{"gene":"IL2RB","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2004,"finding":"CD8+CD122+ T cells function as naturally occurring regulatory T cells that suppress activated CD8+ and CD4+ T cells both in vivo and in vitro; transfer of CD8+CD122+ cells into CD122-deficient neonates prevented development of abnormal (hyperactivated) T cells, establishing CD122 (IL-2Rβ) as a marker of this regulatory population essential for T cell homeostasis.","method":"Adoptive cell transfer into CD122-deficient neonatal mice; in vitro suppression assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function (CD122-KO model) combined with adoptive transfer rescue, replicated across multiple experimental conditions in vivo and in vitro","pmids":["15520244"],"is_preprint":false},{"year":2005,"finding":"CD8+CD122+ regulatory T cells suppress proliferation and IFN-γ production of CD8+ target T cells via secretion of IL-10; blockade of IL-10 (but not TGF-β) abrogated suppression, and CD8+CD122+ cells from IL-10-deficient mice lacked regulatory activity.","method":"In vitro co-culture suppression assays; neutralizing antibody blockade; cytokine-removal from conditioned medium; IL-10-KO mice","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (antibody blockade, cytokine depletion, genetic KO) across in vitro and in vivo systems, replicated by subsequent studies","pmids":["16301610"],"is_preprint":false},{"year":2008,"finding":"CD8+CD122+ regulatory T cells recognize already-activated target T cells through MHC class I–αβTCR–CD8 interactions (not Qa-1 or I-A); this recognition activates Tregs to produce IL-10 and suppress IFN-γ. MHC-congenic experiments confirmed MHC restriction; blocking antibodies against H-2K, H-2D, αβTCR, or CD8 on either Treg or target cells abolished suppression.","method":"In vitro co-culture with MHC-congenic/allogeneic mouse strains; surface molecule blocking antibodies","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal blocking with multiple antibody specificities plus MHC-congenic genetic controls in a defined in vitro system","pmids":["18495626"],"is_preprint":false},{"year":2008,"finding":"CD80/CD86–CD28 co-stimulatory interactions are required for CD8+CD122+ Tregs to become activated and produce IL-10; blocking CD80, CD86, or CD28 prevented IL-10 production and suppression of target T cells, and CD8+CD122+ cells from CD28-KO mice lacked regulatory activity. CTLA-4, ICOS, and PD-1 were not involved.","method":"Neutralizing antibody blockade of costimulatory molecules; CD28-KO mouse cells; in vitro suppression assays","journal":"Immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO combined with multiple blocking antibody experiments in a mechanistically defined in vitro system","pmids":["18205792"],"is_preprint":false},{"year":2010,"finding":"Within the CD8+CD122+ population, PD-1+ cells are the regulatory subset (producing IL-10 and suppressing T cell responses), while PD-1− cells are bona fide memory T cells; suppression by PD-1+ cells requires both CD28 and PD-1 co-stimulatory signaling for optimal IL-10 production.","method":"In vitro and in vivo suppression assays; PD-1 subset fractionation; antibody blockade","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional dissection of subsets with in vitro and in vivo validation, multiple orthogonal methods in one study","pmids":["20548035"],"is_preprint":false},{"year":2016,"finding":"CD8+CD122+CD49d(low) cells are the bona fide regulatory T cell subset within CD8+CD122+ T cells; their suppression of activated T cells operates via Fas/FasL (CD95/CD178)-dependent cytotoxic killing. Tregs from gld (FasL-deficient) mice failed to suppress wild-type targets; targets from lpr (Fas-deficient) mice resisted suppression. IL-10 was found dispensable for this killing mechanism.","method":"In vitro and in vivo regulatory assays using lpr/gld mutant mice; CD49d subset fractionation; IL-10-KO Tregs","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic mutant mouse strains (lpr, gld, IL-10-KO) combined with in vitro and in vivo functional assays in one study","pmids":["26869716"],"is_preprint":false},{"year":2017,"finding":"CD8+CD122+PD-1+ Tregs suppress allograft rejection primarily via Fas ligand-mediated killing of effector T cells in vivo; suppression was largely abolished when Tregs lacked FasL or when effector T cells lacked Fas. In contrast, IL-10 (not FasL) mediates their suppression of T cell proliferation in vitro.","method":"Adoptive T cell transfer model in lymphocyte-deficient mice; FasL-blocking antibodies; Fas-deficient and FasL-deficient genetic mouse strains; in vitro cytotoxicity assays","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic knockouts (Fas-KO, FasL-KO) combined with in vitro killing assays and in vivo adoptive transfer, mechanistic dissection across two distinct suppressive mechanisms","pmids":["28445940"],"is_preprint":false},{"year":2019,"finding":"A homozygous hypomorphic mutation in the WSXWS motif of human IL2RB results in diminished IL-2Rβ surface expression and dysregulated IL-2/IL-15 signaling, manifesting as multisystem autoimmunity, reduced regulatory T cells, and an expanded CD56bright NK cell population with lack of terminally differentiated NK cells.","method":"Human patient genetic analysis; flow cytometry of immune subsets; functional signaling assays in patient cells","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — first human loss-of-function IL2RB mutation with direct correlation between mutation, reduced surface expression, impaired STAT5 signaling, and defined immune phenotype","pmids":["31040184"],"is_preprint":false},{"year":2011,"finding":"Weak CD122-dependent signaling supports CD8+ T central-memory (TCM) cell survival largely through pro-survival (Bcl-2-like) signals, whereas stronger CD122 signaling is required for T effector-memory (TEM) development. This was demonstrated using mouse models with mutations attenuating CD122 cytoplasmic tail signaling and Bcl-2 transgenic CD122-KO CD8+ T cells.","method":"Knock-in mice with CD122 cytoplasmic tail mutations; Bcl-2 transgenic/CD122-KO mixed bone marrow chimeras; in vivo OT-I T cell response tracking","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple transgenic/knock-in models with direct in vivo readouts of memory T cell subset development, two orthogonal genetic strategies in one study","pmids":["21984699"],"is_preprint":false},{"year":2018,"finding":"CD122 (IL-2Rβ) signaling drives costimulation-independent rejection by CD8+ memory T cells; high-affinity IL-15 receptor signaling through CD122 was critical for costimulation-independent memory CD8+ T cell recall, while IL-2 high-affinity receptor signaling was dispensable. Combined CD122 blockade and costimulatory blockade prolonged transplant survival in mice and nonhuman primates.","method":"Murine and nonhuman primate transplant models; CD122-selective blocking antibody; mechanistic dissection of IL-2 vs. IL-15 receptor dependence; antibody-mediated depletion/blockade","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated in two species (murine and NHP), multiple receptor-specific blockade experiments distinguishing IL-2 vs. IL-15 dependence","pmids":["30222140"],"is_preprint":false},{"year":2007,"finding":"Runx3 transcription factor binds to the promoter region of the CD122 (IL2RB) gene and drives its expression during NK cell differentiation; introduction of a dominant-negative Runx form into hematopoietic stem cells decreased CD122 expression in NK cell-inducing culture.","method":"Dominant-negative Runx transgenic mice; chromatin binding (Runx binds CD122 promoter by PCR/binding assay); NK cell differentiation culture system","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, promoter binding plus functional NK culture assay, but limited detail on promoter binding method from abstract","pmids":["18003603"],"is_preprint":false},{"year":2001,"finding":"Fibroblast-like synoviocytes (FLS) express functional IL-2Rβ (CD122) and IL-2Rγ (CD132) but not CD25; IL-2 stimulation through CD122 on FLS induces MCP-1 (monocyte chemoattractant protein-1) production via tyrosine phosphorylation signaling, and neutralizing anti-CD122 antibody partially blocked IL-2-induced MCP-1 secretion.","method":"Flow cytometry; RT-PCR; anti-CD122 neutralizing antibody blockade; MCP-1 ELISA; tyrosine phosphorylation western blot after IL-2 stimulation","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (mRNA, protein, functional signaling, neutralizing antibody) in single lab study","pmids":["11238664"],"is_preprint":false},{"year":1996,"finding":"CD122 (IL-2Rβ) is expressed on early lymphoid progenitors including Sca1+Lin- hematopoietic stem cells in fetal liver and intrathymic T cell progenitors; prepro-B cells (CD43+CD24- fraction A) express CD122 and proliferate vigorously in response to IL-2 but not IL-15 in the absence of stromal cells, implicating IL-2/CD122 signaling in early lymphocyte development.","method":"Flow cytometry of fetal liver and thymus; in vitro proliferation assays with IL-2 or IL-15; embryo section localization","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization plus functional cytokine responsiveness assay, single lab with multiple orthogonal methods","pmids":["8547641"],"is_preprint":false},{"year":2011,"finding":"CD122 (IL-2Rβ)/STAT-5 signaling is continuously active in natural regulatory T cells (Tregs) during thymic selection; pSTAT-5 levels correlated with CD122 and Foxp3 expression (more than with CD25), and IL-2/IL-15 (not IL-7) drove STAT-5 phosphorylation in Treg-lineage cells ex vivo.","method":"Ex vivo phospho-flow cytometry of murine thymocytes; in vitro cytokine stimulation; neonatal thymus time-course analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ex vivo and in vitro cytokine stimulation with multiple cytokine comparisons in single lab, no genetic manipulation of IL-2Rβ","pmids":["21541329"],"is_preprint":false},{"year":2020,"finding":"The abundance of IL-2Rβ (CD122) on the cell surface constrains lymphopenia-induced homeostatic proliferation (LIP) of naive CD4 T cells; naive CD4 T cells express ~5-fold less CD122 than CD8 T cells, limiting IL-15 responsiveness. Forced IL-2Rβ expression by transgenesis bestowed IL-15 responsiveness on CD4 T cells and enabled robust LIP.","method":"Quantitative flow cytometry of surface CD122; IL-2Rβ transgenic CD4 T cells; lymphopenia-induced proliferation assays in mice","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — surface molecule quantification combined with transgenic rescue experiment directly establishing causal role of CD122 abundance in cytokine responsiveness","pmids":["32393513"],"is_preprint":false},{"year":2021,"finding":"IL-2Rβ (CD122) timing and abundance of expression control thymic iNKT cell generation and NKT1 subset differentiation; premature CD122 expression was detrimental to iNKT development, while elevated abundance of CD122 suppressed NKT1 (but not NKT2 or NKT17) generation, establishing cytokine receptor expression level as a determinant of iNKT lineage fate.","method":"Transgenic mouse models with premature or elevated CD122 expression; thymic iNKT cell subset quantification by flow cytometry","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two separate transgenic models (timing and abundance) with defined iNKT subset readout, single lab","pmids":["34054809"],"is_preprint":false},{"year":2024,"finding":"ADAM17 (a disintegrin and metalloprotease) cleaves membrane CD122 as a sheddase, reducing CD122 surface expression and dampening IL-2 and IL-15 signaling in CD8+ T cells; T cell-specific ADAM17 deletion increased CD122 surface expression, enhanced IL-2/IL-15 responsiveness, and augmented effector CD8+ T cell differentiation in both mouse and human CD8+ T cells.","method":"T cell-specific ADAM17 conditional knockout mice; transcriptomic and proteomic analysis; flow cytometry; in vitro IL-2/IL-15 stimulation assays; human CD8+ T cell ADAM17 inhibition","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — post-translational regulatory mechanism identified (shedding of CD122 by ADAM17), validated by genetic KO and pharmacological inhibition with functional readouts in mouse and human cells","pmids":["38918390"],"is_preprint":false},{"year":2025,"finding":"Core fucosylation of IL-2Rβ (CD122) by fucosyltransferase 8 (FUT8) is required for CD122 surface expression and IL-15 receptor signaling in NK cells; NK cell-specific Fut8 deletion caused severe NK lymphopenia with reduced CD122 expression, impaired homeostatic proliferation, decreased cytotoxicity, and impaired tumor and viral immunity.","method":"Genome-wide CRISPR screen in human NK cells identifying FUT8; conditional NK cell-specific Fut8-KO mice (Fut8fl/flNcr1cre/+); flow cytometry; in vivo homeostatic proliferation; cytotoxicity and infection assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genome-wide CRISPR screen discovery validated by conditional KO mouse model with multiple functional readouts; identifies post-translational glycosylation as a regulator of CD122 surface expression","pmids":["40753573"],"is_preprint":false},{"year":2025,"finding":"A hypomorphic IL2RB mutation reduces IL-2Rβ cell-surface expression and impairs IL-2/IL-15-dependent STAT5 signaling, leading to elevated serum IL-2/IL-15, expanded effector memory CD8+ T cells, and severely reduced Tregs; mixed bone marrow chimera and wild-type Treg neonatal transfer experiments demonstrated that Tregs and CD8+ T cells have distinct IL-2Rβ signaling thresholds, and that Treg-extrinsic mechanisms can partly restore conventional T cell distribution.","method":"Homologous knockin mouse model; mixed bone marrow chimeras; neonatal WT Treg transfer; STAT5 phosphorylation assays; flow cytometry","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockin mouse recapitulating human mutation validated by chimera and Treg transfer rescue experiments with direct signaling readouts","pmids":["40570369"],"is_preprint":false},{"year":2020,"finding":"Nicotine increases miR-629-5p expression in CD8+ T cells, which directly targets IL2RB mRNA, suppressing IL-2Rβ (CD122) expression and downstream granzyme B production, thereby exhausting CD8+ T cell cytotoxic function; miR-629-5p mimic transfection reduced both IL2RB and GZMB levels, and this was recapitulated in humanized tumor xenografts.","method":"RNAseq and small RNAseq; miR-629-5p mimic transfection; luciferase reporter/target validation; nuclear imaging of granzyme B; humanized tumor xenograft","journal":"Cancer immunology, immunotherapy : CII","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — miRNA target validation combined with in vitro functional assays and in vivo xenograft, single lab","pmids":["33146402"],"is_preprint":false},{"year":2025,"finding":"IL-27 promotes Treg cell expression of CD122, and IL-27R-deficient Tregs are at a competitive disadvantage during homeostasis associated with reduced CD122 expression; CD122 blockade caused similar loss of Treg cells, and IL-27 improved Treg responsiveness to IL-2/IL-15 via upregulation of CD122.","method":"Mixed IL-27R-sufficient/deficient Treg chimeric mice; aging experiments tracking Treg erosion; CD122 blockade in vivo; in vitro IL-27 stimulation and CD122 expression assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competitive chimera experiments combined with in vitro mechanistic validation, single lab, establishes IL-27 as an upstream regulator of CD122 expression on Tregs","pmids":["41364763"],"is_preprint":false},{"year":2020,"finding":"Chronic circadian disruption (shift-lag) reduces Eomes transcription factor expression in NK cells, which inhibits transcription of CD122 (IL2RB), leading to decreased NK cell cytolytic activity and impaired clearance of MHC-I-deficient tumor cells in vivo.","method":"Light-dark reversal circadian disruption mouse model; flow cytometry; in vivo tumor clearance assay; mRNA expression analysis","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlative mRNA/protein data in a single mouse model; Eomes→CD122 transcriptional link is inferred but not directly proven by Eomes manipulation","pmids":["33185980"],"is_preprint":false},{"year":2020,"finding":"IL-2Rβ (CD122) signaling in CD8+ T cells in Peyer's Patches mediates acute B cell apoptosis; CD122-targeted IL-2 complexes caused selective contraction of B cell subsets in Peyer's Patches (but not lamina propria or intraepithelial lymphocytes) via apoptosis.","method":"In vivo IL-2/anti-IL-2 antibody complexes targeting CD122; flow cytometry of gut compartments; apoptosis assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean in vivo model with compartment-specific readout and apoptosis measurement, single lab, single publication","pmids":["32728053"],"is_preprint":false},{"year":2024,"finding":"IL2RB activates the JAK1/STAT5 signaling pathway in esophageal squamous cell carcinoma cells; IL2RB knockdown inhibited tumor cell proliferation, migration, invasion, and epithelial-mesenchymal transition, and was associated with CD8+ T cell depletion in the tumor microenvironment.","method":"Gain- and loss-of-function (knockdown/overexpression) in cell lines; in vivo tumor models; western blotting for JAK1/STAT5 pathway","journal":"Annals of clinical and laboratory science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional gain/loss-of-function with pathway readout in single lab study; no orthogonal validation","pmids":["40750242"],"is_preprint":false},{"year":2020,"finding":"IL2RB (IL-2Rβ) transfection into peripheral blood mononuclear cells from septic patients elevated IFN-γ and IL-12 levels (Th1 cytokines) while reducing IL-4, IL-10, and IL-17A, demonstrating that IL2RB expression modulates Th1/Th2 balance and suppresses Th17 activation.","method":"PBMC transfection with IL2RB expression construct; ELISA for cytokine levels; bioinformatics dataset analysis","journal":"Allergologia et immunopathologia","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single transfection experiment in PBMCs, no mechanistic pathway dissection, cytokine changes are correlative","pmids":["37169553"],"is_preprint":false}],"current_model":"IL-2Rβ (CD122) is the shared β-chain subunit of the IL-2 and IL-15 receptor complexes; it drives downstream JAK1/STAT5 signaling, with its surface abundance and post-translational regulation (ectodomain shedding by ADAM17, core fucosylation by FUT8) controlling the threshold and magnitude of IL-2/IL-15 responses in T cells and NK cells. On CD8+ T cells, graded CD122 signaling strength directs fate decisions—weak signals support central memory survival, stronger signals are required for effector memory development, and high-affinity IL-15 (not IL-2) receptor signaling through CD122 underlies costimulation-independent memory recall. CD8+CD122+PD-1+ cells constitute a naturally occurring regulatory T cell subset that suppresses activated T cells through two mechanistically distinct pathways: IL-10-dependent suppression of proliferation, and Fas/FasL-dependent cytotoxic killing; their activation requires MHC class I–αβTCR recognition of target cells and CD80/CD86–CD28 co-stimulation. Upstream, Runx3 and c-REL transcription factors regulate CD122 gene expression during NK and Treg development, respectively, and IL-27 promotes CD122 expression on Tregs to maintain their competitive fitness; human loss-of-function IL2RB mutations confirm that sufficient IL-2Rβ surface expression and STAT5 signaling are non-redundantly required for peripheral immune tolerance and proper NK cell maturation."},"narrative":{"mechanistic_narrative":"IL2RB encodes IL-2Rβ (CD122), the shared signaling subunit of the IL-2 and IL-15 receptor complexes that transduces cytokine engagement through the JAK1/STAT5 axis to control lymphocyte development, homeostasis, and effector fate [PMID:40570369, PMID:40750242]. The amount of CD122 displayed on the cell surface acts as a tunable rheostat for IL-2/IL-15 responsiveness: graded signaling strength partitions CD8+ T cell fate, with weak CD122 signaling supporting central-memory survival via Bcl-2-like pro-survival programs and stronger signaling driving effector-memory development [PMID:21984699], and high-affinity IL-15 (but not IL-2) signaling through CD122 underlying costimulation-independent memory recall [PMID:30222140]. Surface abundance itself is set both transcriptionally and post-translationally—Runx3 drives CD122 expression during NK differentiation [PMID:18003603], IL-27 upregulates CD122 to maintain Treg competitive fitness [PMID:41364763], ADAM17 sheddase cleaves membrane CD122 to dampen IL-2/IL-15 signaling [PMID:38918390], and FUT8-mediated core fucosylation is required for CD122 surface expression and IL-15 signaling in NK cells [PMID:40753573]; correspondingly, CD122 levels constrain lymphopenia-induced proliferation by limiting IL-15 responsiveness [PMID:32393513]. CD122 marks a naturally occurring CD8+CD122+PD-1+ regulatory T cell subset that suppresses activated T cells through two distinct mechanisms—IL-10-dependent suppression of proliferation and Fas/FasL-dependent cytotoxic killing—following MHC class I–αβTCR recognition of activated targets and CD80/CD86–CD28 co-stimulation [PMID:15520244, PMID:16301610, PMID:18495626, PMID:18205792, PMID:26869716]. Continuous CD122/STAT5 signaling sustains natural Tregs during thymic selection [PMID:21541329]. Human hypomorphic IL2RB mutation in the WSXWS motif reduces IL-2Rβ surface expression and STAT5 signaling, causing multisystem autoimmunity, reduced Tregs, and aberrant NK maturation, establishing CD122 as non-redundantly required for peripheral tolerance and NK development [PMID:31040184, PMID:40570369].","teleology":[{"year":2004,"claim":"Established that CD122 surface expression marks a functional CD8+ regulatory T cell population essential for T cell homeostasis, defining a non-conventional immunoregulatory role beyond cytokine reception.","evidence":"Adoptive transfer of CD8+CD122+ cells into CD122-deficient neonatal mice plus in vitro suppression assays","pmids":["15520244"],"confidence":"High","gaps":["Did not define the molecular mechanism of suppression","Did not establish how CD122 expression itself contributes to the regulatory program"]},{"year":2005,"claim":"Identified IL-10 as the soluble effector by which CD8+CD122+ Tregs suppress target T cell proliferation and IFN-γ production, providing a first defined suppressive mechanism.","evidence":"In vitro co-culture, neutralizing antibody blockade, cytokine depletion, and IL-10-KO mice","pmids":["16301610"],"confidence":"High","gaps":["Did not address whether other suppressive pathways operate in vivo","Did not link IL-10 production to specific activation signals"]},{"year":2008,"claim":"Defined the activation requirements of CD8+CD122+ Tregs, showing antigen-specific MHC class I–αβTCR recognition of activated targets and CD80/CD86–CD28 co-stimulation are both needed to trigger IL-10-mediated suppression.","evidence":"In vitro co-culture with MHC-congenic strains, blocking antibodies, and CD28-KO cells","pmids":["18495626","18205792"],"confidence":"High","gaps":["Did not resolve which TCR specificities are involved","Did not connect activation route to the choice between IL-10 and cytotoxic mechanisms"]},{"year":2010,"claim":"Resolved the regulatory versus memory heterogeneity within CD8+CD122+ cells, identifying PD-1+ cells as the suppressive subset and PD-1 as a required co-signal for optimal IL-10 production.","evidence":"PD-1 subset fractionation with in vitro and in vivo suppression assays and antibody blockade","pmids":["20548035"],"confidence":"High","gaps":["Did not define how PD-1 signaling mechanistically augments IL-10 output","Did not reconcile PD-1 requirement with earlier finding that PD-1 was dispensable"]},{"year":2016,"claim":"Uncovered a second, IL-10-independent suppressive mechanism—Fas/FasL-dependent cytotoxic killing—operating in the CD49d(low) regulatory subset, establishing dual-pathway suppression.","evidence":"In vitro and in vivo assays using lpr/gld mutant mice, CD49d fractionation, and IL-10-KO Tregs","pmids":["26869716"],"confidence":"High","gaps":["Did not define what dictates use of cytotoxic versus IL-10 pathway","Did not address relative in vivo contributions of the two mechanisms"]},{"year":2017,"claim":"Mapped the two suppressive mechanisms to distinct contexts, showing FasL-mediated killing dominates allograft suppression in vivo while IL-10 mediates suppression of proliferation in vitro.","evidence":"Adoptive transfer transplant model with Fas-KO/FasL-KO strains and in vitro cytotoxicity assays","pmids":["28445940"],"confidence":"High","gaps":["Did not define molecular switch governing pathway selection","Did not test clinical translatability of the suppressive subset"]},{"year":2011,"claim":"Demonstrated that CD122 signaling strength is decoded into distinct CD8+ memory fates—weak signals supporting central-memory survival via Bcl-2-like programs, stronger signals driving effector-memory development.","evidence":"Knock-in mice with CD122 tail mutations, Bcl-2 transgenic/CD122-KO chimeras, and in vivo OT-I tracking","pmids":["21984699"],"confidence":"High","gaps":["Did not identify the discrete signaling thresholds","Did not separate IL-2 from IL-15 contributions to each fate"]},{"year":2018,"claim":"Distinguished IL-2 from IL-15 dependence of CD122 function, showing high-affinity IL-15 receptor signaling through CD122 drives costimulation-independent memory CD8+ recall while IL-2 high-affinity signaling is dispensable.","evidence":"Murine and nonhuman primate transplant models with CD122-selective blockade","pmids":["30222140"],"confidence":"High","gaps":["Did not define the structural basis of IL-2 versus IL-15 discrimination through the shared β-chain","Did not establish downstream effectors of recall signaling"]},{"year":2020,"claim":"Established surface CD122 abundance as a quantitative gate on IL-15 responsiveness and homeostatic proliferation, with low CD122 limiting naive CD4 T cell expansion.","evidence":"Quantitative surface flow cytometry, IL-2Rβ transgenic CD4 T cells, and lymphopenia-induced proliferation assays","pmids":["32393513"],"confidence":"High","gaps":["Did not identify what sets the differential CD122 expression between CD4 and CD8 cells","Did not address post-translational contributions to surface abundance"]},{"year":2024,"claim":"Identified ADAM17-mediated ectodomain shedding as a post-translational brake on CD122 surface abundance, tuning IL-2/IL-15 signaling and effector CD8+ differentiation in mouse and human cells.","evidence":"T cell-specific ADAM17 conditional KO, transcriptomics/proteomics, and human CD8+ ADAM17 inhibition","pmids":["38918390"],"confidence":"High","gaps":["Did not define the precise cleavage site on CD122","Did not establish physiological cues triggering shedding"]},{"year":2025,"claim":"Identified FUT8-mediated core fucosylation as a glycosylation requirement for CD122 surface expression and IL-15 signaling in NK cells, controlling NK homeostasis, cytotoxicity, and antitumor/antiviral immunity.","evidence":"Genome-wide CRISPR screen in human NK cells plus conditional NK-specific Fut8-KO mice with functional readouts","pmids":["40753573"],"confidence":"High","gaps":["Did not determine which CD122 N-glycans are fucosylated","Did not test whether fucosylation regulates CD122 in non-NK lineages"]},{"year":2025,"claim":"Confirmed in a humanized knockin model that hypomorphic IL2RB reduces surface expression and STAT5 signaling, revealing distinct CD122 signaling thresholds for Tregs versus CD8+ T cells that underlie autoimmunity from impaired tolerance.","evidence":"Homologous knockin mouse, mixed bone marrow chimeras, neonatal WT Treg transfer, and STAT5 phosphorylation assays","pmids":["40570369"],"confidence":"High","gaps":["Did not define the molecular basis of the cell-type-specific threshold difference","Did not fully resolve the Treg-extrinsic restoring mechanism"]},{"year":2025,"claim":"Established IL-27 as an upstream inducer of CD122 on Tregs that sustains their IL-2/IL-15 responsiveness and competitive fitness during homeostasis.","evidence":"Mixed IL-27R-sufficient/deficient Treg chimeras, aging experiments, in vivo CD122 blockade, and in vitro IL-27 stimulation","pmids":["41364763"],"confidence":"Medium","gaps":["Did not define the transcriptional path from IL-27R to IL2RB","Single-lab study without independent confirmation"]},{"year":null,"claim":"How the shared β-chain structurally and biochemically discriminates IL-2 versus IL-15 inputs to generate distinct cell-fate outcomes, and how transcriptional, glycosylation, and shedding inputs are integrated to set surface CD122 thresholds in each lineage, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of differential ligand discrimination through CD122 in the corpus","No unified quantitative framework linking the multiple CD122 abundance regulators to threshold setting"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[18,9,23]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[11,14]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[23,18]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,14,16,17]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,7,9,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[18,23,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,12,15]}],"complexes":["IL-2 receptor complex","IL-15 receptor complex"],"partners":["IL2RG","ADAM17","FUT8","JAK1","STAT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P14784","full_name":"Interleukin-2 receptor subunit beta","aliases":["High affinity IL-2 receptor subunit beta","Interleukin-15 receptor subunit beta","p70-75","p75"],"length_aa":551,"mass_kda":61.1,"function":"Receptor for interleukin-2. This beta subunit is involved in receptor mediated endocytosis and transduces the mitogenic signals of IL2. 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33507447","citation_count":7,"is_preprint":false},{"pmid":"29736146","id":"PMC_29736146","title":"Association of the TNF-α, IL-2, and IL-2RB gene variants with susceptibility to psoriasis in a Turkish cohort.","date":"2018","source":"Central-European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29736146","citation_count":7,"is_preprint":false},{"pmid":"38565343","id":"PMC_38565343","title":"A miRNA-7704/IL2RB/AKT feedback loop regulates tumorigenesis and chemoresistance in ovarian cancer.","date":"2024","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/38565343","citation_count":5,"is_preprint":false},{"pmid":"34858732","id":"PMC_34858732","title":"CD122-targeted interleukin-2 and αPD-L1 treat bladder cancer and melanoma via distinct mechanisms, including CD122-driven natural killer cell maturation.","date":"2021","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/34858732","citation_count":5,"is_preprint":false},{"pmid":"39522264","id":"PMC_39522264","title":"Human serum albumin promotes interactions between HSA-IL-2 fusion protein and CD122 for enhancing immunotherapy.","date":"2024","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/39522264","citation_count":4,"is_preprint":false},{"pmid":"40753573","id":"PMC_40753573","title":"Core fucosylation of IL-2RB is required for natural killer cell homeostasis.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/40753573","citation_count":4,"is_preprint":false},{"pmid":"32728053","id":"PMC_32728053","title":"CD122-targetted IL-2 signals cause acute and selective apoptosis of B cells in Peyer's Patches.","date":"2020","source":"Scientific 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Rejection.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32765495","citation_count":2,"is_preprint":false},{"pmid":"40570369","id":"PMC_40570369","title":"A hypomorphic Il2rb mutant mouse model recapitulates and reveals mechanisms of human T cell immune dysregulation in IL-2Rβ deficiency.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/40570369","citation_count":1,"is_preprint":false},{"pmid":"40750242","id":"PMC_40750242","title":"IL2RB Remodels the Immune Microenvironment and Promotes the Progression of Esophageal Squamous Cell Carcinoma.","date":"2025","source":"Annals of clinical and laboratory science","url":"https://pubmed.ncbi.nlm.nih.gov/40750242","citation_count":1,"is_preprint":false},{"pmid":"39153581","id":"PMC_39153581","title":"CD122 is an activation marker ensuring proper proliferation of T cells in teleost.","date":"2024","source":"Fish & shellfish 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science","url":"https://pubmed.ncbi.nlm.nih.gov/36966029","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51955,"output_tokens":6750,"usd":0.128557,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15927,"output_tokens":4456,"usd":0.095518,"stage2_stop_reason":"end_turn"},"total_usd":0.224075,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"CD8+CD122+ T cells function as naturally occurring regulatory T cells that suppress activated CD8+ and CD4+ T cells both in vivo and in vitro; transfer of CD8+CD122+ cells into CD122-deficient neonates prevented development of abnormal (hyperactivated) T cells, establishing CD122 (IL-2Rβ) as a marker of this regulatory population essential for T cell homeostasis.\",\n      \"method\": \"Adoptive cell transfer into CD122-deficient neonatal mice; in vitro suppression assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function (CD122-KO model) combined with adoptive transfer rescue, replicated across multiple experimental conditions in vivo and in vitro\",\n      \"pmids\": [\"15520244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD8+CD122+ regulatory T cells suppress proliferation and IFN-γ production of CD8+ target T cells via secretion of IL-10; blockade of IL-10 (but not TGF-β) abrogated suppression, and CD8+CD122+ cells from IL-10-deficient mice lacked regulatory activity.\",\n      \"method\": \"In vitro co-culture suppression assays; neutralizing antibody blockade; cytokine-removal from conditioned medium; IL-10-KO mice\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (antibody blockade, cytokine depletion, genetic KO) across in vitro and in vivo systems, replicated by subsequent studies\",\n      \"pmids\": [\"16301610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD8+CD122+ regulatory T cells recognize already-activated target T cells through MHC class I–αβTCR–CD8 interactions (not Qa-1 or I-A); this recognition activates Tregs to produce IL-10 and suppress IFN-γ. MHC-congenic experiments confirmed MHC restriction; blocking antibodies against H-2K, H-2D, αβTCR, or CD8 on either Treg or target cells abolished suppression.\",\n      \"method\": \"In vitro co-culture with MHC-congenic/allogeneic mouse strains; surface molecule blocking antibodies\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal blocking with multiple antibody specificities plus MHC-congenic genetic controls in a defined in vitro system\",\n      \"pmids\": [\"18495626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD80/CD86–CD28 co-stimulatory interactions are required for CD8+CD122+ Tregs to become activated and produce IL-10; blocking CD80, CD86, or CD28 prevented IL-10 production and suppression of target T cells, and CD8+CD122+ cells from CD28-KO mice lacked regulatory activity. CTLA-4, ICOS, and PD-1 were not involved.\",\n      \"method\": \"Neutralizing antibody blockade of costimulatory molecules; CD28-KO mouse cells; in vitro suppression assays\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO combined with multiple blocking antibody experiments in a mechanistically defined in vitro system\",\n      \"pmids\": [\"18205792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Within the CD8+CD122+ population, PD-1+ cells are the regulatory subset (producing IL-10 and suppressing T cell responses), while PD-1− cells are bona fide memory T cells; suppression by PD-1+ cells requires both CD28 and PD-1 co-stimulatory signaling for optimal IL-10 production.\",\n      \"method\": \"In vitro and in vivo suppression assays; PD-1 subset fractionation; antibody blockade\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional dissection of subsets with in vitro and in vivo validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"20548035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD8+CD122+CD49d(low) cells are the bona fide regulatory T cell subset within CD8+CD122+ T cells; their suppression of activated T cells operates via Fas/FasL (CD95/CD178)-dependent cytotoxic killing. Tregs from gld (FasL-deficient) mice failed to suppress wild-type targets; targets from lpr (Fas-deficient) mice resisted suppression. IL-10 was found dispensable for this killing mechanism.\",\n      \"method\": \"In vitro and in vivo regulatory assays using lpr/gld mutant mice; CD49d subset fractionation; IL-10-KO Tregs\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic mutant mouse strains (lpr, gld, IL-10-KO) combined with in vitro and in vivo functional assays in one study\",\n      \"pmids\": [\"26869716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD8+CD122+PD-1+ Tregs suppress allograft rejection primarily via Fas ligand-mediated killing of effector T cells in vivo; suppression was largely abolished when Tregs lacked FasL or when effector T cells lacked Fas. In contrast, IL-10 (not FasL) mediates their suppression of T cell proliferation in vitro.\",\n      \"method\": \"Adoptive T cell transfer model in lymphocyte-deficient mice; FasL-blocking antibodies; Fas-deficient and FasL-deficient genetic mouse strains; in vitro cytotoxicity assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic knockouts (Fas-KO, FasL-KO) combined with in vitro killing assays and in vivo adoptive transfer, mechanistic dissection across two distinct suppressive mechanisms\",\n      \"pmids\": [\"28445940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A homozygous hypomorphic mutation in the WSXWS motif of human IL2RB results in diminished IL-2Rβ surface expression and dysregulated IL-2/IL-15 signaling, manifesting as multisystem autoimmunity, reduced regulatory T cells, and an expanded CD56bright NK cell population with lack of terminally differentiated NK cells.\",\n      \"method\": \"Human patient genetic analysis; flow cytometry of immune subsets; functional signaling assays in patient cells\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — first human loss-of-function IL2RB mutation with direct correlation between mutation, reduced surface expression, impaired STAT5 signaling, and defined immune phenotype\",\n      \"pmids\": [\"31040184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Weak CD122-dependent signaling supports CD8+ T central-memory (TCM) cell survival largely through pro-survival (Bcl-2-like) signals, whereas stronger CD122 signaling is required for T effector-memory (TEM) development. This was demonstrated using mouse models with mutations attenuating CD122 cytoplasmic tail signaling and Bcl-2 transgenic CD122-KO CD8+ T cells.\",\n      \"method\": \"Knock-in mice with CD122 cytoplasmic tail mutations; Bcl-2 transgenic/CD122-KO mixed bone marrow chimeras; in vivo OT-I T cell response tracking\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple transgenic/knock-in models with direct in vivo readouts of memory T cell subset development, two orthogonal genetic strategies in one study\",\n      \"pmids\": [\"21984699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD122 (IL-2Rβ) signaling drives costimulation-independent rejection by CD8+ memory T cells; high-affinity IL-15 receptor signaling through CD122 was critical for costimulation-independent memory CD8+ T cell recall, while IL-2 high-affinity receptor signaling was dispensable. Combined CD122 blockade and costimulatory blockade prolonged transplant survival in mice and nonhuman primates.\",\n      \"method\": \"Murine and nonhuman primate transplant models; CD122-selective blocking antibody; mechanistic dissection of IL-2 vs. IL-15 receptor dependence; antibody-mediated depletion/blockade\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated in two species (murine and NHP), multiple receptor-specific blockade experiments distinguishing IL-2 vs. IL-15 dependence\",\n      \"pmids\": [\"30222140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Runx3 transcription factor binds to the promoter region of the CD122 (IL2RB) gene and drives its expression during NK cell differentiation; introduction of a dominant-negative Runx form into hematopoietic stem cells decreased CD122 expression in NK cell-inducing culture.\",\n      \"method\": \"Dominant-negative Runx transgenic mice; chromatin binding (Runx binds CD122 promoter by PCR/binding assay); NK cell differentiation culture system\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, promoter binding plus functional NK culture assay, but limited detail on promoter binding method from abstract\",\n      \"pmids\": [\"18003603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Fibroblast-like synoviocytes (FLS) express functional IL-2Rβ (CD122) and IL-2Rγ (CD132) but not CD25; IL-2 stimulation through CD122 on FLS induces MCP-1 (monocyte chemoattractant protein-1) production via tyrosine phosphorylation signaling, and neutralizing anti-CD122 antibody partially blocked IL-2-induced MCP-1 secretion.\",\n      \"method\": \"Flow cytometry; RT-PCR; anti-CD122 neutralizing antibody blockade; MCP-1 ELISA; tyrosine phosphorylation western blot after IL-2 stimulation\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (mRNA, protein, functional signaling, neutralizing antibody) in single lab study\",\n      \"pmids\": [\"11238664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD122 (IL-2Rβ) is expressed on early lymphoid progenitors including Sca1+Lin- hematopoietic stem cells in fetal liver and intrathymic T cell progenitors; prepro-B cells (CD43+CD24- fraction A) express CD122 and proliferate vigorously in response to IL-2 but not IL-15 in the absence of stromal cells, implicating IL-2/CD122 signaling in early lymphocyte development.\",\n      \"method\": \"Flow cytometry of fetal liver and thymus; in vitro proliferation assays with IL-2 or IL-15; embryo section localization\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization plus functional cytokine responsiveness assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"8547641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD122 (IL-2Rβ)/STAT-5 signaling is continuously active in natural regulatory T cells (Tregs) during thymic selection; pSTAT-5 levels correlated with CD122 and Foxp3 expression (more than with CD25), and IL-2/IL-15 (not IL-7) drove STAT-5 phosphorylation in Treg-lineage cells ex vivo.\",\n      \"method\": \"Ex vivo phospho-flow cytometry of murine thymocytes; in vitro cytokine stimulation; neonatal thymus time-course analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ex vivo and in vitro cytokine stimulation with multiple cytokine comparisons in single lab, no genetic manipulation of IL-2Rβ\",\n      \"pmids\": [\"21541329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The abundance of IL-2Rβ (CD122) on the cell surface constrains lymphopenia-induced homeostatic proliferation (LIP) of naive CD4 T cells; naive CD4 T cells express ~5-fold less CD122 than CD8 T cells, limiting IL-15 responsiveness. Forced IL-2Rβ expression by transgenesis bestowed IL-15 responsiveness on CD4 T cells and enabled robust LIP.\",\n      \"method\": \"Quantitative flow cytometry of surface CD122; IL-2Rβ transgenic CD4 T cells; lymphopenia-induced proliferation assays in mice\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — surface molecule quantification combined with transgenic rescue experiment directly establishing causal role of CD122 abundance in cytokine responsiveness\",\n      \"pmids\": [\"32393513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-2Rβ (CD122) timing and abundance of expression control thymic iNKT cell generation and NKT1 subset differentiation; premature CD122 expression was detrimental to iNKT development, while elevated abundance of CD122 suppressed NKT1 (but not NKT2 or NKT17) generation, establishing cytokine receptor expression level as a determinant of iNKT lineage fate.\",\n      \"method\": \"Transgenic mouse models with premature or elevated CD122 expression; thymic iNKT cell subset quantification by flow cytometry\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two separate transgenic models (timing and abundance) with defined iNKT subset readout, single lab\",\n      \"pmids\": [\"34054809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ADAM17 (a disintegrin and metalloprotease) cleaves membrane CD122 as a sheddase, reducing CD122 surface expression and dampening IL-2 and IL-15 signaling in CD8+ T cells; T cell-specific ADAM17 deletion increased CD122 surface expression, enhanced IL-2/IL-15 responsiveness, and augmented effector CD8+ T cell differentiation in both mouse and human CD8+ T cells.\",\n      \"method\": \"T cell-specific ADAM17 conditional knockout mice; transcriptomic and proteomic analysis; flow cytometry; in vitro IL-2/IL-15 stimulation assays; human CD8+ T cell ADAM17 inhibition\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — post-translational regulatory mechanism identified (shedding of CD122 by ADAM17), validated by genetic KO and pharmacological inhibition with functional readouts in mouse and human cells\",\n      \"pmids\": [\"38918390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Core fucosylation of IL-2Rβ (CD122) by fucosyltransferase 8 (FUT8) is required for CD122 surface expression and IL-15 receptor signaling in NK cells; NK cell-specific Fut8 deletion caused severe NK lymphopenia with reduced CD122 expression, impaired homeostatic proliferation, decreased cytotoxicity, and impaired tumor and viral immunity.\",\n      \"method\": \"Genome-wide CRISPR screen in human NK cells identifying FUT8; conditional NK cell-specific Fut8-KO mice (Fut8fl/flNcr1cre/+); flow cytometry; in vivo homeostatic proliferation; cytotoxicity and infection assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genome-wide CRISPR screen discovery validated by conditional KO mouse model with multiple functional readouts; identifies post-translational glycosylation as a regulator of CD122 surface expression\",\n      \"pmids\": [\"40753573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A hypomorphic IL2RB mutation reduces IL-2Rβ cell-surface expression and impairs IL-2/IL-15-dependent STAT5 signaling, leading to elevated serum IL-2/IL-15, expanded effector memory CD8+ T cells, and severely reduced Tregs; mixed bone marrow chimera and wild-type Treg neonatal transfer experiments demonstrated that Tregs and CD8+ T cells have distinct IL-2Rβ signaling thresholds, and that Treg-extrinsic mechanisms can partly restore conventional T cell distribution.\",\n      \"method\": \"Homologous knockin mouse model; mixed bone marrow chimeras; neonatal WT Treg transfer; STAT5 phosphorylation assays; flow cytometry\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockin mouse recapitulating human mutation validated by chimera and Treg transfer rescue experiments with direct signaling readouts\",\n      \"pmids\": [\"40570369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nicotine increases miR-629-5p expression in CD8+ T cells, which directly targets IL2RB mRNA, suppressing IL-2Rβ (CD122) expression and downstream granzyme B production, thereby exhausting CD8+ T cell cytotoxic function; miR-629-5p mimic transfection reduced both IL2RB and GZMB levels, and this was recapitulated in humanized tumor xenografts.\",\n      \"method\": \"RNAseq and small RNAseq; miR-629-5p mimic transfection; luciferase reporter/target validation; nuclear imaging of granzyme B; humanized tumor xenograft\",\n      \"journal\": \"Cancer immunology, immunotherapy : CII\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — miRNA target validation combined with in vitro functional assays and in vivo xenograft, single lab\",\n      \"pmids\": [\"33146402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-27 promotes Treg cell expression of CD122, and IL-27R-deficient Tregs are at a competitive disadvantage during homeostasis associated with reduced CD122 expression; CD122 blockade caused similar loss of Treg cells, and IL-27 improved Treg responsiveness to IL-2/IL-15 via upregulation of CD122.\",\n      \"method\": \"Mixed IL-27R-sufficient/deficient Treg chimeric mice; aging experiments tracking Treg erosion; CD122 blockade in vivo; in vitro IL-27 stimulation and CD122 expression assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive chimera experiments combined with in vitro mechanistic validation, single lab, establishes IL-27 as an upstream regulator of CD122 expression on Tregs\",\n      \"pmids\": [\"41364763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Chronic circadian disruption (shift-lag) reduces Eomes transcription factor expression in NK cells, which inhibits transcription of CD122 (IL2RB), leading to decreased NK cell cytolytic activity and impaired clearance of MHC-I-deficient tumor cells in vivo.\",\n      \"method\": \"Light-dark reversal circadian disruption mouse model; flow cytometry; in vivo tumor clearance assay; mRNA expression analysis\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlative mRNA/protein data in a single mouse model; Eomes→CD122 transcriptional link is inferred but not directly proven by Eomes manipulation\",\n      \"pmids\": [\"33185980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-2Rβ (CD122) signaling in CD8+ T cells in Peyer's Patches mediates acute B cell apoptosis; CD122-targeted IL-2 complexes caused selective contraction of B cell subsets in Peyer's Patches (but not lamina propria or intraepithelial lymphocytes) via apoptosis.\",\n      \"method\": \"In vivo IL-2/anti-IL-2 antibody complexes targeting CD122; flow cytometry of gut compartments; apoptosis assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean in vivo model with compartment-specific readout and apoptosis measurement, single lab, single publication\",\n      \"pmids\": [\"32728053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL2RB activates the JAK1/STAT5 signaling pathway in esophageal squamous cell carcinoma cells; IL2RB knockdown inhibited tumor cell proliferation, migration, invasion, and epithelial-mesenchymal transition, and was associated with CD8+ T cell depletion in the tumor microenvironment.\",\n      \"method\": \"Gain- and loss-of-function (knockdown/overexpression) in cell lines; in vivo tumor models; western blotting for JAK1/STAT5 pathway\",\n      \"journal\": \"Annals of clinical and laboratory science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional gain/loss-of-function with pathway readout in single lab study; no orthogonal validation\",\n      \"pmids\": [\"40750242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL2RB (IL-2Rβ) transfection into peripheral blood mononuclear cells from septic patients elevated IFN-γ and IL-12 levels (Th1 cytokines) while reducing IL-4, IL-10, and IL-17A, demonstrating that IL2RB expression modulates Th1/Th2 balance and suppresses Th17 activation.\",\n      \"method\": \"PBMC transfection with IL2RB expression construct; ELISA for cytokine levels; bioinformatics dataset analysis\",\n      \"journal\": \"Allergologia et immunopathologia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single transfection experiment in PBMCs, no mechanistic pathway dissection, cytokine changes are correlative\",\n      \"pmids\": [\"37169553\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-2Rβ (CD122) is the shared β-chain subunit of the IL-2 and IL-15 receptor complexes; it drives downstream JAK1/STAT5 signaling, with its surface abundance and post-translational regulation (ectodomain shedding by ADAM17, core fucosylation by FUT8) controlling the threshold and magnitude of IL-2/IL-15 responses in T cells and NK cells. On CD8+ T cells, graded CD122 signaling strength directs fate decisions—weak signals support central memory survival, stronger signals are required for effector memory development, and high-affinity IL-15 (not IL-2) receptor signaling through CD122 underlies costimulation-independent memory recall. CD8+CD122+PD-1+ cells constitute a naturally occurring regulatory T cell subset that suppresses activated T cells through two mechanistically distinct pathways: IL-10-dependent suppression of proliferation, and Fas/FasL-dependent cytotoxic killing; their activation requires MHC class I–αβTCR recognition of target cells and CD80/CD86–CD28 co-stimulation. Upstream, Runx3 and c-REL transcription factors regulate CD122 gene expression during NK and Treg development, respectively, and IL-27 promotes CD122 expression on Tregs to maintain their competitive fitness; human loss-of-function IL2RB mutations confirm that sufficient IL-2Rβ surface expression and STAT5 signaling are non-redundantly required for peripheral immune tolerance and proper NK cell maturation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL2RB encodes IL-2Rβ (CD122), the shared signaling subunit of the IL-2 and IL-15 receptor complexes that transduces cytokine engagement through the JAK1/STAT5 axis to control lymphocyte development, homeostasis, and effector fate [#18, #23]. The amount of CD122 displayed on the cell surface acts as a tunable rheostat for IL-2/IL-15 responsiveness: graded signaling strength partitions CD8+ T cell fate, with weak CD122 signaling supporting central-memory survival via Bcl-2-like pro-survival programs and stronger signaling driving effector-memory development [#8], and high-affinity IL-15 (but not IL-2) signaling through CD122 underlying costimulation-independent memory recall [#9]. Surface abundance itself is set both transcriptionally and post-translationally—Runx3 drives CD122 expression during NK differentiation [#10], IL-27 upregulates CD122 to maintain Treg competitive fitness [#20], ADAM17 sheddase cleaves membrane CD122 to dampen IL-2/IL-15 signaling [#16], and FUT8-mediated core fucosylation is required for CD122 surface expression and IL-15 signaling in NK cells [#17]; correspondingly, CD122 levels constrain lymphopenia-induced proliferation by limiting IL-15 responsiveness [#14]. CD122 marks a naturally occurring CD8+CD122+PD-1+ regulatory T cell subset that suppresses activated T cells through two distinct mechanisms—IL-10-dependent suppression of proliferation and Fas/FasL-dependent cytotoxic killing—following MHC class I–αβTCR recognition of activated targets and CD80/CD86–CD28 co-stimulation [#0, #1, #2, #3, #5]. Continuous CD122/STAT5 signaling sustains natural Tregs during thymic selection [#13]. Human hypomorphic IL2RB mutation in the WSXWS motif reduces IL-2Rβ surface expression and STAT5 signaling, causing multisystem autoimmunity, reduced Tregs, and aberrant NK maturation, establishing CD122 as non-redundantly required for peripheral tolerance and NK development [#7, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that CD122 surface expression marks a functional CD8+ regulatory T cell population essential for T cell homeostasis, defining a non-conventional immunoregulatory role beyond cytokine reception.\",\n      \"evidence\": \"Adoptive transfer of CD8+CD122+ cells into CD122-deficient neonatal mice plus in vitro suppression assays\",\n      \"pmids\": [\"15520244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular mechanism of suppression\", \"Did not establish how CD122 expression itself contributes to the regulatory program\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified IL-10 as the soluble effector by which CD8+CD122+ Tregs suppress target T cell proliferation and IFN-γ production, providing a first defined suppressive mechanism.\",\n      \"evidence\": \"In vitro co-culture, neutralizing antibody blockade, cytokine depletion, and IL-10-KO mice\",\n      \"pmids\": [\"16301610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether other suppressive pathways operate in vivo\", \"Did not link IL-10 production to specific activation signals\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the activation requirements of CD8+CD122+ Tregs, showing antigen-specific MHC class I–αβTCR recognition of activated targets and CD80/CD86–CD28 co-stimulation are both needed to trigger IL-10-mediated suppression.\",\n      \"evidence\": \"In vitro co-culture with MHC-congenic strains, blocking antibodies, and CD28-KO cells\",\n      \"pmids\": [\"18495626\", \"18205792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which TCR specificities are involved\", \"Did not connect activation route to the choice between IL-10 and cytotoxic mechanisms\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved the regulatory versus memory heterogeneity within CD8+CD122+ cells, identifying PD-1+ cells as the suppressive subset and PD-1 as a required co-signal for optimal IL-10 production.\",\n      \"evidence\": \"PD-1 subset fractionation with in vitro and in vivo suppression assays and antibody blockade\",\n      \"pmids\": [\"20548035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how PD-1 signaling mechanistically augments IL-10 output\", \"Did not reconcile PD-1 requirement with earlier finding that PD-1 was dispensable\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered a second, IL-10-independent suppressive mechanism—Fas/FasL-dependent cytotoxic killing—operating in the CD49d(low) regulatory subset, establishing dual-pathway suppression.\",\n      \"evidence\": \"In vitro and in vivo assays using lpr/gld mutant mice, CD49d fractionation, and IL-10-KO Tregs\",\n      \"pmids\": [\"26869716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define what dictates use of cytotoxic versus IL-10 pathway\", \"Did not address relative in vivo contributions of the two mechanisms\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapped the two suppressive mechanisms to distinct contexts, showing FasL-mediated killing dominates allograft suppression in vivo while IL-10 mediates suppression of proliferation in vitro.\",\n      \"evidence\": \"Adoptive transfer transplant model with Fas-KO/FasL-KO strains and in vitro cytotoxicity assays\",\n      \"pmids\": [\"28445940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define molecular switch governing pathway selection\", \"Did not test clinical translatability of the suppressive subset\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that CD122 signaling strength is decoded into distinct CD8+ memory fates—weak signals supporting central-memory survival via Bcl-2-like programs, stronger signals driving effector-memory development.\",\n      \"evidence\": \"Knock-in mice with CD122 tail mutations, Bcl-2 transgenic/CD122-KO chimeras, and in vivo OT-I tracking\",\n      \"pmids\": [\"21984699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the discrete signaling thresholds\", \"Did not separate IL-2 from IL-15 contributions to each fate\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Distinguished IL-2 from IL-15 dependence of CD122 function, showing high-affinity IL-15 receptor signaling through CD122 drives costimulation-independent memory CD8+ recall while IL-2 high-affinity signaling is dispensable.\",\n      \"evidence\": \"Murine and nonhuman primate transplant models with CD122-selective blockade\",\n      \"pmids\": [\"30222140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of IL-2 versus IL-15 discrimination through the shared β-chain\", \"Did not establish downstream effectors of recall signaling\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established surface CD122 abundance as a quantitative gate on IL-15 responsiveness and homeostatic proliferation, with low CD122 limiting naive CD4 T cell expansion.\",\n      \"evidence\": \"Quantitative surface flow cytometry, IL-2Rβ transgenic CD4 T cells, and lymphopenia-induced proliferation assays\",\n      \"pmids\": [\"32393513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify what sets the differential CD122 expression between CD4 and CD8 cells\", \"Did not address post-translational contributions to surface abundance\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified ADAM17-mediated ectodomain shedding as a post-translational brake on CD122 surface abundance, tuning IL-2/IL-15 signaling and effector CD8+ differentiation in mouse and human cells.\",\n      \"evidence\": \"T cell-specific ADAM17 conditional KO, transcriptomics/proteomics, and human CD8+ ADAM17 inhibition\",\n      \"pmids\": [\"38918390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the precise cleavage site on CD122\", \"Did not establish physiological cues triggering shedding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified FUT8-mediated core fucosylation as a glycosylation requirement for CD122 surface expression and IL-15 signaling in NK cells, controlling NK homeostasis, cytotoxicity, and antitumor/antiviral immunity.\",\n      \"evidence\": \"Genome-wide CRISPR screen in human NK cells plus conditional NK-specific Fut8-KO mice with functional readouts\",\n      \"pmids\": [\"40753573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not determine which CD122 N-glycans are fucosylated\", \"Did not test whether fucosylation regulates CD122 in non-NK lineages\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Confirmed in a humanized knockin model that hypomorphic IL2RB reduces surface expression and STAT5 signaling, revealing distinct CD122 signaling thresholds for Tregs versus CD8+ T cells that underlie autoimmunity from impaired tolerance.\",\n      \"evidence\": \"Homologous knockin mouse, mixed bone marrow chimeras, neonatal WT Treg transfer, and STAT5 phosphorylation assays\",\n      \"pmids\": [\"40570369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular basis of the cell-type-specific threshold difference\", \"Did not fully resolve the Treg-extrinsic restoring mechanism\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established IL-27 as an upstream inducer of CD122 on Tregs that sustains their IL-2/IL-15 responsiveness and competitive fitness during homeostasis.\",\n      \"evidence\": \"Mixed IL-27R-sufficient/deficient Treg chimeras, aging experiments, in vivo CD122 blockade, and in vitro IL-27 stimulation\",\n      \"pmids\": [\"41364763\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the transcriptional path from IL-27R to IL2RB\", \"Single-lab study without independent confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the shared β-chain structurally and biochemically discriminates IL-2 versus IL-15 inputs to generate distinct cell-fate outcomes, and how transcriptional, glycosylation, and shedding inputs are integrated to set surface CD122 thresholds in each lineage, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of differential ligand discrimination through CD122 in the corpus\", \"No unified quantitative framework linking the multiple CD122 abundance regulators to threshold setting\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [18, 9, 23]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [11, 14]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [23, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 14, 16, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 7, 9, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [18, 23, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 12, 15]}\n    ],\n    \"complexes\": [\"IL-2 receptor complex\", \"IL-15 receptor complex\"],\n    \"partners\": [\"IL2RG\", \"ADAM17\", \"FUT8\", \"JAK1\", \"STAT5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}