Affinage

IL7R

Interleukin-7 receptor subunit alpha · UniProt P16871

Length
459 aa
Mass
51.6 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL-7Rα (encoded by IL7R) is the ligand-binding subunit of the IL-7 receptor, essential for T-cell development, B lymphopoiesis, regulatory T-cell generation, innate lymphoid cell differentiation, and tissue-resident macrophage establishment. IL-7Rα pairs with the common γ chain (γc) to signal through JAK1/JAK3–STAT5 and PI3K/Akt pathways; the intracellular Y449 motif is specifically required for lymphocyte survival and transformation, and loss-of-function IL7R mutations cause T(−)B(+)NK(+) SCID (PMID:9843216, PMID:20440272). Gain-of-function mutations—predominantly introducing unpaired cysteines in the extracellular juxtamembrane-transmembrane region—drive ligand-independent homodimerization and constitutive JAK1 signaling that transforms T- and B-cell progenitors in acute lymphoblastic leukemia (PMID:21892159, PMID:21536738, PMID:31530562). Receptor availability is tightly controlled at multiple levels: alternative splicing of exon 6 (regulated by CPSF1 and DDX39B) sets the ratio of membrane-bound to soluble isoforms influencing autoimmune disease risk, IL-7 binding triggers clathrin/dynamin-dependent endocytosis and proteasomal degradation, and polyglutamylation by TTLL4/TTLL13 (reversed by CCP2) activates STAT5-Sall3 signaling to direct ILC3 fate (PMID:17660817, PMID:23151878, PMID:28340352, PMID:26272555, PMID:28794449).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 High

    The fundamental question of whether IL-7Rα is required for human lymphocyte development was answered: loss-of-function IL7R mutations cause T(−)B(+)NK(+) SCID, establishing that IL-7Rα signaling is essential for T-cell but dispensable for NK-cell ontogeny.

    Evidence Identification of IL7R mutations in SCID patients with defined T/B/NK cell phenotyping

    PMID:9843216

    Open questions at the time
    • Precise downstream signaling pathways mediating the T-cell developmental block were not delineated
    • Whether IL-7Rα contributes to non-lymphoid lineages was unknown
  2. 2007 High

    A key regulatory question—how IL-7Rα surface expression is controlled—was addressed by demonstrating that alternative splicing of exon 6 governs the ratio of membrane-bound to soluble receptor isoforms, and that a common SNP (rs6897932) disrupting an exonic splicing silencer alters this ratio and confers multiple sclerosis risk.

    Evidence Functional splicing assays with minigenes; genetic association replicated across four independent MS cohorts

    PMID:17660817

    Open questions at the time
    • Trans-acting splicing factors controlling exon 6 inclusion were unidentified
    • How soluble IL-7Rα modulates IL-7 bioavailability in vivo was unclear
  3. 2008 High

    IL-7Rα's role was extended beyond conventional T cells to thymic regulatory T-cell development: double-deficient IL-2Rβ/IL-7Rα mice phenocopy γc deficiency for Foxp3+ Treg loss, establishing IL-7Rα as a non-redundant contributor to Treg ontogeny.

    Evidence IL-2Rβ/IL-7Rα double-knockout mice with thymic reconstitution and Foxp3+ Treg quantification

    PMID:18566388

    Open questions at the time
    • Whether IL-7Rα acts at the commitment or survival stage of Treg development was not resolved
    • The relative quantitative contributions of IL-2 vs. IL-7 signaling to Treg generation remained unclear
  4. 2010 High

    The specific intracellular signaling motif responsible for IL-7Rα's pro-survival and transforming activity was identified: Y449F knock-in mice showed that the Y449 motif is required for IL-7-driven lymphocyte transformation and bone marrow B-cell survival.

    Evidence IL-7Rα Y449F knock-in mice crossed with transgenic IL-7 and Eμ-myc lymphomagenesis models

    PMID:20440272

    Open questions at the time
    • Which specific downstream effectors (STAT5 vs. PI3K) are recruited to Y449 in vivo to mediate transformation was not separated
    • Whether Y449 is sufficient or merely necessary for transformation was unresolved
  5. 2011 High

    The oncogenic mechanism of IL7R mutations in T-ALL and B-ALL was elucidated: gain-of-function mutations introduce unpaired cysteines that promote receptor homodimerization via de novo disulfide bonds, driving constitutive JAK1 signaling independent of IL-7, γc, or JAK3; in B-ALL, mutant IL-7Rα partners with CRLF2 for TSLP signaling.

    Evidence Disulfide bond biochemistry, cysteine requirement by mutagenesis, cell transformation assays, tumor formation in mice (two independent studies)

    PMID:21536738 PMID:21892159

    Open questions at the time
    • Structural basis for how a single cysteine substitution promotes homodimerization was not resolved at atomic resolution
    • Cooperating genetic events in full leukemogenesis were only partially characterized
  6. 2012 High

    Two regulatory layers of IL-7Rα were mechanistically defined: CPSF1 was identified as a trans-acting factor repressing exon 6 inclusion via intronic polyadenylation competition, and IL-7Rα signaling was shown to maintain telomere integrity through POT1 expression.

    Evidence RNA affinity chromatography/mass spectrometry with CPSF1 knockdown for splicing; IL-7Rα-null/p53-null double-KO mice with POT1 and telomere analyses

    PMID:22281704 PMID:23151878

    Open questions at the time
    • Additional trans-acting splicing factors beyond CPSF1 were not identified
    • Whether POT1 regulation is direct (transcriptional) or indirect via STAT5 was not determined
  7. 2013 High

    The biological function of soluble IL-7Rα was clarified: sIL-7Rα binds IL-7 with moderate affinity, competes with membrane-bound receptor to preserve IL-7 bioavailability under limiting conditions, and potentiates autoimmune pathology in vivo.

    Evidence Binding affinity measurements; murine homeostatic expansion and EAE models with sIL-7Rα administration

    PMID:23610432

    Open questions at the time
    • Physiological concentrations of sIL-7Rα in disease states were incompletely characterized
    • Whether sIL-7Rα functions as agonist or antagonist may depend on tissue IL-7 concentration, which was not fully mapped
  8. 2015 High

    The negative feedback mechanism for IL-7Rα surface expression was mapped: IL-7 binding triggers clathrin-dependent, dynamin-dependent internalization through lipid rafts, with trafficking from early to late endosomes and proteasomal degradation.

    Evidence Confocal microscopy with endosomal markers (EEA1, RAB7, 20S proteasome) and pharmacological inhibitors in primary human CD8 T cells

    PMID:26272555

    Open questions at the time
    • Ubiquitin ligase(s) targeting internalized IL-7Rα for proteasomal degradation were not identified
    • Whether lysosomal degradation also contributes was not resolved
  9. 2017 High

    DDX39B was established as a second major trans-acting regulator of IL7R splicing: it promotes exon 6 inclusion (membrane-bound isoform), and a DDX39B 5′ UTR variant reducing its translation shows strong epistasis with the IL7R exon 6 SNP for MS susceptibility.

    Evidence Splicing minigene assays; translational reporter assays; genetic epistasis analysis

    PMID:28340352

    Open questions at the time
    • Whether DDX39B acts directly on IL7R pre-mRNA or through an intermediary was not biochemically resolved
    • Additional helicase cofactors in the splicing complex were not identified
  10. 2017 High

    A novel post-translational modification—polyglutamylation—was discovered on IL-7Rα: TTLL4/TTLL13 catalyze this modification in innate lymphoid progenitors, triggering STAT5 activation and Sall3-driven ILC3 differentiation, while CCP2 reverses it.

    Evidence Enzymatic writer/eraser identification; IL-7Rα E446A knock-in mouse with reduced ILC3 numbers and Sall3 expression

    PMID:28794449

    Open questions at the time
    • The precise glutamate residues modified and the stoichiometry of polyglutamylation were not fully mapped
    • How polyglutamylation mechanistically enhances JAK/STAT signaling was not determined
  11. 2018 High

    Pharmacological dissection confirmed that gain-of-function IL-7Rα mutants signal through JAK1 and upregulate BCL-2 as a critical survival effector: ruxolitinib blocks mutant signaling and venetoclax kills mutant-transformed cells.

    Evidence In vitro signaling assays and in vivo leukemia models with JAK1/2 and BCL-2 inhibitors

    PMID:29854301

    Open questions at the time
    • Whether drug resistance mechanisms emerge upon prolonged JAK inhibition was not tested
    • Combination synergy was not systematically optimized
  12. 2019 High

    Multiple studies converged to define IL-7Rα's roles beyond classical lymphopoiesis and its therapeutic targetability: IL-7Rα marks and is required for leukemia-initiating cells in T-ALL; it is expressed on fetal monocytes and required for tissue-resident macrophage development; CD53 physically interacts with IL-7Rα to stabilize its surface expression; and anti-IL-7Rα antibodies show therapeutic efficacy via signaling blockade, ADCC, and internalization-based drug delivery.

    Evidence Il7r-KO Notch1 T-ALL model and PDX transplantation; Il7r-Cre lineage tracing with gestational blockade; Co-IP/PLA for CD53 interaction with CD53-KO mice; phage-display antibodies with crystal structures, ADCC assays, and xenograft models

    PMID:30850736 PMID:31332039 PMID:31439943 PMID:31530562 PMID:31748347 PMID:32581241

    Open questions at the time
    • Whether IL-7Rα's LIC-maintaining role is signaling-dependent or expression-level-dependent is not fully separated
    • The structural basis for CD53-mediated stabilization of IL-7Rα at the membrane is unknown
    • Optimal therapeutic antibody format (naked vs. ADC vs. bispecific) is not resolved
  13. 2021 High

    Overexpression of wild-type IL-7Rα—even without activating mutations—was shown to be sufficient for thymocyte self-renewal and T-ALL development, with activation of JAK/STAT, PI3K/Akt/mTOR, and Notch pathways.

    Evidence Two independent inducible IL7R transgenic mouse models with pharmacological pathway inhibition

    PMID:33970999

    Open questions at the time
    • Whether wild-type IL-7Rα overexpression requires IL-7 ligand for transformation or can signal ligand-independently at high density is not resolved
    • Cooperating mutations arising during leukemogenesis were not fully catalogued
  14. 2022 Medium

    IL-7Rα's requirement was extended to multiple tissue-resident lymphoid populations (B1a, MZ B, ILC2, Treg) via both cell-intrinsic signaling and extrinsic niche effects, and mutant IL7R was shown to cooperate with MYC in an in vivo zebrafish T-ALL model activating STAT5 and AKT.

    Evidence Il7r-Cre and Flk2-Cre lineage tracing with reciprocal transplantation in mice; transgenic zebrafish with limiting-dilution transplantation

    PMID:35072209 PMID:35581375

    Open questions at the time
    • The molecular nature of the IL-7Rα-dependent extrinsic niche signal is unknown
    • Whether zebrafish IL7R mutant cooperativity with MYC translates to mammalian models remains to be tested
  15. 2024 High

    The therapeutic mechanism of anti-IL-7Rα antibody lusvertikimab was defined as dual-acting: direct receptor antagonism plus macrophage-mediated ADCP, with efficacy correlating with CD127 surface density.

    Evidence PDX models with ADCP assays and CD127 expression correlation; combination with polychemotherapy

    PMID:38518105

    Open questions at the time
    • Patient selection biomarkers beyond CD127 expression are not established
    • Mechanisms of resistance to anti-IL-7Rα therapy are undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic structure of full-length IL-7Rα homodimers formed by gain-of-function cysteine mutations, the identity of ubiquitin ligases mediating post-endocytic degradation, the precise mechanism by which polyglutamylation enhances JAK/STAT activation, and whether soluble IL-7Rα is agonistic or antagonistic in different tissue microenvironments.
  • No full-length structural model of mutant IL-7Rα homodimer
  • Ubiquitin ligase(s) for IL-7Rα degradation not identified
  • Mechanistic link between polyglutamylation and STAT5 activation unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005576 extracellular region 3 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 6 R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 2
Partners
CD53CPSF1CRLF2CXCR4DDX39BIL2RGJAK1JAK3
Complex memberships
IL-7R (IL-7Rα/γc heterodimer)IL-7Rα/CRLF2 heterodimer

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(+) SCID, demonstrating that IL-7Rα signaling is required for human T-cell development but not NK-cell development, and that the T-cell (but not NK-cell) defect in X-linked SCID results from inactivation of IL-7Rα signaling. Genetic identification of IL7R mutations in SCID patients; comparison of T, B, NK cell phenotypes across SCID genotypes Nature genetics High 9843216
2007 A SNP (rs6897932) in alternatively spliced exon 6 of IL7R influences the ratio of soluble to membrane-bound IL-7Rα isoforms by disrupting an exonic splicing silencer, thereby affecting IL-7R signaling levels and multiple sclerosis risk. Functional SNP analysis; alternative splicing assays measuring soluble vs. membrane-bound isoform ratios Nature genetics High 17660817
2011 Somatic gain-of-function IL7R mutations in T-ALL (mostly in exon 6) introduce unpaired cysteines in the extracellular juxtamembrane-transmembrane region, promoting de novo intermolecular disulfide bonds between mutant IL-7Rα subunits and driving constitutive JAK1 signaling independently of IL-7, γc, or JAK3, leading to cell transformation and tumor formation. Biochemical assays (disulfide bond formation), signaling assays (JAK1 phosphorylation), cell transformation assays, mutagenesis (cysteine requirement), tumor formation in mice Nature genetics High 21892159
2011 Gain-of-function IL7R mutations in pediatric B- and T-ALL cause either S185C extracellular substitution or transmembrane domain insertions/deletions; the cysteine is essential for constitutive receptor activation; in B-cell precursor leukemias, mutant IL-7Rα forms a functional receptor with CRLF2 for TSLP signaling; these mutations confer cytokine-independent growth. Biochemical activation assays, cytokine-independent growth assays, mutagenesis confirming cysteine requirement, functional CRLF2 co-receptor assays The Journal of experimental medicine High 21536738
2013 Soluble IL-7Rα (sIL7Rα) has moderate affinity for IL-7 but does not bind TSLP; sIL7Rα competes with cell-associated IL-7R to reduce excessive IL-7 consumption, thereby enhancing IL-7 bioactivity when cytokine is limited; sIL7Rα also diminishes CD95 and SOCS1 expression during IL-7 signaling and potentiates homeostatic expansion and autoimmune encephalomyelitis in murine models. Binding affinity assays (sIL7Rα vs. IL-7/TSLP), in vitro signaling assays, murine homeostatic expansion models, EAE model Proceedings of the National Academy of Sciences of the United States of America High 23610432
2012 CPSF1 (cleavage and polyadenylation specificity factor 1) binds to a consensus polyadenylation signal (AAUAAA) in intron 6 of IL7R downstream of the exon 6 5' splice site and represses exon 6 inclusion; competing mRNA splicing and polyadenylation regulate the ratio of soluble to membrane-bound IL7R isoforms. RNA affinity chromatography/mass spectrometry to identify trans-acting factors; CPSF1 knockdown splicing assays; mutagenesis of polyadenylation signal RNA (New York, N.Y.) High 23151878
2017 The RNA helicase DDX39B is a potent activator of IL7R exon 6 splicing (promoting membrane-bound isoform) and repressor of soluble IL7R production; a genetic variant in the 5' UTR of DDX39B reduces its translation and shows strong genetic and functional epistasis with IL7R exon 6 allelic variants to increase MS risk. RNA helicase functional assays, genetic association analysis, translational reporter assays, splicing minigene assays, epistasis analysis Cell High 28340352
2015 IL-7 stimulation induces clathrin-mediated endocytosis of CD127 (IL-7Rα) in primary human CD8 T cells through a process dependent on lipid-raft formation and dynamin activity; internalized CD127 traffics from early endosomes (EEA1+) to late endosomes (RAB7+) and is subsequently degraded by the proteasome (20S subunit co-localization), providing a negative feedback mechanism on IL-7 signaling. Confocal microscopy with endosomal markers, inhibitor studies (clathrin, dynamin, lipid rafts), proteasome inhibition assays in primary human CD8 T cells Immunology and cell biology High 26272555
2017 IL-7Rα undergoes polyglutamylation catalyzed by TTLL4 and TTLL13 in common helper-like innate lymphoid progenitors; this polyglutamylation triggers STAT5 activation to initiate Sall3 transcription factor expression, driving ILC3 differentiation; CCP2 deglutamylase reverses this modification, and IL-7Rα E446A mutation reduces Sall3 expression and ILC3 numbers. Enzymatic assays identifying TTLL4/TTLL13 as writers and CCP2 as eraser; IL-7Rα E446A knockin mouse; ILC3 quantification; STAT5 phosphorylation assays Nature communications High 28794449
2010 Selective disruption of the Y449xxM motif of IL-7Rα (IL-7Rα(449F) knock-in mice) prevents IL-7-mediated T- and B-lymphocyte transformation in transgenic IL-7 and Eμ-myc models, and decreases B-cell viability in bone marrow progenitors; this demonstrates that IL-7Rα Y449 signaling is specifically required for lymphocyte transformation and survival signaling. Knock-in mouse model (IL-7Rα Y449F); crossing with transgenic IL-7 and Eμ-myc lymphomagenesis models; survival/viability assays Oncogene High 20440272
2019 IL-7R is essential for leukemia-initiating cell (LIC) activity in T-ALL: IL-7Rα-deficient hematopoietic progenitors transduced with constitutively active Notch1 fail to generate leukemia in vivo; IL-7R expression marks T-ALL cells with LIC potential; impaired IL-7R signaling hampers engraftment of patient-derived T-ALL xenografts; IL-7R-dependent LIC activity extends to B-ALL. Loss-of-function (Il7r-deficient mice), Notch1-induced T-ALL transplantation model, patient-derived xenografts, limiting-dilution transplantation assays Blood High 31530562
2021 Overexpression of wild-type IL-7Rα (without mutational activation) in mouse models drives thymocyte self-renewal, thymus hyperplasia, and fatal T-ALL with activation of JAK/STAT, PI3K/Akt/mTOR, and Notch signaling, with frequent PI3K/Akt hyperactivation and Bcl-2 upregulation; tumors remain sensitive to IL-7R-mediated signaling inhibitors. Tetracycline-inducible Il7r transgenic mice; Rosa26 IL7R knockin mice; pharmacological inhibitors (ruxolitinib, AZD1208, dactolisib, palbociclib, venetoclax); transcriptional profiling Blood High 33970999
2012 IL-7/IL-7Rα signaling maintains telomere integrity via regulation of POT1 (protection of telomere 1) expression; withdrawal of IL-7/IL-7Rα signaling diminishes POT1 protein synthesis, leading to telomere erosion, chromosomal anomalies (including Robertsonian translocations), and p53 pathway activation in developing T cells. IL-7Rα(null)p53(null) double-knockout mice; molecular analysis of POT1 expression; chromosomal and telomere analyses in thymic lymphomas; IL-7 withdrawal in IL-7-dependent p53(null) cells Cell death and differentiation High 22281704
2019 IL7R interacts physically with CXCR4 to recruit BCR-ABL1 and JAK kinases in proximity, forming a molecular platform for BCR-ABL1-induced transformation in Ph+ ALL; BCR-ABL1 kinase inhibitor treatment elevates IL7R expression enabling cytokine-dependent survival; anti-IL7R antibody treatment prevents leukemia development in xenotransplantation models. Co-immunoprecipitation of IL7R/CXCR4 interaction; signaling assays; BCR-ABL1 inhibitor experiments; patient-derived xenograft models with anti-IL7R antibody Nature communications High 32581241
2008 IL-7R signaling contributes to thymic T regulatory (Treg) cell development: mice doubly deficient in IL-2Rβ and IL-7Rα lack CD4+Foxp3+ Tregs to the same extent as γc-deficient mice; IL-7R signaling is also required for peripheral survival of CD4+Foxp3low cells in IL-2Rβ-deficient mice. IL-2Rβ/IL-7Rα double-knockout mice; thymic reconstitution experiments; Foxp3+ Treg quantification Journal of immunology High 18566388
2019 IL-7Rα is expressed on fetal monocytes and is required for tissue-resident macrophage (trMac) development; blockade of IL-7R function during late gestation specifically impairs establishment of fetal-derived trMacs in vivo; IL-7Rα surface expression is dynamically upregulated upon transition from fetal monocyte to macrophage within fetal tissues. Il7r-Cre lineage tracing; IL-7R blockade in vivo during late gestation; fetal monocyte in vitro differentiation; IL-7Rα surface expression tracking across fetal development Development (Cambridge, England) High 31332039
2019 Antibody B12 against human IL-7Rα impairs IL-7/IL-7R-mediated signaling, is rapidly internalized and traffics to the lysosome upon binding, sensitizes T-ALL cells to dexamethasone, induces NK-mediated ADCC in vitro, and delays T-cell leukemia development in vivo; an B12-MMAE antibody-drug conjugate shows increased leukemia cell killing. Phage-display antibody generation; signaling assays; confocal microscopy of receptor internalization/lysosomal trafficking; in vitro ADCC assays; in vivo xenograft models; ADC efficacy assays Leukemia High 30850736
2019 Anti-IL-7Rα monoclonal antibodies (two distinct epitopes shown by crystal structures) mediate ADCC-dependent and independent therapeutic efficacy against T-ALL patient-derived xenografts in vivo; relapsed T-ALL cells display elevated IL-7Rα expression and remain sensitive to anti-IL7Rα MAb treatment. Crystal structures of MAb-IL-7Rα complexes; ADCC assays with PDX cells; in vivo xenograft models (minimal residual and established disease) Leukemia High 31439943
2024 The IL-7Rα antagonist antibody lusvertikimab (LUSV) reduces ALL burden in xenograft models via a dual mechanism: direct IL-7R antagonism and macrophage-mediated antibody-dependent cellular phagocytosis (ADCP); ADCP levels correlate with CD127 surface expression and with in vivo leukemia burden reduction. Patient-derived xenograft (PDX) models; ADCP assays; CD127 expression correlation analysis; combination with polychemotherapy in phase 2-like PDX study Blood High 38518105
2019 CD53 physically interacts with IL-7R (co-immunoprecipitation and proximity ligation) and promotes IL-7Rα surface expression; loss of CD53 reduces IL-7Rα surface expression and diminishes PI3K and JAK/STAT signaling in prepro- and pro-B cells, leading to increased B cell apoptosis and reduced B lymphopoiesis. Co-immunoprecipitation; proximity ligation assay; CD53-deficient mice; flow cytometry of IL-7Rα surface expression; signaling assays (PI3K, JAK/STAT) Journal of immunology High 31748347
2018 JAK1 (associated with IL-7Rα) mediates signaling from gain-of-function mutant IL-7Rα; JAK1/2 inhibitor ruxolitinib inhibits ligand-independent signaling from mutant IL-7Rα and induces cell death in vitro and reduces leukemic burden in vivo; BCL-2 is an anti-apoptotic downstream mediator of IL-7R survival signaling and venetoclax (BCL-2 inhibitor) shows activity against mutant IL-7Rα-transformed cells. In vitro signaling assays with ruxolitinib; in vivo mouse leukemia model with ruxolitinib treatment; venetoclax in vitro and combination in vivo assays Oncotarget High 29854301
2017 In lymphatic endothelial cells, IL-7Rα signaling supports lymphatic drainage; endothelial-specific deletion of IL-7Rα impairs lymphatic drainage and increases edema during skin inflammation, while systemic IL-7 treatment exacerbates edema and immune cell infiltration despite increased drainage, showing that IL-7Rα's pro-inflammatory effects on immune cells override anti-inflammatory drainage effects. Endothelial-specific IL-7Rα knockout mice (IL-7RαΔEC); IL-7 administration to wild-type mice; IL-7Rα blocking antibody treatment; psoriasis-like inflammation model Scientific reports Medium 31406267
2017 IL-7Rα down-regulation in zebrafish activates JAK/STAT signaling leading to apoptosis in oligodendrocytes; IL-7R is essential for myelination in embryonic and larval zebrafish. Targeted knockdown of IL-7R in zebrafish; demyelination model; JAK/STAT signaling assays; apoptosis analysis in oligodendrocytes Oncotarget Medium 28415697
2015 In IL-7-stimulated CD8 T cells activated with IL12, enhanced IL-7Rα expression is critical for antitumor immunity in lymphodepleted recipients; elevated IL7Rα expression confers responsiveness to host IL-7 (not IL-15) for maximal engraftment of effector CD8 T cells. IL7Rα-deficient T cells; IL12 activation conditioning; adoptive transfer into lymphodepleted mice; antitumor efficacy assays Cancer immunology research Medium 26297711
2022 In IL7Rα-deficient T cells from Schimke immuno-osseous dysplasia (SIOD) patients, the IL7R promoter is hypermethylated (CpG methylation), leading to absent IL7Rα protein and mRNA and unresponsiveness to IL-7 stimulation; no pathogenic mutations were found in IL7R exons, implicating epigenetic silencing as the mechanism. IL7Rα protein and mRNA measurement; IL-7 stimulation assays; CpG methylation analysis of IL7R promoter; Sanger sequencing of IL7R exons Clinical immunology Medium 26499378
2018 IL7R overexpression in esophageal squamous cell carcinoma promotes cancer cell survival; HDAC inhibitor apicidin downregulates IL7R by inducing acetylation of FOXO1, which then acts as a transcriptional repressor at the IL7R promoter, accompanied by decreased active histone modifications (ChIP assay). HDAC inhibitor (apicidin) treatment; ChIP assay for acetylated FOXO1 at IL7R promoter; histone modification analysis; IL7R knockdown anti-oncogenic effect assays International journal of oncology Medium 29749437
2019 In monocytes, monocyte surface and soluble IL-7R expression are induced by LPS and strongly associate with allelic carriage of rs6897932 (disease-associated IL7R polymorphism); sIL7R production by monocytes exceeds that of CD4+ T cells; sIL7R expression additionally correlates with DDX39A (a splicing factor) expression. Protein-level genetic regulation analysis; LPS stimulation assays; flow cytometry of surface IL7R; sIL7R ELISA; genotype-protein association in healthy individuals Nature communications Medium 31594933
2022 Loss of IL7Rα (but not Flk2) intrinsically and essentially impairs generation of tissue-resident lymphoid cells including B1a cells, marginal zone B cells, lung ILC2s, and regulatory T cells; an IL7Rα-deficient environment also selectively impairs reconstitution of these cells by wild-type HSCs, indicating both cell-intrinsic and extrinsic roles. Flk2-Cre and Il7r-Cre lineage tracing; Flk2 and IL7Rα single and double knockout mice; reciprocal transplantation experiments Development (Cambridge, England) Medium 35072209
2011 IL-7 treatment of CD4+CD25+CD127+ FoxP3+ T cells induces their phenotypic maturation into classical FoxP3+CD4+CD25hi CD127- regulatory T cells, with increased nuclear FoxP3 accumulation, CD25 upregulation, and concurrent CD127 downregulation in vitro. In vitro IL-7 treatment of sorted T cell populations; flow cytometry of CD127/CD25/FoxP3 expression; nuclear FoxP3 localization assay Clinical and experimental immunology Medium 21413939
2014 lnc-IL7R (a long noncoding RNA overlapping the 3'UTR of IL7R) suppresses LPS-induced inflammatory response by maintaining trimethylation of histone H3 at lysine 27 (H3K27me3) at the proximal promoters of inflammatory mediators (E-selectin, VCAM-1, IL-6, IL-8); knockdown of lnc-IL7R diminishes H3K27me3 and increases inflammatory gene expression. lnc-IL7R knockdown; ChIP assay for H3K27me3 at inflammatory gene promoters; LPS stimulation with cytokine/adhesion molecule measurement European journal of immunology Medium 24723426
2019 IL-7R overexpression in ESCC cells (induced by direct co-culture with macrophages) promotes cancer cell survival and growth via activation of Akt and Erk1/2 signaling pathways; the IL-7/IL-7R axis also promotes ESCC cell migration through the same pathways. Co-culture of ESCC cells with macrophages; cDNA microarray; IL7R overexpression; signaling assays (Akt, Erk1/2 phosphorylation); migration assays Cancers Medium 36672342
2022 Mutant IL7R collaborates with MYC to induce early-onset T-ALL in zebrafish; mutant IL7R alone can induce T-ALL with long latency; T-ALLs co-expressing mutant IL7R and Myc show STAT5 and AKT pathway activation; mutant IL7R increases the frequency of leukemia propagating cells as shown by limiting-dilution transplantation. Stable transgenic zebrafish expressing mutant IL7R and/or Myc; limiting-dilution cell transplantation; signaling assays (STAT5, AKT); apoptosis assays Leukemia Medium 35581375

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. The Journal of experimental medicine 2120 16818678
1998 Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Nature genetics 602 9843216
2007 Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nature genetics 500 17660817
2016 The heterogeneity of human CD127(+) innate lymphoid cells revealed by single-cell RNA sequencing. Nature immunology 407 26878113
2011 Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nature genetics 326 21892159
2012 BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood 324 22904298
2014 The transcription factor GATA3 is critical for the development of all IL-7Rα-expressing innate lymphoid cells. Immunity 315 24631153
2019 Flip the coin: IL-7 and IL-7R in health and disease. Nature immunology 296 31745336
2011 Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias. The Journal of experimental medicine 278 21536738
2014 The human long noncoding RNA lnc-IL7R regulates the inflammatory response. European journal of immunology 164 24723426
2015 Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia. Haematologica 134 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 122 23610432
2008 A function for IL-7R for CD4+CD25+Foxp3+ T regulatory cells. Journal of immunology (Baltimore, Md. : 1950) 119 18566388
2010 Increased CD127 expression on activated FOXP3+CD4+ regulatory T cells. European journal of immunology 111 20690182
2008 IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations. Genes and immunity 102 18354419
2022 The Role of IL-7 and IL-7R in Cancer Pathophysiology and Immunotherapy. International journal of molecular sciences 87 36142322
2017 Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk. Cell 84 28340352
2006 Omenn syndrome in an infant with IL7RA gene mutation. The Journal of pediatrics 71 16492442
2019 The lymphoid-associated interleukin 7 receptor (IL7R) regulates tissue-resident macrophage development. Development (Cambridge, England) 56 31332039
2010 Genetic variation in the IL7RA/IL7 pathway increases multiple sclerosis susceptibility. Human genetics 54 20112030
2022 Significance of IL-7 and IL-7R in RA and autoimmunity. Autoimmunity reviews 53 35595051
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 47 30850736
2020 Optimal identification of human conventional and nonconventional (CRTH2-IL7Rα-) ILC2s using additional surface markers. The Journal of allergy and clinical immunology 46 32032632
2021 Overexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma. Blood 45 33970999
2006 HIV-specific CD8 T cells express low levels of IL-7Ralpha: implications for HIV-specific T cell memory. Virology 43 16860834
2022 Single-cell profiling of human CD127+ innate lymphoid cells reveals diverse immune phenotypes in hepatocellular carcinoma. Hepatology (Baltimore, Md.) 41 35243668
2010 Molecular diagnosis of severe combined immunodeficiency--identification of IL2RG, JAK3, IL7R, DCLRE1C, RAG1, and RAG2 mutations in a cohort of Chinese and Southeast Asian children. Journal of clinical immunology 41 21184155
2016 Therapeutic targeting of IL-7Rα signaling pathways in ALL treatment. Blood 40 27268088
2019 IL-7R is essential for leukemia-initiating cell activity of T-cell acute lymphoblastic leukemia. Blood 39 31530562
2019 Maturing Human CD127+ CCR7+ PDL1+ Dendritic Cells Express AIRE in the Absence of Tissue Restricted Antigens. Frontiers in immunology 38 30692988
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
2019 Expression of IL-7Rα and KLRG1 defines functionally distinct CD8+ T-cell populations in humans. European journal of immunology 36 30883723
2019 Context-specific regulation of surface and soluble IL7R expression by an autoimmune risk allele. Nature communications 36 31594933
2018 Inhibiting Janus Kinase 1 and BCL-2 to treat T cell acute lymphoblastic leukemia with IL7-Rα mutations. Oncotarget 36 29854301
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 36 30105620
2021 Expression of KLRG1 and CD127 defines distinct CD8+ subsets that differentially impact patient outcome in follicular lymphoma. Journal for immunotherapy of cancer 35 34226281
2018 Human CD4+ CD25+ CD127hi cells and the Th1/Th2 phenotype. Clinical immunology (Orlando, Fla.) 35 29330114
2020 Tissue memory CD4+ T cells expressing IL-7 receptor-alpha (CD127) preferentially support latent HIV-1 infection. PLoS pathogens 33 32353080
2009 Variation in IL7R predisposes to sarcoid inflammation. Genes and immunity 33 19626041
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
2021 CD127+ CD94+ innate lymphoid cells expressing granulysin and perforin are expanded in patients with Crohn's disease. Nature communications 31 34615883
2022 Lnc-IL7R alleviates PM2.5-mediated cellular senescence and apoptosis through EZH2 recruitment in chronic obstructive pulmonary disease. Cell biology and toxicology 30 35303175
2019 New anti-IL-7Rα monoclonal antibodies show efficacy against T cell acute lymphoblastic leukemia in pre-clinical models. Leukemia 30 31439943
2017 IL-7Rα glutamylation and activation of transcription factor Sall3 promote group 3 ILC development. Nature communications 30 28794449
2016 CD4(+)CD25(+)CD127(-) and CD4(+)CD25(+)Foxp3(+) Regulatory T Cell Subsets in Mediating Autoimmune Reactivity in Systemic Lupus Erythematosus Patients. Archivum immunologiae et therapiae experimentalis 29 27156107
2022 IL7R Is Correlated With Immune Cell Infiltration in the Tumor Microenvironment of Lung Adenocarcinoma. Frontiers in pharmacology 28 35264973
2019 Analysis of the frequencies and functions of CD4+CD25+CD127low/neg, CD4+HLA-G+, and CD8+HLA-G+ regulatory T cells in pre-eclampsia. Journal of reproductive immunology 26 31255887
2016 Decreased proportions of CD4 + IL17+/CD4 + CD25 + CD127- and CD4 + IL17+/CD4 + CD25 + CD127 - FoxP3+ T cells in children with autoimmune thyroid diseases (.). Autoimmunity 26 27206624
2019 The Tetraspanin CD53 Regulates Early B Cell Development by Promoting IL-7R Signaling. Journal of immunology (Baltimore, Md. : 1950) 25 31748347
2019 CD4+CD25highCD127low/-FoxP3 + Regulatory T-Cell Population in Acute Leukemias: A Review of the Literature. Journal of immunology research 24 30944830
2019 Terminal Effector CD8 T Cells Defined by an IKZF2+IL-7R- Transcriptional Signature Express FcγRIIIA, Expand in HIV Infection, and Mediate Potent HIV-Specific Antibody-Dependent Cellular Cytotoxicity. Journal of immunology (Baltimore, Md. : 1950) 24 31519862
2015 Effector CD8+ T-cell Engraftment and Antitumor Immunity in Lymphodepleted Hosts Is IL7Rα Dependent. Cancer immunology research 23 26297711
2011 Interleukin-7 matures suppressive CD127(+) forkhead box P3 (FoxP3)(+) T cells into CD127(-) CD25(high) FoxP3(+) regulatory T cells. Clinical and experimental immunology 23 21413939
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
2023 Regulatory T cells suppress the formation of potent KLRK1 and IL-7R expressing effector CD8 T cells by limiting IL-2. eLife 21 36705564
2020 Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia. Nature communications 20 32581241
2019 Deleterious and Oncogenic Mutations in the IL7RA. Cancers 20 31817502
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
2025 The development and potent antitumor efficacy of CD44/CD133 dual-targeting IL7Rα-armored CAR-T cells against glioblastoma. Cancer letters 19 39952598
2019 Notch signaling pathway regulates CD4+CD25+CD127dim/- regulatory T cells and T helper 17 cells function in gastric cancer patients. Bioscience reports 19 30988066
2019 Low CD4⁺/CD25⁺/CD127⁻ regulatory T cell- and high INF-γ levels are associated with improved survival of neuroblastoma patients treated with long-term infusion of ch14.18/CHO combined with interleukin-2. Oncoimmunology 19 31741754
2024 Human CD127 negative ILC2s show immunological memory. The Journal of experimental medicine 18 38889332
2012 IL-7Rα deficiency in p53null mice exacerbates thymocyte telomere erosion and lymphomagenesis. Cell death and differentiation 18 22281704
2022 Human CD4+CD25+CD226- Tregs Demonstrate Increased Purity, Lineage Stability, and Suppressive Capacity Versus CD4+CD25+CD127lo/- Tregs for Adoptive Cell Therapy. Frontiers in immunology 17 35693814
2017 Human IL-6RhiTIGIT- CD4+CD127lowCD25+ T cells display potent in vitro suppressive capacity and a distinct Th17 profile. Clinical immunology (Orlando, Fla.) 17 28284938
2016 Identification of Heterozygous Single- and Multi-exon Deletions in IL7R by Whole Exome Sequencing. Journal of clinical immunology 17 27807805
2015 IL-7 induces clathrin-mediated endocytosis of CD127 and subsequent degradation by the proteasome in primary human CD8 T cells. Immunology and cell biology 17 26272555
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
2012 Unusual timing of CD127 expression by mouse uterine natural killer cells. Journal of leukocyte biology 17 22227963
2023 PD-1 blockade potentiates neoadjuvant chemotherapy in NSCLC via increasing CD127+ and KLRG1+ CD8 T cells. NPJ precision oncology 16 37231145
2016 CD127 Expression in Naive and Memory T Cells in HIV Patients Who Have Undergone Long-Term HAART. Laboratory medicine 16 27760802
2023 BMI1-induced CD127+KLRG1+ memory T cells enhance the efficacy of liver cancer immunotherapy. Cancer letters 15 37562671
2022 Mutant IL7R collaborates with MYC to induce T-cell acute lymphoblastic leukemia. Leukemia 15 35581375
2020 Association of Multiple Sclerosis Phenotypes with Single Nucleotide Polymorphisms of IL7R, LAG3, and CD40 Genes in a Jordanian Population: A Genotype-Phenotype Study. Biomolecules 14 32111053
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 Opposing roles of endothelial and leukocyte-expressed IL-7Rα in the regulation of psoriasis-like skin inflammation. Scientific reports 14 31406267
2018 Oncogenic IL7R is downregulated by histone deacetylase inhibitor in esophageal squamous cell carcinoma via modulation of acetylated FOXO1. International journal of oncology 14 29749437
2024 The IL-7R antagonist lusvertikimab reduces leukemic burden in xenograft ALL via antibody-dependent cellular phagocytosis. Blood 13 38518105
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
2015 Expression and significance of CD4(+)CD25(+)CD127(-) regulatory T cells in peripheral blood of patients with different phenotypes of Guillain-Barré syndrome. International journal of clinical and experimental medicine 13 26770543
2014 CD127 expression, exhaustion status and antigen specific proliferation predict sustained virologic response to IFN in HCV/HIV co-infected individuals. PloS one 13 25007250
2010 Variation in SNPs of the IL7Ra gene is associated with multiple sclerosis in the Iranian population. Immunological investigations 13 21190413
2019 TCR activation mimics CD127lowPD-1high phenotype and functional alterations of T lymphocytes from septic shock patients. Critical care (London, England) 12 30995946
2017 IL-7Rα Expression Regulates Murine Dendritic Cell Sensitivity to Thymic Stromal Lymphopoietin. Journal of immunology (Baltimore, Md. : 1950) 12 28404633
2017 Down-regulation of interleukin 7 receptor (IL-7R) contributes to central nervous system demyelination. Oncotarget 12 28415697
2013 Downregulation of IL7R, CCR7, and TLR4 in the cord blood of children with respiratory syncytial virus disease. The Journal of infectious diseases 12 23888080
2011 Relevance of IL7R genotype and mRNA expression in Dutch patients with multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England) 12 21543551
2010 Selective ablation of the YxxM motif of IL-7Ralpha suppresses lymphomagenesis but maintains lymphocyte development. Oncogene 12 20440272
2023 Roles of IL-7R Induced by Interactions between Cancer Cells and Macrophages in the Progression of Esophageal Squamous Cell Carcinoma. Cancers 11 36672342
2022 IL7Rα, but not Flk2, is required for hematopoietic stem cell reconstitution of tissue-resident lymphoid cells. Development (Cambridge, England) 11 35072209
2021 CHBP induces stronger immunosuppressive CD127+ M-MDSC via erythropoietin receptor. Cell death & disease 11 33579907
2021 Characterization of Circulating IL-7R Positive Cell Populations for Early Detection of Pancreatic Ductal Adenocarcinoma. Journal of clinical medicine 11 34575268
2020 Macrophages represent the major pool of IL-7Rα expressing cells in patients with myocarditis. Cytokine 11 32203694
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