Affinage

IL7R

Interleukin-7 receptor subunit alpha · UniProt P16871

Length
459 aa
Mass
51.6 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL7R encodes IL-7Rα, the ligand-specific subunit of the IL-7 receptor that, paired with the common γc chain, transduces signals required for lymphoid development and homeostasis; in humans, loss-of-function mutations cause T(-)B(+)NK(+) severe combined immunodeficiency, establishing a non-redundant requirement for IL-7Rα in T-cell but not NK-cell development (PMID:9843216). Glycosylation of the IL-7Rα ectodomain accelerates the on-rate for IL-7 and raises binding affinity ~300-fold, and SCID mutations map outside the ligand interface, implicating folding defects rather than disrupted contact (PMID:19141282). Engaged receptor signals through a Tyr449 SH2-binding motif to STAT5, driving Mcl-1 expression and supporting B-lineage survival and immunoglobulin rearrangement (PMID:25143441), and the same receptor controls regulatory T-cell development, where either IL-7 or TSLP can supply the required IL-7Rα signal (PMID:18664628). Beyond canonical lymphopoiesis, IL-7Rα directs ILC3 differentiation via polyglutamylation-coupled STAT5/Sall3 signaling (PMID:28794449), supports establishment of fetal-derived tissue-resident macrophages (PMID:31332039) and tissue-resident lymphoid cells (PMID:35072209), and restrains inflammatory gene expression in monocytes (PMID:35015026). Receptor abundance is tightly governed: IL-7 triggers clathrin-mediated endocytosis and JAK3-dependent lysosomal/proteasomal degradation that is itself required for efficient signaling (PMID:20190194), cytokines repress IL7R transcription via GFI1 (PMID:15308108), and DNA methylation (PMID:17442928), Ikaros (PMID:27322554), and Notch–RBP-Jκ (PMID:25429074) further tune expression. Competing splicing/polyadenylation controlled by CPSF1 (PMID:23151878) and the helicase DDX39B (PMID:28340352) sets the ratio of membrane-bound to soluble IL-7Rα, the latter potentiating IL-7 bioavailability and modulating autoimmunity (PMID:23610432). IL-7Rα also sequesters γc to limit IL-2R signaling, explaining why its downregulation maximizes Treg IL-2 responsiveness (PMID:32791329). In disease, somatic gain-of-function mutations introducing unpaired cysteines drive ligand-independent IL-7Rα homodimerization and constitutive JAK1 signaling in T-ALL (PMID:21892159, PMID:21536738) or assemble with CRLF2 to signal in B-ALL (PMID:21536738), while overexpression of wild-type IL-7Rα alone is sufficient to promote T-cell leukemogenesis through PI3K/Akt, JAK/STAT, Notch, and Bcl-2 (PMID:33970999), and IL-7Rα is required for leukemia-initiating cell activity (PMID:31530562).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1998 High

    Established that IL-7Rα signaling is non-redundantly required for human T-cell development, distinguishing its role from γc and JAK3.

    Evidence Genetic analysis of SCID patients with defective IL7R, compared with XSCID and JAK3-SCID phenotypes

    PMID:9843216

    Open questions at the time
    • Did not resolve which downstream effectors are essential
    • B-cell and NK lineage requirements left to ortholog studies
  2. 2002 High

    Defined IL-7Rα as one of two parallel survival inputs for lymphoid progenitors, acting separately from the E2A/caspase-3 pathway.

    Evidence IL-7Rα/E47 double-knockout mice with caspase-3 assays and Bcl-2 rescue

    PMID:11782430

    Open questions at the time
    • Molecular identity of the IL-7Rα survival effector not pinpointed
  3. 2004 High

    Revealed a homeostatic feedback whereby prosurvival cytokines repress IL7R transcription to share limiting IL-7, identifying GFI1 in CD8 T cells.

    Evidence Transcriptional reporter assays and GFI1 functional analysis in primary T cells

    PMID:15308108

    Open questions at the time
    • CD4 repressor remained unidentified
    • Did not map GFI1 binding directly on the locus
  4. 2009 High

    Explained how IL-7Rα achieves high-affinity ligand binding and reframed SCID mutations as folding rather than interface defects.

    Evidence Crystal structure of glycosylated and unglycosylated IL-7/IL-7Rα complex with biophysical binding measurements

    PMID:19141282

    Open questions at the time
    • No structure of the ternary IL-7/IL-7Rα/γc signaling complex
    • Glycan-specific contributions to signaling not measured
  5. 2010 High

    Showed receptor internalization is not merely downregulation but a required step for efficient signaling, coupling endocytosis to JAK3-dependent degradation.

    Evidence Live-cell imaging, clathrin and JAK inhibitors, pulse-chase degradation in T cells

    PMID:20190194

    Open questions at the time
    • Adaptor proteins linking IL-7Rα to clathrin not identified
    • How endocytosis enhances signaling mechanistically unresolved
  6. 2011 High

    Identified oncogenic gain-of-function mutations that drive ligand-independent IL-7Rα homodimerization and constitutive JAK1 activation in T-ALL, and γc-independent assembly with CRLF2 in B-ALL.

    Evidence Disulfide bond biochemistry, cytokine-independent growth, cysteine mutagenesis, in vivo tumor formation

    PMID:21536738 PMID:21892159

    Open questions at the time
    • Did not define why JAK1 rather than JAK3 is engaged
    • Therapeutic vulnerability not yet mapped in this study
  7. 2011 Medium

    Demonstrated that Vps34/class III PI3K routes internalized IL-7Rα through retromer recycling, linking endosomal trafficking to surface receptor levels and T-cell survival.

    Evidence Conditional Vps34 knockout mice, subcellular fractionation, endosomal marker localization, flow cytometry

    PMID:22021616

    Open questions at the time
    • Single lab
    • Direct interaction of retromer with IL-7Rα not shown
  8. 2012 High

    Established competing splicing/polyadenylation, mediated by CPSF1, as a mechanism setting the soluble-to-membrane IL-7Rα ratio.

    Evidence RNA affinity chromatography/MS, CPSF1 knockdown, polyadenylation-signal mutagenesis, splicing assays

    PMID:23151878

    Open questions at the time
    • Physiological triggers altering CPSF1 activity unclear
  9. 2012 Medium

    Dissected IL-7-driven CD127 downregulation into a rapid JAK-independent protein loss and a delayed STAT5-dependent transcriptional suppression.

    Evidence Human CD8 T cell stimulation with JAK inhibitor, protein/mRNA kinetics, dose-response

    PMID:23207282

    Open questions at the time
    • Single lab
    • Mechanism of the early JAK-independent loss not defined
  10. 2012 Medium

    Identified IL-15, not IL-7 or Foxo1, as the organ-specific driver of CD127 downregulation on bone marrow memory CD8 T cells.

    Evidence Multiple cytokine and receptor KO mouse comparisons with mRNA quantification

    PMID:22539288

    Open questions at the time
    • Single lab
    • Downstream transcriptional mediator not identified
  11. 2012 Medium

    Linked IL-7Rα signaling withdrawal to telomere protection via POT1 and p53, uncovering a tumor-suppressive axis whose loss enables thymic lymphomagenesis.

    Evidence IL-7Rα/p53 double-null mice, POT1 expression, telomere and chromosomal analysis

    PMID:22281704

    Open questions at the time
    • Single lab
    • Mechanism of POT1 translational control not detailed
  12. 2013 High

    Defined soluble IL-7Rα as a functional modulator that potentiates IL-7 bioactivity and exacerbates autoimmunity by limiting cytokine consumption.

    Evidence Binding affinity measurements plus in vitro signaling and in vivo homeostatic expansion and EAE models

    PMID:23610432

    Open questions at the time
    • In vivo source and concentration thresholds of sIL-7Rα not established
  13. 2014 High

    Mapped the IL-7Rα Tyr449 STAT5-recruiting motif as essential for B-lineage survival via Mcl-1 and for immunoglobulin rearrangement, distinct from Bcl-2 rescue.

    Evidence Tyr449Phe knock-in mice, STAT5 phosphorylation, Bcl-2 transgene rescue, B-cell staging

    PMID:25143441

    Open questions at the time
    • Other cytoplasmic tyrosines' contributions not resolved
  14. 2017 High

    Revealed that polyglutamylation/deglutamylation of IL-7Rα tunes STAT5-driven Sall3 induction to control ILC3 development, a non-canonical post-translational regulatory layer.

    Evidence CCP2, TTLL4/TTLL13 KO and IL-7Rα E446A knock-in mice with STAT5 and Sall3 readouts

    PMID:28794449

    Open questions at the time
    • Whether glutamylation regulates other IL-7Rα-dependent lineages unknown
  15. 2017 High

    Established DDX39B as an activator of IL7R exon 6 inclusion whose translation-reducing variant raises soluble IL-7Rα, with genetic epistasis to IL7R in MS risk.

    Evidence Genetic epistasis, splicing reporters, DDX39B over/knockdown, translation reporters

    PMID:28340352

    Open questions at the time
    • How DDX39B mechanistically promotes exon inclusion not fully resolved
  16. 2019 High

    Showed IL-7Rα is required for leukemia-initiating cell activity in Notch1-driven T-ALL and for xenograft engraftment across leukemia types.

    Evidence Il7r-deficient Notch1 leukemia transplantation and patient-derived xenografts

    PMID:31530562

    Open questions at the time
    • Effector pathway sustaining LIC self-renewal not isolated
  17. 2019 Medium

    Identified a physical IL-7R/CXCR4 platform recruiting BCR-ABL1 and JAKs in Ph+ ALL and a kinase-inhibitor-induced IL7R upregulation enabling survival escape.

    Evidence Co-IP of IL7R with CXCR4, patient-derived xenotransplantation, anti-IL7R antibody treatment

    PMID:32581241

    Open questions at the time
    • Single lab
    • Stoichiometry and directness of the multi-protein platform not fully defined
  18. 2019 High

    Extended IL-7Rα function beyond lymphocytes by showing it is required to establish fetal-derived tissue-resident macrophages.

    Evidence Il7r-Cre lineage tracing, IL-7R-deficient mice, gestational blockade, in vitro differentiation

    PMID:31332039

    Open questions at the time
    • Signaling output in myeloid context not mechanistically dissected
  19. 2020 Medium

    Demonstrated that IL-7Rα abundance limits IL-2R signaling by sequestering γc through extracellular pre-association, rationalizing IL-7Rα downregulation in Tregs.

    Evidence IL-7Rα overexpression including tailless mutant, STAT5 readouts, γc Co-IP

    PMID:32791329

    Open questions at the time
    • Single lab
    • Endogenous physiological relevance beyond overexpression not established
  20. 2021 High

    Showed wild-type IL-7Rα overexpression alone is sufficient to drive T-cell leukemogenesis via PI3K/Akt, Notch, JAK/STAT and Bcl-2, with pharmacological vulnerabilities.

    Evidence Inducible transgenic and Rosa26 knock-in mice, immunophenotyping, pathway inhibitors

    PMID:33970999

    Open questions at the time
    • Mechanism by which established tumors become IL-7Rα-level-independent unclear
  21. 2022 Medium

    Defined an anti-inflammatory IL-7/CD127/STAT5 program in human monocytes, expanding IL-7Rα biology into innate inflammation control.

    Evidence Single-cell transcriptomics and IL-7 stimulation in COVID-19 and rheumatoid arthritis monocytes

    PMID:35015026

    Open questions at the time
    • Single study
    • STAT5 target genes restraining inflammation not enumerated
  22. 2022 High

    Distinguished cell-intrinsic and niche (extrinsic) roles of IL-7Rα in establishing tissue-resident lymphoid cells beyond conventional lymphopoiesis.

    Evidence Flk2- and Il7r-Cre lineage tracing, single/double KO mice, reciprocal transplants

    PMID:35072209

    Open questions at the time
    • Identity of the IL-7Rα-dependent niche signal not defined
  23. 2024 High

    Established a continuous peripheral requirement for IL-7Rα on mature CD4 T cells to sustain numbers, effector cytokine output, and autoimmune (EAE) pathogenesis.

    Evidence Inducible CD4-specific IL-7Rα KO mice, EAE model, cytokine and antigen-specific proliferation assays

    PMID:39380064

    Open questions at the time
    • Whether effect reflects survival versus functional reprogramming not fully separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple post-translational regulatory layers (endocytosis, polyglutamylation, γc sequestration) are integrated with transcriptional and splicing control to set context-specific IL-7Rα output remains unresolved.
  • No unified model linking trafficking, modification, and isoform balance
  • Structure of the active signaling complex on the cell surface lacking
  • Effectors driving non-lymphoid (myeloid, niche) IL-7Rα functions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0048018 receptor ligand activity 2 GO:0140313 molecular sequestering activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005576 extracellular region 2 GO:0005768 endosome 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-8953854 Metabolism of RNA 2
Partners
CCP2CRLF2CXCR4IL2RGJAK1JAK3STAT5TTLL4
Complex memberships
IL-7 receptor (IL-7Rα/γc)IL-7Rα/CRLF2 (TSLP receptor)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Loss-of-function mutations in IL7R cause T(-)B(+)NK(+) severe combined immunodeficiency (SCID), demonstrating that IL-7Rα signaling is specifically required for T-cell but not NK-cell development in humans. Genetic analysis of SCID patients with defective IL7R expression; comparison with XSCID and JAK3-SCID phenotypes Nature genetics High 9843216
2004 IL-7 and other prosurvival cytokines (IL-2, IL-4, IL-6, IL-15) suppress IL7Rα transcription in T cells, creating a homeostatic mechanism to share limiting IL-7. In CD8+ T cells this involves the transcriptional repressor GFI1, while CD4+ T cells use a different molecular mechanism. Transcriptional reporter assays, GFI1 functional analysis, cytokine stimulation of primary T cells with measurement of IL7R mRNA Immunity High 15308108
2009 The IL-7Rα ectodomain uses glycosylation to modulate binding to IL-7; glycosylated IL-7Rα binds IL-7 ~300-fold more tightly than unglycosylated IL-7Rα, primarily due to an accelerated on-rate. SCID-causing mutations in IL-7Rα locate outside the IL-7 binding interface, suggesting they cause protein folding defects rather than disrupting direct ligand contact. Crystal structure of IL-7/IL-7Rα complex (with both glycosylated and unglycosylated receptor), biophysical binding measurements Structure High 19141282
2010 IL-7 triggers rapid clathrin-mediated endocytosis of IL-7Rα, decreases receptor recycling, and accelerates lysosomal and proteasomal degradation, reducing IL-7Rα half-life from ~24 hours to ~3 hours. Clathrin-dependent endocytosis is required for efficient IL-7 signal transduction, and IL-7Rα degradation depends on JAK3 activation. Live-cell imaging, clathrin inhibitor experiments, JAK3/pan-JAK inhibitor pretreatment, pulse-chase degradation assays in T cells Blood High 20190194
2011 Somatic gain-of-function mutations in IL7R exon 6 (predominantly introducing an unpaired cysteine in the extracellular juxtamembrane-transmembrane region) found in ~9% of T-ALL patients drive constitutive IL-7Rα homodimerization via intermolecular disulfide bonds and activate JAK1 signaling independently of IL-7, γc, or JAK3, promoting cell transformation and tumor formation. Biochemical analysis (disulfide bond formation), cytokine-independent growth assays, tumor formation in mice, gene expression profiling Nature genetics High 21536738 21892159
2011 In B-cell precursor ALL, IL7R gain-of-function mutations (serine-to-cysteine at aa185 or transmembrane domain indels) enable formation of a functional receptor with CRLF2 that signals in response to TSLP. A cysteine residue is essential for constitutive receptor activation conferring cytokine-independent growth. Biochemical and functional assays for cytokine-independent growth, co-expression with CRLF2, cysteine mutagenesis The Journal of experimental medicine High 21536738
2011 Vps34 (class III PI3K) regulates IL-7Rα intracellular trafficking in T cells. Loss of Vps34 mislocates endosomal markers (Eea1, HRS, Vps36), preventing internalized IL-7Rα from entering the retromer pathway for surface recycling, leading to reduced IL-7Rα surface expression and T lymphocyte death. Conditional Vps34 knockout mice, subcellular fractionation, endosomal marker localization, IL-7Rα surface expression by flow cytometry Journal of immunology Medium 22021616
2008 Regulatory T cell development requires IL-7Rα signaling. IL-7Rα-deficient mice have a striking reduction in Treg cells and Foxp3 expression. Either IL-7 or TSLP can provide the required IL-7Rα signal for Treg development in the thymus, as combined loss of IL-7 and TSLP receptor (but not either alone) greatly reduces thymic Treg development. IL-7Rα−/− mice, IL-7 KO mice, TSLP receptor KO mice, double KO mice; phenotypic analysis by flow cytometry and Foxp3 expression; Treg suppression assays Blood High 18664628
2013 Soluble IL-7Rα (sIL-7Rα) has moderate affinity for IL-7 but does not bind TSLP. It competes with cell-associated IL-7R to reduce excessive IL-7 consumption, thereby potentiating IL-7 bioactivity when cytokine is limited. sIL-7Rα also diminishes IL-7 signaling-induced expression of CD95 and SOCS1. In vivo, sIL-7Rα enhances homeostatic T cell expansion and exacerbates experimental autoimmune encephalomyelitis. Binding affinity measurements, functional IL-7 signaling assays, murine in vivo models of homeostatic expansion and EAE PNAS High 23610432
2007 DNA methylation of the IL7R gene promoter regulates IL-7Rα expression in human T cells. IL-7Rαhigh CD8+ T cells have decreased methylation at the IL7Rα promoter compared with IL-7Rαlow cells. Treatment with the demethylating agent 5-aza-2'-deoxycytidine increased IL-7Rα expression, and unmethylated promoter constructs showed higher luciferase reporter activity. Bisulfite sequencing of IL7R promoter, 5-aza-2'-deoxycytidine treatment, luciferase reporter assay with methylated vs. unmethylated promoter constructs Journal of immunology Medium 17442928
2012 IL-7 downregulates IL-7Rα (CD127) surface expression on human CD8+ T cells by two independent mechanisms: (1) early reduction of surface CD127 protein independent of transcriptional suppression and independent of JAK activity; (2) delayed JAK/STAT5-dependent suppression of CD127 transcripts. The magnitude and duration of suppression depend on IL-7 concentration. Primary human CD8+ T cell stimulation with IL-7, JAK inhibitor treatment, surface protein and mRNA kinetics, dose-response experiments Immunology and cell biology Medium 23207282
2012 CPSF1 (cleavage and polyadenylation specificity factor 1) binds a consensus polyadenylation signal (AAUAAA) in intron 6 of IL7R and promotes skipping of exon 6, increasing production of the soluble IL-7Rα isoform. Mutations to this intronic site or CPSF1 knockdown both increase exon 6 inclusion. This establishes competing splicing/polyadenylation as a mechanism regulating the ratio of soluble to membrane-bound IL-7R. RNA affinity chromatography coupled to mass spectrometry, CPSF1 knockdown, mutagenesis of polyadenylation signal, alternative splicing assays RNA High 23151878
2017 The RNA helicase DDX39B is a potent activator of IL7R exon 6 inclusion (repressing soluble IL-7Rα production). A genetic variant in the 5' UTR of DDX39B reduces DDX39B translation, increasing soluble IL-7Rα. DDX39B variants show strong genetic and functional epistasis with IL7R exon 6 alleles in determining MS risk. Genetic epistasis analysis, functional reporter assays for exon 6 splicing, DDX39B overexpression/knockdown, translation reporter assays Cell High 28340352
2014 IL-7 signaling through IL-7Rα suppresses premature immunoglobulin light-chain rearrangement in developing human B cells. Neutralization of IL-7 in xenogeneic cultures led to increased Ig light-chain rearrangements in CD127+ cells, identifying this as the most definitive function of IL-7 in human B-cell development characterized in this system. Human/murine xenogeneic B-cell cultures, IL-7 neutralization, IGH locus conformation by 3D FISH, Ig gene rearrangement analysis Blood Medium 21680796
2014 The IL-7Rα Tyr449 cytoplasmic SH2-binding motif is critical for IL-7-mediated pro-B and pre-B cell survival and differentiation in the bone marrow. IL-7Rα(449F/449F) knock-in mice show loss of STAT5 activation and diminished Mcl1 expression in pro-B cells, and defective Igμ rearrangement in pre-B cells. Bcl-2 overexpression does not rescue the pro-B cell defect. Tyr449Phe knock-in mouse, flow cytometry of B cell stages, STAT5 phosphorylation assay, Bcl-2 transgene rescue experiment, Rag1/Rag2/Irf4 expression analysis Journal of immunology High 25143441
2017 IL-7Rα polyglutamylation (catalyzed by TTLL4 and TTLL13) and deglutamylation (by CCP2) regulate ILC3 development. IL-7Rα polyglutamylation triggers STAT5 activation and induces transcription factor Sall3 in innate lymphoid progenitors, driving ILC3 differentiation. The IL-7Rα E446A mutation reduces Sall3 expression and the ILC3 population. CCP2-deficient mice, TTLL4/TTLL13 knockout mice, IL-7Rα E446A knock-in mice, STAT5 phosphorylation, Sall3 expression analysis Nature communications High 28794449
2020 IL-7Rα (γc-shared subunit) sequesters γc by direct binding and pre-association, limiting γc availability for IL-2R assembly. Overexpression of IL-7Rα (including signaling-deficient tailless versions) suppresses IL-2R signaling via extracellular domain interactions, demonstrating that IL-7Rα abundance governs IL-2R signaling capacity and that downregulation of IL-7Rα in Treg cells is mechanistically necessary to maximize IL-2R signaling. IL-7Rα overexpression (including tailless mutant), IL-2 and IL-7 signaling readouts (STAT5 phosphorylation), co-immunoprecipitation of γc with IL-7Rα iScience Medium 32791329
2021 Overexpression of wild-type IL-7Rα (without activating mutations) is sufficient to drive T-cell leukemogenesis in mice, associated with hyperactivation of PI3K/Akt, Notch, and JAK/STAT signaling pathways, increased Bcl-2, and downregulation of p27Kip1. Established tumors can progress independently of high IL-7Rα levels but remain sensitive to IL-7R-mediated signaling inhibitors. Tetracycline-inducible Il7r transgenic mice and Rosa26 IL7R knock-in mice; immunophenotyping; pathway inhibitor assays (ruxolitinib, AZD1208, dactolisib, palbociclib, venetoclax) Blood High 33970999
2019 IL-7R interacts physically with CXCR4 and recruits BCR-ABL1 and JAK kinases in close proximity, forming a molecular platform for BCR-ABL1-induced transformation in Ph+ ALL. BCR-ABL1 kinase inhibitor treatment elevates IL7R expression, enabling leukemia cell survival via IL-7 when combined with inhibitors. Anti-IL-7R antibody treatment prevents leukemia in xenotransplantation models. Co-immunoprecipitation of IL7R with CXCR4, patient-derived Ph+ ALL xenotransplantation, anti-IL7R antibody treatment, IL7R expression analysis upon kinase inhibitor treatment Nature communications Medium 32581241
2019 IL-7R expression is essential for leukemia-initiating cell (LIC) activity in Notch1-induced T-ALL. Il7r-deficient hematopoietic progenitors expressing constitutively active Notch1 fail to generate leukemia in transplantation models. IL-7R expression is an early functional biomarker of T-ALL LIC potential, and impaired IL-7R signaling hampers engraftment of patient-derived T-ALL and B-ALL xenografts. Genetic loss-of-function (Il7r-deficient mice), Notch1-induced leukemia transplantation model, patient-derived xenograft engraftment assays Blood High 31530562
2002 IL-7Rα and E47 (E2A) promote lymphoid progenitor development through distinct survival pathways. E2A acts through suppression of caspase-3 activation (not rescued by Bcl-2), whereas IL-7Rα acts through a separate pathway. Mice lacking both IL-7Rα and E47 show a synergistic reduction of T-cell, NK-cell, and multipotent progenitors in the thymus. Double-knockout mice (IL-7Rα−/− × E47−/−), caspase-3 assays, Bcl-2 overexpression rescue experiment The EMBO journal High 11782430
2005 IL-7Rα is required for proliferative expansion at the pre-BII stage of B-cell development in vivo, independently of the pre-BCR. Both the pre-BCR and IL-7Rα are required for optimal pre-BII cell expansion (double-KO shows greater reduction than either single KO). The pre-BCR does not mediate down-regulation of IL-7Rα, as IL-7Rα expression is normal in pre-BCR-deficient mice. Pre-BCR/IL-7Rα double-knockout mice, flow cytometric analysis of B-cell stages, IL-7Rα expression in pre-BCR KO mice European journal of immunology High 15909309
2012 IL-15 (not IL-7) mediates downregulation of IL-7Rα (CD127) mRNA and protein on memory-phenotype CD8+ T cells in the bone marrow. CD127 mRNA was lower in bone marrow than spleen CD44hi CD8+ T cells. Neither Foxo1 nor IL-7 was responsible for this organ-specific regulation. Comparison of CD127tg, IL-7 KO, IL-15 KO, IL-15Rα KO and wild-type mice; mRNA quantification; Foxo1 level analysis European journal of immunology Medium 22539288
2014 Notch-RBP-Jκ signaling drives IL-7Rα expression in γδ T cells via a novel IL-7Rα promoter. Conditional RBP-Jκ deletion selectively abolishes IL-7Rα expression on γδ T cells and reduces IL-17+ γδ T cell pool size. Without IL-7Rα-mediated signaling, IL-17+ γδ T cells are barely maintained, and exogenous IL-7 selectively expands this subset in vitro. Genome-wide Notch target gene analysis, RBP-Jκ conditional KO mice, constitutive Notch signaling in vivo and in vitro, IL-7 supplementation assays Journal of immunology Medium 25429074
2019 IL-7Rα is expressed on fetal monocytes during differentiation into tissue-resident macrophages (trMacs). Blockade of IL-7R function during late gestation specifically impairs establishment of fetal-derived trMacs in vivo. Yolk sac erythromyeloid progenitors do not express IL-7R and yolk sac hematopoiesis is unperturbed in IL-7R-deficient mice, demonstrating a distinct fetal myeloid role for IL-7Rα. Il7r-Cre lineage tracing, IL-7R-deficient mice, IL-7R blockade during gestation, fetal monocyte in vitro differentiation, IL-7Rα surface expression tracking across fetal development Development High 31332039
2012 IL-7/IL-7Rα signaling withdrawal reduces POT1 protein synthesis, a component of the telomere-protective shelterin complex, leading to telomere erosion and activation of the p53 pathway. In IL-7Rα/p53 double-null mice, loss of apoptosis uncovers augmented thymic lymphomagenesis with chromosomal anomalies. IL-7Rα null/p53 null double KO mice, POT1 protein expression assays, telomere length analysis, chromosomal analysis of lymphomas Cell death and differentiation Medium 22281704
2015 Ikaros directly binds the IL7R promoter and suppresses its expression; loss of Ikaros function in B-ALL is associated with high IL7R expression. Casein kinase inhibition (which increases Ikaros function) suppresses IL7R expression in an Ikaros-dependent manner. Ikaros ChIP at the IL7R promoter, casein kinase inhibitor treatment, Ikaros knockdown/overexpression with IL7R expression readout Oncotarget Medium 27322554
2022 IL-7 signaling through CD127 (IL-7Rα) in monocytes engages STAT5-coordinated transcriptional programs that restrain inflammatory gene expression. CD127-positive monocytes display hypoinflammatory phenotypes within highly inflammatory environments (COVID-19 and rheumatoid arthritis). Single-cell transcriptomics of human inflammatory monocytes, flow cytometry, functional IL-7 stimulation assays measuring inflammatory gene expression The Journal of experimental medicine Medium 35015026
2022 IL7Rα, but not Flk2, is intrinsically required for HSC reconstitution of tissue-resident lymphoid cells (B1a, marginal zone B cells, lung ILC2s, and Tregs). IL7Rα-deficient environments also impair TLC reconstitution upon transplantation, revealing a cell-extrinsic (niche) role for IL7Rα in TLC establishment. Flk2-Cre and Il7r-Cre lineage tracing, Flk2 and IL7Rα single and double KO mice, reciprocal bone marrow transplants Development High 35072209
2024 Inducible deletion of IL-7Rα specifically on peripheral CD4+ T cells leads to gradual, substantial decrease in CD4+ T cell numbers and prevents EAE development. IL-7Rα-deficient CD4+ T cells show decreased numbers and reduced production of TNF, IFN-γ, IL-17A, GM-CSF, and reduced antigen-specific proliferation. Il7rafl/fl/CD4CreERT2 inducible conditional KO mice, EAE model, flow cytometry, cytokine production assays, MOG-specific T cell tracking Journal of neuroinflammation High 39380064
2022 IL-7 stimulation promotes sCD127 mRNA expression and sCD127 (soluble IL-7Rα) release from CD8+ T cells via a PI3K-dependent pathway, and enhances CD8+ T cell cytotoxicity. PI3K inhibition dampens IL-7-induced elevation of CD8+ T cell cytotoxicity. IL-7 stimulation of primary human CD8+ T cells, PI3K pathway inhibitors, sCD127 ELISA, mRNA measurement, cytotoxicity co-culture assays BMC immunology Low 35850640
2016 TSLP or IL-7 (both signaling via IL-7Rα) can provide the critical signal for human B-cell production. In vitro human B-cell production is almost completely blocked without IL-7Rα stimulation. In xenograft models, human pro-B cell production depends on IL-7 (neutralizable by anti-IL-7 antibody), and this loss can be restored by physiological levels of human TSLP. In vitro xenograft models of human B-cell development, IL-7 neutralizing antibody, TSLP supplementation, pro-B cell quantification European journal of immunology Medium 27325567

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Nature genetics 602 9843216
2004 Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity 386 15308108
2011 Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nature genetics 329 21892159
2019 Flip the coin: IL-7 and IL-7R in health and disease. Nature immunology 300 31745336
2011 Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias. The Journal of experimental medicine 281 21536738
2012 IL-7 signaling and CD127 receptor regulation in the control of T cell homeostasis. Seminars in immunology 206 22551764
2014 The human long noncoding RNA lnc-IL7R regulates the inflammatory response. European journal of immunology 165 24723426
2015 Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia. Haematologica 135 26206799
2005 Interleukin-7 receptor alpha (IL-7Ralpha) deficiency: cellular and molecular bases. Analysis of clinical, immunological, and molecular features in 16 novel patients. Immunological reviews 128 15661025
2013 Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity. Proceedings of the National Academy of Sciences of the United States of America 124 23610432
2010 Increased CD127 expression on activated FOXP3+CD4+ regulatory T cells. European journal of immunology 111 20690182
2008 Development of regulatory T cells requires IL-7Ralpha stimulation by IL-7 or TSLP. Blood 105 18664628
2010 IL-7 induces rapid clathrin-mediated internalization and JAK3-dependent degradation of IL-7Ralpha in T cells. Blood 103 20190194
2005 Altered IL-7Ralpha expression with aging and the potential implications of IL-7 therapy on CD8+ T-cell immune responses. Blood 103 16357322
2008 CD127 and CD25 expression defines CD4+ T cell subsets that are differentially depleted during HIV infection. Journal of immunology (Baltimore, Md. : 1950) 101 18390743
2022 The Role of IL-7 and IL-7R in Cancer Pathophysiology and Immunotherapy. International journal of molecular sciences 90 36142322
2017 Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk. Cell 85 28340352
2006 IL-7Ralpha expression on CD4+ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation. European journal of immunology 84 16421946
2004 Mutations in genes required for T-cell development: IL7R, CD45, IL2RG, JAK3, RAG1, RAG2, ARTEMIS, and ADA and severe combined immunodeficiency: HuGE review. Genetics in medicine : official journal of the American College of Medical Genetics 81 14726805
2011 The class III kinase Vps34 promotes T lymphocyte survival through regulating IL-7Rα surface expression. Journal of immunology (Baltimore, Md. : 1950) 77 22021616
2009 Structural and biophysical studies of the human IL-7/IL-7Ralpha complex. Structure (London, England : 1993) 77 19141282
2019 The lymphoid-associated interleukin 7 receptor (IL7R) regulates tissue-resident macrophage development. Development (Cambridge, England) 56 31332039
2022 CD127 imprints functional heterogeneity to diversify monocyte responses in inflammatory diseases. The Journal of experimental medicine 55 35015026
2022 Significance of IL-7 and IL-7R in RA and autoimmunity. Autoimmunity reviews 55 35595051
2010 Genetic variation in the IL7RA/IL7 pathway increases multiple sclerosis susceptibility. Human genetics 54 20112030
2007 Down-regulation of IL-7Ralpha expression in human T cells via DNA methylation. Journal of immunology (Baltimore, Md. : 1950) 53 17442928
2003 Interleukin-7 (IL-7) and IL-7 receptor (IL-7R) signalling complex in human solid tumours. Histology and histopathology 52 12792903
2009 Variation in the IL7RA and IL2RA genes in German multiple sclerosis patients. Journal of autoimmunity 51 19231135
2019 A fully human anti-IL-7Rα antibody promotes antitumor activity against T-cell acute lymphoblastic leukemia. Leukemia 48 30850736
2020 Optimal identification of human conventional and nonconventional (CRTH2-IL7Rα-) ILC2s using additional surface markers. The Journal of allergy and clinical immunology 47 32032632
2021 Overexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma. Blood 45 33970999
2022 Single-cell profiling of human CD127+ innate lymphoid cells reveals diverse immune phenotypes in hepatocellular carcinoma. Hepatology (Baltimore, Md.) 44 35243668
2002 IL-7Ralpha and E47: independent pathways required for development of multipotent lymphoid progenitors. The EMBO journal 41 11782430
2016 Therapeutic targeting of IL-7Rα signaling pathways in ALL treatment. Blood 40 27268088
2012 Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients. Genes and immunity 40 22914435
2019 IL-7R is essential for leukemia-initiating cell activity of T-cell acute lymphoblastic leukemia. Blood 39 31530562
2019 Context-specific regulation of surface and soluble IL7R expression by an autoimmune risk allele. Nature communications 37 31594933
2018 Long-Term Health Outcome and Quality of Life Post-HSCT for IL7Rα-, Artemis-, RAG1- and RAG2-Deficient Severe Combined Immunodeficiency: a Single Center Report. Journal of clinical immunology 37 30105620
2012 Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6. RNA (New York, N.Y.) 37 23151878
2021 Expression of KLRG1 and CD127 defines distinct CD8+ subsets that differentially impact patient outcome in follicular lymphoma. Journal for immunotherapy of cancer 36 34226281
2019 Expression of IL-7Rα and KLRG1 defines functionally distinct CD8+ T-cell populations in humans. European journal of immunology 36 30883723
2018 Human CD4+ CD25+ CD127hi cells and the Th1/Th2 phenotype. Clinical immunology (Orlando, Fla.) 36 29330114
2012 The influence of HIV on CD127 expression and its potential implications for IL-7 therapy. Seminars in immunology 36 22421574
2020 Tissue memory CD4+ T cells expressing IL-7 receptor-alpha (CD127) preferentially support latent HIV-1 infection. PLoS pathogens 35 32353080
2016 TSLP or IL-7 provide an IL-7Rα signal that is critical for human B lymphopoiesis. European journal of immunology 35 27325567
2009 IL7RA polymorphisms and chronic inflammatory arthropathies. Tissue antigens 35 19744146
2016 Co-existence of IL7R high and SH2B3 low expression distinguishes a novel high-risk acute lymphoblastic leukemia with Ikaros dysfunction. Oncotarget 32 27322554
2007 Prevention of graft-versus-host disease by anti IL-7Ralpha antibody. Blood 32 17595335
2022 Lnc-IL7R alleviates PM2.5-mediated cellular senescence and apoptosis through EZH2 recruitment in chronic obstructive pulmonary disease. Cell biology and toxicology 31 35303175
2019 New anti-IL-7Rα monoclonal antibodies show efficacy against T cell acute lymphoblastic leukemia in pre-clinical models. Leukemia 31 31439943
2017 IL-7Rα glutamylation and activation of transcription factor Sall3 promote group 3 ILC development. Nature communications 30 28794449
2022 IL7R Is Correlated With Immune Cell Infiltration in the Tumor Microenvironment of Lung Adenocarcinoma. Frontiers in pharmacology 29 35264973
2012 IL-7 downregulates IL-7Rα expression in human CD8 T cells by two independent mechanisms. Immunology and cell biology 27 23207282
2014 A genome-wide analysis identifies a notch-RBP-Jκ-IL-7Rα axis that controls IL-17-producing γδ T cell homeostasis in mice. Journal of immunology (Baltimore, Md. : 1950) 26 25429074
2011 IL-7R expression and IL-7 signaling confer a distinct phenotype on developing human B-lineage cells. Blood 26 21680796
2005 Both the pre-BCR and the IL-7Ralpha are essential for expansion at the pre-BII cell stage in vivo. European journal of immunology 26 15909309
2012 The IL-7Rα pathway is quantitatively and functionally altered in CD8 T cells in multiple sclerosis. Journal of immunology (Baltimore, Md. : 1950) 25 22262655
2010 IL-7Rα confers susceptibility to experimental autoimmune encephalomyelitis. Genes and immunity 25 20861865
2017 Lnc‑IL7R promotes the growth of fibroblast‑like synoviocytes through interaction with enhancer of zeste homolog 2 in rheumatoid arthritis. Molecular medicine reports 24 28138707
2015 Effector CD8+ T-cell Engraftment and Antitumor Immunity in Lymphodepleted Hosts Is IL7Rα Dependent. Cancer immunology research 23 26297711
2025 The development and potent antitumor efficacy of CD44/CD133 dual-targeting IL7Rα-armored CAR-T cells against glioblastoma. Cancer letters 22 39952598
2024 Human CD127 negative ILC2s show immunological memory. The Journal of experimental medicine 22 38889332
2020 The Cytokine Receptor IL-7Rα Impairs IL-2 Receptor Signaling and Constrains the In Vitro Differentiation of Foxp3+ Treg Cells. iScience 22 32791329
2017 Variants in the IL7RA gene confer susceptibility to multiple sclerosis in Caucasians: evidence based on 9734 cases and 10436 controls. Scientific reports 22 28446795
2012 IL-15 inhibits IL-7Rα expression by memory-phenotype CD8⁺ T cells in the bone marrow. European journal of immunology 22 22539288
2020 Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia. Nature communications 21 32581241
2019 Deleterious and Oncogenic Mutations in the IL7RA. Cancers 21 31817502
2017 CD56bright NK IL-7Rα expression negatively associates with HCV level, and IL-7-induced NK function is impaired during HCV and HIV infections. Journal of leukocyte biology 21 28400540
2016 Decreased IL7Rα and TdT expression underlie the skewed immunoglobulin repertoire of human B-cell precursors from fetal origin. Scientific reports 21 27658954
2014 The survival and differentiation of pro-B and pre-B cells in the bone marrow is dependent on IL-7Rα Tyr449. Journal of immunology (Baltimore, Md. : 1950) 21 25143441
2013 IL7Rα contributes to experimental autoimmune encephalomyelitis through altered T cell responses and nonhematopoietic cell lineages. Journal of immunology (Baltimore, Md. : 1950) 20 23530149
2012 Identification of IL7RA risk alleles for rapid progression during HIV-1 infection: a comprehensive study in the GRIV cohort. Current HIV research 20 22329520
2012 IL-7Rα deficiency in p53null mice exacerbates thymocyte telomere erosion and lymphomagenesis. Cell death and differentiation 18 22281704
2015 Lack of IL7Rα expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD). Clinical immunology (Orlando, Fla.) 17 26499378
2023 PD-1 blockade potentiates neoadjuvant chemotherapy in NSCLC via increasing CD127+ and KLRG1+ CD8 T cells. NPJ precision oncology 16 37231145
2023 BMI1-induced CD127+KLRG1+ memory T cells enhance the efficacy of liver cancer immunotherapy. Cancer letters 16 37562671
2024 The IL-7R antagonist lusvertikimab reduces leukemic burden in xenograft ALL via antibody-dependent cellular phagocytosis. Blood 15 38518105
2023 Dexamethasone potentiates chimeric antigen receptor T cell persistence and function by enhancing IL-7Rα expression. Molecular therapy : the journal of the American Society of Gene Therapy 15 38140726
2022 Mutant IL7R collaborates with MYC to induce T-cell acute lymphoblastic leukemia. Leukemia 15 35581375
2019 Opposing roles of endothelial and leukocyte-expressed IL-7Rα in the regulation of psoriasis-like skin inflammation. Scientific reports 15 31406267
2008 IL-2 receptor gamma chain cytokines differentially regulate human CD8+CD127+ and CD8+CD127- T cell division and susceptibility to apoptosis. International immunology 15 19011158
2020 Expression of CD4+CD25+CD127Low regulatory T cells and cytokines in peripheral blood of patients with primary liver carcinoma. International journal of medical sciences 14 32218692
2019 Reduced Function and Diversity of T Cell Repertoire and Distinct Clinical Course in Patients With IL7RA Mutation. Frontiers in immunology 14 31379863
2015 IL7RA polymorphisms predict the CD4+ recovery in HIV patients on cART. European journal of clinical investigation 14 26402121
2020 Impaired lnc-IL7R modulatory mechanism of Toll-like receptors is associated with an exacerbator phenotype of chronic obstructive pulmonary disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 13 32780913
2018 Knockout of zebrafish interleukin 7 receptor (IL7R) by the CRISPR/Cas9 system delays retinal neurodevelopment. Cell death & disease 13 29449560
2016 Screening for peptides targeted to IL-7Rα for molecular imaging of rheumatoid arthritis synovium. Arthritis research & therapy 13 27729062
2010 Variation in SNPs of the IL7Ra gene is associated with multiple sclerosis in the Iranian population. Immunological investigations 13 21190413
2017 IL-7Rα Expression Regulates Murine Dendritic Cell Sensitivity to Thymic Stromal Lymphopoietin. Journal of immunology (Baltimore, Md. : 1950) 12 28404633
2011 Relevance of IL7R genotype and mRNA expression in Dutch patients with multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England) 12 21543551
2004 IgH DJ rearrangements within T-ALL correlate with cCD79a expression, an immature/TCRgammadelta phenotype and absence of IL7Ralpha/CD127 expression. Leukemia 12 15483677
2022 IL7Rα, but not Flk2, is required for hematopoietic stem cell reconstitution of tissue-resident lymphoid cells. Development (Cambridge, England) 11 35072209
2022 Interleukin-7 regulates CD127 expression and promotes CD8+ T cell activity in patients with primary cutaneous melanoma. BMC immunology 11 35850640
2022 IL-7/IL7R axis dysfunction in adults with severe community-acquired pneumonia (CAP): a cross-sectional study. Scientific reports 11 35907923
2021 CHBP induces stronger immunosuppressive CD127+ M-MDSC via erythropoietin receptor. Cell death & disease 11 33579907
2016 Blockade of IL-7Rα alleviates collagen-induced arthritis via inhibiting Th1 cell differentiation and CD4+ T cell migration. Molecular immunology 11 27736699
2012 Somatic mutation of IL7R exon 6 in acute leukemias and solid cancers. Human pathology 11 23069254
2010 Association between the IL7R T244I polymorphism and multiple sclerosis: a meta-analysis. Molecular biology reports 11 21161391
2024 IL-7Rα on CD4+ T cells is required for their survival and the pathogenesis of experimental autoimmune encephalomyelitis. Journal of neuroinflammation 10 39380064
2020 IL7RA genetic variants differentially affect IL-7Rα expression and alternative splicing: a role in autoimmune and infectious diseases? Genes and immunity 10 31929513

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