on Th fate acts through direct regulation of CD25 and novel differentiation regulators (Eef1e1, Gbp2) in naive T cells, not through preferential T cell–dendritic cell interactions. Adoptive transfer of TCR transgenic T cells with defined affinity variants, flow cytometry for CD25 and Th subset markers post-infection, gene expression analysis (Eef1e1, Gbp2), DC subset interaction tracking Journal of immunology Medium 30858199
2020 IL2RA promotes proliferation, cell-cycle activity, and inhibits apoptosis in AML cells; IL2RA inhibits differentiation and promotes leukemic stem cell properties; genetic knockdown or antibody-mediated inhibition of IL2RA reduces leukemogenesis in two genetically distinct mouse AML models while sparing normal hematopoietic cells, demonstrating a cell-autonomous oncogenic role for IL2RA in AML independent of its classical immune regulatory function. Genetic manipulation (shRNA knockdown, overexpression) and antibody inhibition of IL2RA in human AML cell lines and primary patient samples; two mouse AML models (genetic knockdown); flow cytometry for differentiation and stem cell markers; proliferation, apoptosis, and cell-cycle assays; drug synergy experiments Cancer research High 32873636
2021 Transcription factor Bach2 directly represses CD25 (IL-2Rα) expression in regulatory T cells; Bach2 deficiency in Tregs upregulates CD25 and IL-2R signaling, which partially compensates for poor resting Treg survival; Bach2 also suppresses CD25/IL-2R signaling in T follicular regulatory (Tfr) cells, and its deficiency prevents formation of highly differentiated Tfr cells and causes aberrant germinal center responses. Bach2 conditional knockout in Tregs, ChIP for Bach2 binding at CD25/Il2ra locus, flow cytometry for CD25 and IL-2R signaling markers, Tfr cell enumeration and GC analysis, in vitro IL-2 signaling assays Cell reports High 33979619
2023 Tumor-specific CD8+ T cells (TSTs) co-express elevated CD25 and PD-1 and are more susceptible to stimulation by IL-2Rα-proficient agonists than by IL-2Rβγ-biased analogs; anti-PD-1 antitumor efficacy depends on activation of PD-1+CD25+ TSTs through autocrine IL-2–CD25 signaling; IL-2Rα-biased agonists (preserving CD25 activity) restore IL-2 signaling and synergize with anti-PD-1 to eradicate large established tumors in mouse models. Comparison of IL-2 variants (wild-type, IL-2Rα-biased, IL-2Rβγ-biased, non-α) in mouse tumor models; flow cytometry for CD25/PD-1 co-expression on TSTs; autocrine IL-2 signaling blockade experiments; anti-PD-1 combination experiments; human cancer patient IL-2 signature correlations Nature cancer High 37550516

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. The Journal of experimental medicine 3776 14676299
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2011 Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2101 21833088
2010 Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature genetics 2036 21102463
2013 Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 1778 24390342
2009 Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nature genetics 1382 19430480
2007 Risk alleles for multiple sclerosis identified by a genomewide study. The New England journal of medicine 1319 17660530
2002 Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nature immunology 1313 11812990
1994 A genome-wide search for human type 1 diabetes susceptibility genes. Nature 1167 8072542
2010 Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nature genetics 1018 20453842
1984 Molecular cloning and expression of cDNAs for the human interleukin-2 receptor. Nature 936 6090948
1993 Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science (New York, N.Y.) 772 8493579
1989 Interleukin-2 receptor beta chain gene: generation of three receptor forms by cloned human alpha and beta chain cDNA's. Science (New York, N.Y.) 750 2785715
2009 Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science (New York, N.Y.) 747 19264985
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2009 Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nature genetics 639 19525953
2010 Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature 621 20596022
1984 Molecular cloning of cDNA encoding human interleukin-2 receptor. Nature 608 6090949
2008 Shared and distinct genetic variants in type 1 diabetes and celiac disease. The New England journal of medicine 566 19073967
1985 Interleukin 2 regulates its own receptors. Proceedings of the National Academy of Sciences of the United States of America 546 2983318
1994 Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science (New York, N.Y.) 540 7973659
2007 IL-2 is essential for TGF-beta to convert naive CD4+CD25- cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. Journal of immunology (Baltimore, Md. : 1950) 499 17277105
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2001 Homeostasis and anergy of CD4(+)CD25(+) suppressor T cells in vivo. Nature immunology 486 11740498
2012 Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'. Nature 461 22446627
1987 Regulation of the human interleukin-2 receptor alpha chain promoter: activation of a nonfunctional promoter by the transactivator gene of HTLV-I. Cell 449 3030566
2009 Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nature genetics 433 19525955
2008 Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nature genetics 415 18978792
2002 SATB1 targets chromatin remodelling to regulate genes over long distances. Nature 414 12374985
2005 Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors. Science (New York, N.Y.) 407 16293754
2006 Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo. The Journal of clinical investigation 392 16955142
2005 Reduced frequency of FOXP3+ CD4+CD25+ regulatory T cells in patients with chronic graft-versus-host disease. Blood 377 15972448
1994 Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q. Nature 377 8072544
2001 Human anergic/suppressive CD4(+)CD25(+) T cells: a highly differentiated and apoptosis-prone population. European journal of immunology 371 11298337
2006 Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. Journal of immunology (Baltimore, Md. : 1950) 369 17056509
2001 Activation of CD25(+)CD4(+) regulatory T cells by oral antigen administration. Journal of immunology (Baltimore, Md. : 1950) 335 11591746
2002 Phenotype, localization, and mechanism of suppression of CD4(+)CD25(+) human thymocytes. The Journal of experimental medicine 300 12163566
2003 Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes. Blood 292 12893750
2002 Both CD4(+)CD25(+) and CD4(+)CD25(-) regulatory cells mediate dominant transplantation tolerance. Journal of immunology (Baltimore, Md. : 1950) 286 12023351
2004 CD25- T cells generate CD25+Foxp3+ regulatory T cells by peripheral expansion. Journal of immunology (Baltimore, Md. : 1950) 279 15585848
2004 CCR6 expression defines regulatory effector/memory-like cells within the CD25(+)CD4+ T-cell subset. Blood 240 15613550
2009 Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nature genetics 226 19701192
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