{"gene":"IL2RB","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2004,"finding":"CD8+CD122+ T cells constitute a naturally occurring regulatory T cell population that can directly suppress both CD8+ and CD4+ T cell activity in vivo and in vitro, with transfer of these cells into CD122-deficient neonates preventing development of abnormal activated T cells.","method":"Adoptive cell transfer into CD122-deficient mice; in vitro co-culture suppression assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — clean KO model with defined cellular phenotype, replicated across multiple labs subsequently","pmids":["15520244"],"is_preprint":false},{"year":2005,"finding":"CD8+CD122+ regulatory T cells suppress IFN-γ production and proliferation of CD8+ target cells primarily through 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 with neutralizing antibodies; conditioned medium depletion experiments; cells from IL-10 knockout mice","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (antibody blockade, conditioned medium, KO cells), replicated in vivo","pmids":["16301610"],"is_preprint":false},{"year":2008,"finding":"CD8+CD122+ regulatory T cells recognize activated target T cells via conventional MHC class I–αβTCR interaction (involving H-2K, H-2D, αβTCR, and CD8, but not I-A or Qa-1), and this recognition activates them to produce IL-10 and suppress IFN-γ production.","method":"MHC-congenic mouse strains; blocking antibodies against cell-surface molecules; in vitro co-culture system","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal blocking with defined surface molecules using MHC-congenic strains; multiple orthogonal approaches","pmids":["18495626"],"is_preprint":false},{"year":2008,"finding":"CD8+CD122+ regulatory T cell activation and IL-10 production requires CD80/CD86–CD28 co-stimulatory signaling; cells from CD28-knockout mice lacked regulatory activity, and blocking CD80, CD86, or CD28 (but not CTLA-4, ICOS, or PD-1) abrogated suppression.","method":"Blocking antibodies; CD28-/- knockout mice; in vitro co-culture assays","journal":"Immunology","confidence":"High","confidence_rationale":"Tier 2 — KO mouse combined with specific antibody blockade, multiple molecules tested","pmids":["18205792"],"is_preprint":false},{"year":2010,"finding":"PD-1 expression distinguishes regulatory (PD-1+) from memory (PD-1−) CD8+CD122+ T cells; only the PD-1+ subset suppressed T cell responses via IL-10, while PD-1− cells were antigen-specific memory T cells. Both CD28 and PD-1 co-stimulatory signals are required for optimal IL-10 production by the Treg subset.","method":"In vitro suppression assays; in vivo transfer experiments; PD-1 subset sorting; antibody blockade of co-stimulatory molecules","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, clean functional dissection of subsets, replicated in vivo","pmids":["20548035"],"is_preprint":false},{"year":2016,"finding":"CD8+CD122+CD49dlow regulatory T cells kill activated T cells via Fas/FasL (CD95/CD178)-mediated cytotoxicity; cells from lpr (Fas-deficient) mice were resistant to Treg-mediated suppression, and gld (FasL-deficient) Tregs could not regulate wild-type T cells. IL-10 was not required for this killing mechanism but was separable from it.","method":"In vitro and in vivo regulation assays using lpr and gld mutant mice; CD49d subset fractionation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic mutant mice (lpr, gld) with defined cellular phenotype, in vitro and in vivo validation","pmids":["26869716"],"is_preprint":false},{"year":2019,"finding":"A homozygous hypomorphic human IL2RB mutation in the WSXWS motif results in diminished IL-2Rβ surface expression, dysregulated IL-2/IL-15 signaling (reduced STAT5 phosphorylation), reduced regulatory T cells, expansion of CD56bright NK cells, and absence of terminally differentiated NK cells — establishing IL-2Rβ as essential for human immune tolerance and NK cell maturation.","method":"Human patient genetic and immunological analysis; flow cytometry; functional IL-2/IL-15 signaling assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — human loss-of-function mutation with direct molecular and cellular phenotyping, independently reported in same journal issue","pmids":["31040184"],"is_preprint":false},{"year":2011,"finding":"Weak CD122-dependent signaling supports development and survival of CD8+ T central-memory (TCM) cells but not T effector-memory (TEM) cells; stronger CD122 signals are required for TEM development independently of Bcl-2 survival signals. Proximal IL-2 signaling sustains p-STAT5 and p-S6 longer than IL-15 due to limited IL-15Rα expression.","method":"Cytoplasmic-tail CD122 mutant mouse models; transgenic Bcl-2 rescue; OT-I adoptive transfer; in vivo primary and memory CD8+ T cell response analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — engineered CD122 signaling mutants with defined in vivo phenotype, Bcl-2 epistasis","pmids":["21984699"],"is_preprint":false},{"year":2018,"finding":"Costimulation-independent CD8+ memory T cell alloreactivity is mediated through CD122 (IL-2/IL-15Rβ) signaling; combined costimulatory and CD122 blockade improved transplant survival in mice and nonhuman primates. Signaling through CD122 as part of the high-affinity IL-15R (but not the high-affinity IL-2R) was critical for costimulation-independent memory CD8+ T cell recall.","method":"Mouse and nonhuman primate transplant models; antibody blockade of CD122; genetic dissection of IL-2 vs. IL-15 receptor contributions","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — in vivo blockade in two species with defined mechanistic pathway placement","pmids":["30222140"],"is_preprint":false},{"year":2001,"finding":"Fibroblast-like synoviocytes (FLS) express functional IL-2Rβ (CD122) and IL-2Rγ (CD132) but not CD25, and IL-2 stimulation through CD122 induces MCP-1 production in FLS; this was blocked by anti-CD122 antibody, and IL-2 treatment caused increased tyrosine phosphorylation in FLS.","method":"Western blot; ELISA; flow cytometry; neutralizing antibody blockade; tyrosine phosphorylation assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional assay with antibody blockade and signaling readout, single lab","pmids":["11238664"],"is_preprint":false},{"year":2007,"finding":"Runx3 transcription factor binds to the promoter region of the CD122 (IL2RB) gene and regulates its expression; introduction of a dominant-negative Runx form into hematopoietic stem cells in NK-cell-inducing culture decreased CD122 expression, and transgenic dominant-negative Runx expression in NK cells decreased Ly49 family maturation markers.","method":"Promoter binding assay; dominant-negative Runx transgenic mice; in vitro NK differentiation cultures; RT-PCR","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter binding plus functional transgenic mouse phenotype, single lab","pmids":["18003603"],"is_preprint":false},{"year":2011,"finding":"IL-15/CD122 signaling drives continuous STAT5 phosphorylation in regulatory T cell precursors during thymic selection; pSTAT5 was higher in Foxp3+ Tregs than other CD4+ thymocytes, correlated better with Foxp3 and CD122 than with CD25, and disappeared rapidly without in vivo cytokine signals.","method":"Ex vivo pSTAT5 flow cytometry in neonatal and adult murine thymus; in vitro IL-2/IL-15/IL-7 stimulation; neonatal thymus analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — direct intracellular signaling measurement in primary tissue, single lab","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, and forced transgenic expression of CD122 on CD4+ T cells conferred IL-15 responsiveness and robust LIP.","method":"Surface IL-2Rβ quantification by flow cytometry; transgenic CD122 overexpression on CD4+ T cells; lymphopenic in vivo LIP assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — transgenic rescue experiment with quantitative receptor enumeration and in vivo functional phenotype","pmids":["32393513"],"is_preprint":false},{"year":2024,"finding":"ADAM17 (a disintegrin and metalloprotease) cleaves membrane CD122 via ectodomain shedding, thereby restraining CD8+ T cell effector differentiation; T cell-specific deletion of ADAM17 increased CD122 surface expression and enhanced IL-2 and IL-15 responsiveness in both mouse and human CD8+ T cells, promoting anti-tumor and anti-pathogen immunity.","method":"T cell-specific ADAM17 conditional knockout mice; transcriptomic and proteomic analysis; IL-2/IL-15 stimulation assays; human CD8+ T cell experiments; CAR-T tumor models","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO with mechanistic identification of shedding, validated in mouse and human cells with multiple orthogonal approaches","pmids":["38918390"],"is_preprint":false},{"year":2025,"finding":"Core fucosylation of IL-2Rβ (CD122) by fucosyltransferase 8 (FUT8) is required for NK cell homeostasis; loss of FUT8 in NK cells (Fut8fl/fl Ncr1cre/+) caused severe NK lymphopenia with reduced CD122 surface expression, impaired IL-15-driven homeostatic proliferation, reduced cytotoxicity, and impaired tumor and viral immunity.","method":"Genome-wide CRISPR screen in human NK cells; conditional NK-specific Fut8 knockout mouse; flow cytometry; in vivo NK homeostatic proliferation; tumor and viral immunity assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — genome-wide CRISPR screen discovery validated by conditional KO mouse with multiple functional readouts","pmids":["40753573"],"is_preprint":false},{"year":1996,"finding":"CD122 is expressed on Sca1+Lin− hematopoietic stem cells in fetal liver and on intrathymic Sca1+ T cell progenitors, and its expression marks the earliest B220+ prepro-B cells (fraction A) that proliferate in response to IL-2 but not IL-15, suggesting a role for CD122/IL-2 signaling in early lymphocyte development.","method":"Flow cytometry; in situ mRNA localization; functional IL-2 proliferation assay of sorted progenitors","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization and functional proliferation assays; single lab","pmids":["8547641"],"is_preprint":false},{"year":2021,"finding":"The timing and abundance of IL-2Rβ (CD122) expression control iNKT cell development and NKT1 subset differentiation in the thymus; premature CD122 expression on immature iNKT cells was detrimental to their development, while CD122 is necessary for NKT1 (but not NKT2 or NKT17) generation, and increased CD122 abundance paradoxically suppressed NKT1 differentiation.","method":"Genetic mouse models with altered IL-2Rβ expression timing and abundance; thymic iNKT subset analysis by flow cytometry","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — defined genetic models with specific subset phenotype, single lab","pmids":["34054809"],"is_preprint":false},{"year":2020,"finding":"Nicotine increases miR-629-5p expression in CD8+ T cells, which targets IL2RB mRNA and reduces IL-2Rβ protein levels, consequently suppressing granzyme B expression and exhausting CD8+ T cell cytotoxic function against tumor cells.","method":"RNAseq; small RNAseq; miR-629-5p mimic transfection; IL2RB knockdown; luciferase/target validation; humanized tumor xenograft model","journal":"Cancer immunology, immunotherapy","confidence":"Medium","confidence_rationale":"Tier 2 — miRNA target validation with transfection rescue and in vivo xenograft, single lab","pmids":["33146402"],"is_preprint":false},{"year":2025,"finding":"IL-27 promotes Treg cell expression of CD122 and improves Treg responsiveness to IL-2/IL-15; IL-27R-deficient Tregs were at a competitive disadvantage and were preferentially eroded with aging, associated with reduced CD122 expression; blockade of CD122 led to similar loss of Treg cells, placing IL-27 upstream of CD122 in Treg homeostasis.","method":"Mixed bone marrow chimeras with IL-27R-sufficient and -deficient Tregs; aging experiments; CD122 blockade; in vitro and in vivo IL-27 stimulation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — competitive chimera approach with epistasis, multiple in vivo methods, single lab","pmids":["41364763"],"is_preprint":false},{"year":2025,"finding":"A hypomorphic IL2RB knockin mouse recapitulates human IL-2Rβ deficiency: decreased IL-2Rβ surface expression, impaired IL-2/IL-15-dependent STAT5 signaling, elevated serum IL-2/IL-15, expanded effector memory CD8+ T cells, and severely reduced Tregs. Mixed bone marrow chimeras and WT Treg neonatal transfers demonstrate that Tregs and CD8+ T cells have distinct IL-2/15 signaling thresholds, with WT Treg transfer achieving near-complete restoration of T cell distribution and STAT5 signaling.","method":"Homologous knockin mouse; mixed bone marrow chimeras; WT Treg adoptive transfer; flow cytometry; STAT5 phosphorylation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — homologous knockin model with epistasis via chimeras and Treg transfer, multiple molecular readouts, recapitulates human disease","pmids":["40570369"],"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, EMT, and induced CD8+ T cell depletion in the tumor microenvironment.","method":"Gain- and loss-of-function experiments; in vivo tumor models; western blotting for JAK1/STAT5 pathway","journal":"Annals of clinical and laboratory science","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined pathway (JAK1/STAT5) and cellular phenotype, in vitro and in vivo, single lab","pmids":["40750242"],"is_preprint":false},{"year":2020,"finding":"IL-2Rβ (CD122)-selective IL-2 complexes reduce Treg-mediated immunosuppression by inhibiting high-affinity IL-2R signaling in Tregs while simultaneously stimulating effector T cells through CD122; this preferential CD122 targeting induces a fragile Treg phenotype with reduced suppressive function specifically within the tumor microenvironment.","method":"Orthotopic mouse tumor models; antibody-mediated cell depletions; flow cytometry; in vivo IL-2 complex treatment","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo mechanistic dissection with cell depletions, receptor-selective reagents, single lab","pmids":["32948605"],"is_preprint":false},{"year":1994,"finding":"Activation of PKC β1 isozyme induces expression of both IL-2Rα (CD25) and IL-2Rβ (CD122) on human peripheral blood T and B lymphocytes alongside IL-2 production and DNA synthesis, implicating PKC β1 in upstream regulation of CD122 expression during lymphocyte activation.","method":"PKC isozyme-selective agonist (dPPA) treatment; flow cytometry for CD122/CD25 surface expression; PKC translocation assay; DNA synthesis measurement","journal":"Journal of clinical immunology","confidence":"Low","confidence_rationale":"Tier 3 — pharmacological activation without direct mechanistic link; single method per readout","pmids":["7929699"],"is_preprint":false},{"year":2024,"finding":"miR-7704 inhibits ovarian cancer cell proliferation and promotes cisplatin sensitivity by targeting IL2RB to inactivate AKT signaling; IL2RB overexpression reversed miR-7704-mediated cisplatin sensitization, establishing a miR-7704/IL2RB/AKT regulatory feedback loop.","method":"miRNA mimic/inhibitor transfection; IL2RB knockdown and overexpression; AKT pathway western blotting; in vitro and in vivo tumor models","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — target validation with rescue experiment and pathway readout in vitro and in vivo, single lab","pmids":["38565343"],"is_preprint":false},{"year":2020,"finding":"IL2RB is a target gene of the Wilms' tumor 1 (WT1) transcription factor; WT1 silencing by lentiviral siRNA in K562 myeloid leukemia cells suppressed IL2RB (and IL-2, IL-2RG) mRNA expression alongside induction of apoptosis and growth inhibition.","method":"Lentiviral siRNA knockdown of WT1; qPCR for target gene expression; apoptosis and cell cycle assays","journal":"BioMed research international","confidence":"Low","confidence_rationale":"Tier 3 — indirect transcriptional target identification by KD, no direct promoter binding shown, single method","pmids":["33110919"],"is_preprint":false}],"current_model":"IL-2Rβ (CD122) is the shared β-chain subunit of the IL-2 and IL-15 receptors that drives JAK1/STAT5 signaling upon cytokine binding; its surface abundance — regulated post-translationally by ADAM17-mediated ectodomain shedding and core fucosylation by FUT8, and transcriptionally by Runx3 and WT1 — determines the magnitude of IL-2/IL-15 responsiveness in T cells, NK cells, and Tregs, thereby controlling CD8+ T cell effector and memory differentiation, NK cell homeostasis and cytotoxicity, iNKT subset fate, and Treg development, with CD8+CD122+ regulatory T cells suppressing immune responses through IL-10 secretion and Fas/FasL-mediated cytotoxicity in an MHC class I–TCR and CD28-dependent manner."},"narrative":{"teleology":[{"year":1996,"claim":"Early expression mapping established that CD122 marks hematopoietic stem cells and the earliest lymphoid progenitors, suggesting a developmental role for IL-2Rβ signaling before mature lymphocyte differentiation.","evidence":"Flow cytometry and in situ mRNA localization on fetal liver and thymic progenitors with functional IL-2 proliferation assays","pmids":["8547641"],"confidence":"Medium","gaps":["No loss-of-function evidence at the progenitor stage","Relative contributions of IL-2 vs. IL-15 signaling through CD122 in progenitors undefined"]},{"year":2004,"claim":"The discovery that CD8+CD122+ T cells constitute a naturally occurring regulatory population capable of preventing autoimmune-like disease in CD122-deficient mice established a non-redundant immunosuppressive function for CD122-expressing CD8+ T cells.","evidence":"Adoptive transfer of CD8+CD122+ cells into CD122-knockout neonates; in vitro co-culture suppression assays","pmids":["15520244"],"confidence":"High","gaps":["Mechanism of suppression (soluble vs. contact) was unresolved","Antigen specificity of recognition unknown"]},{"year":2005,"claim":"Identification of IL-10 as the essential effector cytokine of CD8+CD122+ Tregs resolved the suppressive mechanism, showing it was soluble-factor-mediated rather than TGF-β-dependent.","evidence":"In vitro co-culture with neutralizing anti-IL-10 and anti-TGF-β antibodies; cells from IL-10 knockout mice","pmids":["16301610"],"confidence":"High","gaps":["Whether contact-dependent killing also contributes was not addressed","In vivo relevance of IL-10 production in Treg function not fully demonstrated"]},{"year":2008,"claim":"Two studies defined the recognition and costimulatory requirements of CD8+CD122+ Tregs: target recognition occurs via conventional MHC class I–αβTCR interaction, and activation requires CD28 costimulation through CD80/CD86, placing these Tregs within classical T cell activation paradigms.","evidence":"MHC-congenic mouse strains with blocking antibodies against MHC I, TCR, CD8, CD28, CD80, CD86; CD28-knockout mice","pmids":["18495626","18205792"],"confidence":"High","gaps":["Specific antigens recognized by these Tregs remain unidentified","Whether CD28 signals directly drive IL-10 transcription or act indirectly was unknown"]},{"year":2010,"claim":"PD-1 expression was shown to distinguish regulatory (PD-1+) from memory (PD-1−) cells within the CD8+CD122+ compartment, resolving the heterogeneity of this population and revealing that both CD28 and PD-1 signals cooperate for optimal IL-10 production.","evidence":"PD-1 subset sorting with in vitro suppression assays and in vivo transfer experiments; antibody blockade","pmids":["20548035"],"confidence":"High","gaps":["Developmental origin of PD-1+ vs. PD-1− subsets unclear","Whether PD-1 provides a costimulatory or survival signal to Tregs not mechanistically resolved"]},{"year":2011,"claim":"Engineered CD122 cytoplasmic-tail mutant mice demonstrated that graded signal strength through IL-2Rβ specifies CD8+ T cell memory fate: weak signaling sustains central-memory cells while stronger signaling is required for effector-memory differentiation independently of Bcl-2 survival.","evidence":"CD122 signaling-domain mutant knockin mice; Bcl-2 transgenic epistasis; OT-I adoptive transfer","pmids":["21984699"],"confidence":"High","gaps":["Which specific STAT5 target genes drive TEM vs. TCM fate not identified","Contribution of IL-2 vs. IL-15 to each memory subset in vivo not fully dissected"]},{"year":2011,"claim":"Continuous IL-15/CD122-driven STAT5 phosphorylation in Foxp3+ thymic Treg precursors was shown to exceed that in other CD4+ thymocytes and to correlate with CD122 rather than CD25 expression, placing CD122 signaling upstream of Treg lineage commitment.","evidence":"Ex vivo intracellular pSTAT5 flow cytometry in neonatal and adult murine thymus; IL-2/IL-15/IL-7 stimulation","pmids":["21541329"],"confidence":"Medium","gaps":["Causal requirement (not just correlation) of CD122 for Treg thymic selection was not directly tested","Whether IL-15 or IL-2 is the dominant ligand in vivo at this stage was unclear"]},{"year":2016,"claim":"A second, contact-dependent suppressive mechanism of CD8+CD122+ Tregs was uncovered: Fas/FasL-mediated cytotoxicity kills activated target T cells, operating independently of IL-10 secretion and refining the subset to CD49dlow cells.","evidence":"In vitro and in vivo suppression assays using lpr (Fas-deficient) and gld (FasL-deficient) mutant mice; CD49d fractionation","pmids":["26869716"],"confidence":"High","gaps":["Relative in vivo contribution of IL-10 vs. Fas/FasL pathways not quantified","Whether both mechanisms operate simultaneously or in distinct contexts is unknown"]},{"year":2018,"claim":"CD122 was identified as the critical receptor enabling costimulation-independent recall of CD8+ memory T cells during allograft rejection, with IL-15R (not IL-2R) signaling through CD122 being the operative pathway—providing a therapeutic rationale for CD122 blockade in transplantation.","evidence":"Mouse and nonhuman primate transplant models with anti-CD122 antibody blockade; genetic dissection of IL-2 vs. IL-15 receptor contributions","pmids":["30222140"],"confidence":"High","gaps":["Precise intracellular signaling differences between IL-2R and IL-15R through CD122 in memory recall not defined","Long-term immunological consequences of CD122 blockade not assessed"]},{"year":2019,"claim":"A homozygous hypomorphic WSXWS-motif mutation in human IL2RB established the gene as essential for human immune tolerance and NK cell terminal maturation, directly linking reduced CD122 surface expression to diminished STAT5 phosphorylation, Treg deficiency, and CD56bright NK cell expansion.","evidence":"Human patient genetic analysis; flow cytometry; functional IL-2/IL-15 signaling assays","pmids":["31040184"],"confidence":"High","gaps":["Only one family reported initially; broader mutational spectrum unknown","Whether gene therapy or cytokine supplementation can rescue the phenotype not tested"]},{"year":2020,"claim":"Quantitative receptor-level control was demonstrated: naive CD4+ T cells express ~5-fold less CD122 than CD8+ T cells, and transgenic CD122 overexpression on CD4+ T cells conferred IL-15 responsiveness and lymphopenia-induced homeostatic proliferation, establishing surface CD122 abundance as the rate-limiting factor.","evidence":"Surface receptor quantification; transgenic CD122 overexpression on CD4+ T cells; in vivo lymphopenic proliferation assays","pmids":["32393513"],"confidence":"High","gaps":["What controls the differential CD122 expression between CD4+ and CD8+ lineages at the transcriptional level was not addressed"]},{"year":2021,"claim":"Precise timing and abundance of CD122 expression were shown to control iNKT cell development: premature expression was detrimental, CD122 was necessary for NKT1 but not NKT2/NKT17 generation, and supraphysiological CD122 paradoxically suppressed NKT1 differentiation—revealing a Goldilocks requirement.","evidence":"Genetic mouse models with altered IL-2Rβ expression timing and abundance; thymic iNKT subset flow cytometry","pmids":["34054809"],"confidence":"Medium","gaps":["Molecular basis for the biphasic dose-response (too much CD122 being inhibitory) not elucidated","Whether IL-2 or IL-15 mediates the NKT1-promoting signal is not resolved"]},{"year":2024,"claim":"ADAM17 was identified as the sheddase that cleaves membrane CD122, providing the first post-translational mechanism controlling CD122 surface abundance: T cell-specific ADAM17 deletion increased CD122 levels and enhanced IL-2/IL-15 responsiveness, boosting anti-tumor and anti-pathogen CD8+ T cell immunity.","evidence":"Conditional ADAM17 knockout in T cells; transcriptomic/proteomic analysis; human and mouse CD8+ T cell IL-2/IL-15 stimulation; CAR-T tumor models","pmids":["38918390"],"confidence":"High","gaps":["Specific cleavage site on CD122 not mapped","Whether soluble cleaved CD122 ectodomain has biological activity is unknown","Regulation of ADAM17 activity toward CD122 during immune responses not characterized"]},{"year":2025,"claim":"Core fucosylation by FUT8 was identified as essential for CD122 surface stability and NK cell homeostasis: NK-specific Fut8 deletion caused severe NK lymphopenia with reduced CD122 surface expression and impaired IL-15-driven proliferation, tumor immunity, and antiviral defense.","evidence":"Genome-wide CRISPR screen in human NK cells validated by conditional NK-specific Fut8 knockout mouse; flow cytometry; in vivo functional assays","pmids":["40753573"],"confidence":"High","gaps":["Specific fucosylation sites on CD122 not identified","Whether FUT8 affects CD122 folding, trafficking, or protection from shedding is unclear"]},{"year":2025,"claim":"IL-27 was placed upstream of CD122 in Treg homeostasis: IL-27 promotes CD122 expression on Tregs, and IL-27R-deficient Tregs were competitively disadvantaged and eroded with aging—phenocopied by CD122 blockade—establishing a cytokine–receptor cascade maintaining long-term Treg fitness.","evidence":"Mixed bone marrow chimeras with IL-27R-sufficient and -deficient Tregs; aging experiments; CD122 blockade; in vivo and in vitro IL-27 stimulation","pmids":["41364763"],"confidence":"Medium","gaps":["Whether IL-27 directly drives IL2RB transcription or acts indirectly is not resolved","Relevance of IL-27/CD122 axis in human Treg biology not tested"]},{"year":2025,"claim":"A hypomorphic IL2RB knockin mouse fully recapitulated human IL-2Rβ deficiency and demonstrated that Tregs and CD8+ T cells have distinct IL-2/IL-15 signaling thresholds through CD122, with WT Treg transfer alone being sufficient to normalize the T cell compartment—establishing a potential therapeutic principle.","evidence":"Homologous knockin mouse; mixed bone marrow chimeras; neonatal WT Treg adoptive transfer; STAT5 phosphorylation assays","pmids":["40570369"],"confidence":"High","gaps":["Whether the signaling threshold difference is cell-intrinsic to CD122 expression level or involves co-receptor differences is not fully resolved","Long-term outcomes of Treg transfer therapy not assessed"]},{"year":null,"claim":"Key unresolved questions include the precise structural basis of the ADAM17 cleavage site and FUT8 fucosylation sites on CD122, whether soluble cleaved CD122 ectodomain has decoy-receptor activity, and the transcription factor network that establishes differential CD122 expression between CD4+ and CD8+ T cell lineages.","evidence":"","pmids":[],"confidence":"Low","gaps":["Structural mapping of ADAM17 cleavage site and FUT8-modified residues on CD122","Function of soluble CD122 ectodomain","Complete transcriptional regulatory network for IL2RB across lineages"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,7,8,9,19]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,12,13,14,15]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,5,6,8,12,14,19]}],"complexes":["IL-2 receptor complex (IL-2Rα/IL-2Rβ/γc)","IL-15 receptor complex (IL-15Rα/IL-2Rβ/γc)"],"partners":["IL2RG","IL2RA","IL15RA","JAK1","STAT5","ADAM17","FUT8"],"other_free_text":[]},"mechanistic_narrative":"IL-2Rβ (CD122) is the shared β-chain subunit of the interleukin-2 and interleukin-15 receptors that transduces JAK1/STAT5 signals to control lymphocyte homeostasis, effector differentiation, and immune tolerance. Surface abundance of IL-2Rβ is the rate-limiting determinant of IL-2/IL-15 responsiveness: it is regulated post-translationally by ADAM17-mediated ectodomain shedding and FUT8-dependent core fucosylation, and transcriptionally by Runx3 and IL-27 signaling [PMID:38918390, PMID:40753573, PMID:18003603, PMID:41364763]. Graded CD122 signal strength specifies distinct cell fates—weak signaling supports CD8+ central-memory T cells while stronger signaling is required for effector-memory differentiation, and precise timing of CD122 expression governs iNKT subset and Treg development [PMID:21984699, PMID:34054809, PMID:21541329]. Homozygous hypomorphic IL2RB mutations in humans cause immune dysregulation with defective Treg development, impaired NK cell maturation, and expanded effector CD8+ T cells, establishing IL-2Rβ as essential for human immune tolerance [PMID:31040184, PMID:40570369]."},"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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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31134763","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":"33507447","id":"PMC_33507447","title":"Impact of genetic variants in IL-2RA and IL-2RB on breast cancer risk in Chinese Han women.","date":"2021","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33507447","citation_count":7,"is_preprint":false},{"pmid":"40791580","id":"PMC_40791580","title":"Targeting the IL-15/CD122 signaling pathway: reversing TRM cell-mediated immune memory in vitiligo.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40791580","citation_count":6,"is_preprint":false},{"pmid":"34054809","id":"PMC_34054809","title":"The Timing and Abundance of IL-2Rβ (CD122) Expression Control Thymic iNKT Cell Generation and NKT1 Subset Differentiation.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34054809","citation_count":6,"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":"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":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 reports","url":"https://pubmed.ncbi.nlm.nih.gov/32728053","citation_count":3,"is_preprint":false},{"pmid":"8976644","id":"PMC_8976644","title":"Quantitation of IL-2Rp75 (CD122) expression on mononuclear cells in rheumatic disease.","date":"1996","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/8976644","citation_count":3,"is_preprint":false},{"pmid":"38968861","id":"PMC_38968861","title":"Human placental mesenchymal stromal cells promote the formation of CD8+CD122+PD-1+Tregs via CD73/Foxo1 to alleviate liver injury in graft-versus-host disease mice.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38968861","citation_count":3,"is_preprint":false},{"pmid":"26569069","id":"PMC_26569069","title":"Donor-antigen Inoculation in the Testis Promotes Skin Allograft Acceptance Induced by Conventional Costimulatory Blockade via Induction of CD8 + CD122+ and CD4 + CD25+ Regulatory T Cells.","date":"2016","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/26569069","citation_count":3,"is_preprint":false},{"pmid":"33110919","id":"PMC_33110919","title":"Novel WT1 Target Genes: IL-2, IL-2RB, and IL-2RG Discovered during WT1 Silencing Using Lentiviral-Based RNAi in Myeloid Leukemia Cells.","date":"2020","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/33110919","citation_count":3,"is_preprint":false},{"pmid":"32616380","id":"PMC_32616380","title":"CD8+CD122+ T cell homeostasis is controlled by different levels of IL-15 trans-presentation.","date":"2020","source":"Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/32616380","citation_count":2,"is_preprint":false},{"pmid":"32765495","id":"PMC_32765495","title":"Corrigendum: A New Immunosuppressive Molecule Emodin Induces both CD4+FoxP3+ and CD8+CD122+ Regulatory T Cells and Suppresses Murine Allograft Rejection.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32765495","citation_count":2,"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":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 immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39153581","citation_count":1,"is_preprint":false},{"pmid":"40185434","id":"PMC_40185434","title":"A dual-mode nanoplatform based on Cu2O@Au-Pt nanoenzyme and CHA-HCR DNA framework circuit for sensitive detection of CD122 and CD17.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40185434","citation_count":1,"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":0,"is_preprint":false},{"pmid":"41364763","id":"PMC_41364763","title":"IL-27 promotes Treg cell expression of CD122 and fitness at homeostasis.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/41364763","citation_count":0,"is_preprint":false},{"pmid":"36966029","id":"PMC_36966029","title":"Blockade of CD122 on memory T cells in the skin suppresses sclerodermatous graft-versus-host disease.","date":"2023","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/36966029","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51194,"output_tokens":5998,"usd":0.121776},"stage2":{"model":"claude-opus-4-6","input_tokens":9698,"output_tokens":4064,"usd":0.225135},"total_usd":0.346911,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"CD8+CD122+ T cells constitute a naturally occurring regulatory T cell population that can directly suppress both CD8+ and CD4+ T cell activity in vivo and in vitro, with transfer of these cells into CD122-deficient neonates preventing development of abnormal activated T cells.\",\n      \"method\": \"Adoptive cell transfer into CD122-deficient mice; in vitro co-culture suppression assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO model with defined cellular phenotype, replicated across multiple labs subsequently\",\n      \"pmids\": [\"15520244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD8+CD122+ regulatory T cells suppress IFN-γ production and proliferation of CD8+ target cells primarily through 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 with neutralizing antibodies; conditioned medium depletion experiments; cells from IL-10 knockout mice\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (antibody blockade, conditioned medium, KO cells), replicated in vivo\",\n      \"pmids\": [\"16301610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD8+CD122+ regulatory T cells recognize activated target T cells via conventional MHC class I–αβTCR interaction (involving H-2K, H-2D, αβTCR, and CD8, but not I-A or Qa-1), and this recognition activates them to produce IL-10 and suppress IFN-γ production.\",\n      \"method\": \"MHC-congenic mouse strains; blocking antibodies against cell-surface molecules; in vitro co-culture system\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal blocking with defined surface molecules using MHC-congenic strains; multiple orthogonal approaches\",\n      \"pmids\": [\"18495626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD8+CD122+ regulatory T cell activation and IL-10 production requires CD80/CD86–CD28 co-stimulatory signaling; cells from CD28-knockout mice lacked regulatory activity, and blocking CD80, CD86, or CD28 (but not CTLA-4, ICOS, or PD-1) abrogated suppression.\",\n      \"method\": \"Blocking antibodies; CD28-/- knockout mice; in vitro co-culture assays\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse combined with specific antibody blockade, multiple molecules tested\",\n      \"pmids\": [\"18205792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PD-1 expression distinguishes regulatory (PD-1+) from memory (PD-1−) CD8+CD122+ T cells; only the PD-1+ subset suppressed T cell responses via IL-10, while PD-1− cells were antigen-specific memory T cells. Both CD28 and PD-1 co-stimulatory signals are required for optimal IL-10 production by the Treg subset.\",\n      \"method\": \"In vitro suppression assays; in vivo transfer experiments; PD-1 subset sorting; antibody blockade of co-stimulatory molecules\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, clean functional dissection of subsets, replicated in vivo\",\n      \"pmids\": [\"20548035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD8+CD122+CD49dlow regulatory T cells kill activated T cells via Fas/FasL (CD95/CD178)-mediated cytotoxicity; cells from lpr (Fas-deficient) mice were resistant to Treg-mediated suppression, and gld (FasL-deficient) Tregs could not regulate wild-type T cells. IL-10 was not required for this killing mechanism but was separable from it.\",\n      \"method\": \"In vitro and in vivo regulation assays using lpr and gld mutant mice; CD49d subset fractionation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic mutant mice (lpr, gld) with defined cellular phenotype, in vitro and in vivo validation\",\n      \"pmids\": [\"26869716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A homozygous hypomorphic human IL2RB mutation in the WSXWS motif results in diminished IL-2Rβ surface expression, dysregulated IL-2/IL-15 signaling (reduced STAT5 phosphorylation), reduced regulatory T cells, expansion of CD56bright NK cells, and absence of terminally differentiated NK cells — establishing IL-2Rβ as essential for human immune tolerance and NK cell maturation.\",\n      \"method\": \"Human patient genetic and immunological analysis; flow cytometry; functional IL-2/IL-15 signaling assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human loss-of-function mutation with direct molecular and cellular phenotyping, independently reported in same journal issue\",\n      \"pmids\": [\"31040184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Weak CD122-dependent signaling supports development and survival of CD8+ T central-memory (TCM) cells but not T effector-memory (TEM) cells; stronger CD122 signals are required for TEM development independently of Bcl-2 survival signals. Proximal IL-2 signaling sustains p-STAT5 and p-S6 longer than IL-15 due to limited IL-15Rα expression.\",\n      \"method\": \"Cytoplasmic-tail CD122 mutant mouse models; transgenic Bcl-2 rescue; OT-I adoptive transfer; in vivo primary and memory CD8+ T cell response analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — engineered CD122 signaling mutants with defined in vivo phenotype, Bcl-2 epistasis\",\n      \"pmids\": [\"21984699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Costimulation-independent CD8+ memory T cell alloreactivity is mediated through CD122 (IL-2/IL-15Rβ) signaling; combined costimulatory and CD122 blockade improved transplant survival in mice and nonhuman primates. Signaling through CD122 as part of the high-affinity IL-15R (but not the high-affinity IL-2R) was critical for costimulation-independent memory CD8+ T cell recall.\",\n      \"method\": \"Mouse and nonhuman primate transplant models; antibody blockade of CD122; genetic dissection of IL-2 vs. IL-15 receptor contributions\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo blockade in two species with defined mechanistic pathway placement\",\n      \"pmids\": [\"30222140\"],\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, and IL-2 stimulation through CD122 induces MCP-1 production in FLS; this was blocked by anti-CD122 antibody, and IL-2 treatment caused increased tyrosine phosphorylation in FLS.\",\n      \"method\": \"Western blot; ELISA; flow cytometry; neutralizing antibody blockade; tyrosine phosphorylation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assay with antibody blockade and signaling readout, single lab\",\n      \"pmids\": [\"11238664\"],\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 regulates its expression; introduction of a dominant-negative Runx form into hematopoietic stem cells in NK-cell-inducing culture decreased CD122 expression, and transgenic dominant-negative Runx expression in NK cells decreased Ly49 family maturation markers.\",\n      \"method\": \"Promoter binding assay; dominant-negative Runx transgenic mice; in vitro NK differentiation cultures; RT-PCR\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding plus functional transgenic mouse phenotype, single lab\",\n      \"pmids\": [\"18003603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-15/CD122 signaling drives continuous STAT5 phosphorylation in regulatory T cell precursors during thymic selection; pSTAT5 was higher in Foxp3+ Tregs than other CD4+ thymocytes, correlated better with Foxp3 and CD122 than with CD25, and disappeared rapidly without in vivo cytokine signals.\",\n      \"method\": \"Ex vivo pSTAT5 flow cytometry in neonatal and adult murine thymus; in vitro IL-2/IL-15/IL-7 stimulation; neonatal thymus analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct intracellular signaling measurement in primary tissue, single lab\",\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, and forced transgenic expression of CD122 on CD4+ T cells conferred IL-15 responsiveness and robust LIP.\",\n      \"method\": \"Surface IL-2Rβ quantification by flow cytometry; transgenic CD122 overexpression on CD4+ T cells; lymphopenic in vivo LIP assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — transgenic rescue experiment with quantitative receptor enumeration and in vivo functional phenotype\",\n      \"pmids\": [\"32393513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ADAM17 (a disintegrin and metalloprotease) cleaves membrane CD122 via ectodomain shedding, thereby restraining CD8+ T cell effector differentiation; T cell-specific deletion of ADAM17 increased CD122 surface expression and enhanced IL-2 and IL-15 responsiveness in both mouse and human CD8+ T cells, promoting anti-tumor and anti-pathogen immunity.\",\n      \"method\": \"T cell-specific ADAM17 conditional knockout mice; transcriptomic and proteomic analysis; IL-2/IL-15 stimulation assays; human CD8+ T cell experiments; CAR-T tumor models\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO with mechanistic identification of shedding, validated in mouse and human cells with multiple orthogonal approaches\",\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 NK cell homeostasis; loss of FUT8 in NK cells (Fut8fl/fl Ncr1cre/+) caused severe NK lymphopenia with reduced CD122 surface expression, impaired IL-15-driven homeostatic proliferation, reduced cytotoxicity, and impaired tumor and viral immunity.\",\n      \"method\": \"Genome-wide CRISPR screen in human NK cells; conditional NK-specific Fut8 knockout mouse; flow cytometry; in vivo NK homeostatic proliferation; tumor and viral immunity assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-wide CRISPR screen discovery validated by conditional KO mouse with multiple functional readouts\",\n      \"pmids\": [\"40753573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD122 is expressed on Sca1+Lin− hematopoietic stem cells in fetal liver and on intrathymic Sca1+ T cell progenitors, and its expression marks the earliest B220+ prepro-B cells (fraction A) that proliferate in response to IL-2 but not IL-15, suggesting a role for CD122/IL-2 signaling in early lymphocyte development.\",\n      \"method\": \"Flow cytometry; in situ mRNA localization; functional IL-2 proliferation assay of sorted progenitors\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization and functional proliferation assays; single lab\",\n      \"pmids\": [\"8547641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The timing and abundance of IL-2Rβ (CD122) expression control iNKT cell development and NKT1 subset differentiation in the thymus; premature CD122 expression on immature iNKT cells was detrimental to their development, while CD122 is necessary for NKT1 (but not NKT2 or NKT17) generation, and increased CD122 abundance paradoxically suppressed NKT1 differentiation.\",\n      \"method\": \"Genetic mouse models with altered IL-2Rβ expression timing and abundance; thymic iNKT subset analysis by flow cytometry\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined genetic models with specific subset phenotype, single lab\",\n      \"pmids\": [\"34054809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nicotine increases miR-629-5p expression in CD8+ T cells, which targets IL2RB mRNA and reduces IL-2Rβ protein levels, consequently suppressing granzyme B expression and exhausting CD8+ T cell cytotoxic function against tumor cells.\",\n      \"method\": \"RNAseq; small RNAseq; miR-629-5p mimic transfection; IL2RB knockdown; luciferase/target validation; humanized tumor xenograft model\",\n      \"journal\": \"Cancer immunology, immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — miRNA target validation with transfection rescue 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 improves Treg responsiveness to IL-2/IL-15; IL-27R-deficient Tregs were at a competitive disadvantage and were preferentially eroded with aging, associated with reduced CD122 expression; blockade of CD122 led to similar loss of Treg cells, placing IL-27 upstream of CD122 in Treg homeostasis.\",\n      \"method\": \"Mixed bone marrow chimeras with IL-27R-sufficient and -deficient Tregs; aging experiments; CD122 blockade; in vitro and in vivo IL-27 stimulation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — competitive chimera approach with epistasis, multiple in vivo methods, single lab\",\n      \"pmids\": [\"41364763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A hypomorphic IL2RB knockin mouse recapitulates human IL-2Rβ deficiency: decreased IL-2Rβ surface expression, impaired IL-2/IL-15-dependent STAT5 signaling, elevated serum IL-2/IL-15, expanded effector memory CD8+ T cells, and severely reduced Tregs. Mixed bone marrow chimeras and WT Treg neonatal transfers demonstrate that Tregs and CD8+ T cells have distinct IL-2/15 signaling thresholds, with WT Treg transfer achieving near-complete restoration of T cell distribution and STAT5 signaling.\",\n      \"method\": \"Homologous knockin mouse; mixed bone marrow chimeras; WT Treg adoptive transfer; flow cytometry; STAT5 phosphorylation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — homologous knockin model with epistasis via chimeras and Treg transfer, multiple molecular readouts, recapitulates human disease\",\n      \"pmids\": [\"40570369\"],\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, EMT, and induced CD8+ T cell depletion in the tumor microenvironment.\",\n      \"method\": \"Gain- and loss-of-function experiments; 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 — KD with defined pathway (JAK1/STAT5) and cellular phenotype, in vitro and in vivo, single lab\",\n      \"pmids\": [\"40750242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-2Rβ (CD122)-selective IL-2 complexes reduce Treg-mediated immunosuppression by inhibiting high-affinity IL-2R signaling in Tregs while simultaneously stimulating effector T cells through CD122; this preferential CD122 targeting induces a fragile Treg phenotype with reduced suppressive function specifically within the tumor microenvironment.\",\n      \"method\": \"Orthotopic mouse tumor models; antibody-mediated cell depletions; flow cytometry; in vivo IL-2 complex treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mechanistic dissection with cell depletions, receptor-selective reagents, single lab\",\n      \"pmids\": [\"32948605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Activation of PKC β1 isozyme induces expression of both IL-2Rα (CD25) and IL-2Rβ (CD122) on human peripheral blood T and B lymphocytes alongside IL-2 production and DNA synthesis, implicating PKC β1 in upstream regulation of CD122 expression during lymphocyte activation.\",\n      \"method\": \"PKC isozyme-selective agonist (dPPA) treatment; flow cytometry for CD122/CD25 surface expression; PKC translocation assay; DNA synthesis measurement\",\n      \"journal\": \"Journal of clinical immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological activation without direct mechanistic link; single method per readout\",\n      \"pmids\": [\"7929699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"miR-7704 inhibits ovarian cancer cell proliferation and promotes cisplatin sensitivity by targeting IL2RB to inactivate AKT signaling; IL2RB overexpression reversed miR-7704-mediated cisplatin sensitization, establishing a miR-7704/IL2RB/AKT regulatory feedback loop.\",\n      \"method\": \"miRNA mimic/inhibitor transfection; IL2RB knockdown and overexpression; AKT pathway western blotting; in vitro and in vivo tumor models\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — target validation with rescue experiment and pathway readout in vitro and in vivo, single lab\",\n      \"pmids\": [\"38565343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL2RB is a target gene of the Wilms' tumor 1 (WT1) transcription factor; WT1 silencing by lentiviral siRNA in K562 myeloid leukemia cells suppressed IL2RB (and IL-2, IL-2RG) mRNA expression alongside induction of apoptosis and growth inhibition.\",\n      \"method\": \"Lentiviral siRNA knockdown of WT1; qPCR for target gene expression; apoptosis and cell cycle assays\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — indirect transcriptional target identification by KD, no direct promoter binding shown, single method\",\n      \"pmids\": [\"33110919\"],\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 receptors that drives JAK1/STAT5 signaling upon cytokine binding; its surface abundance — regulated post-translationally by ADAM17-mediated ectodomain shedding and core fucosylation by FUT8, and transcriptionally by Runx3 and WT1 — determines the magnitude of IL-2/IL-15 responsiveness in T cells, NK cells, and Tregs, thereby controlling CD8+ T cell effector and memory differentiation, NK cell homeostasis and cytotoxicity, iNKT subset fate, and Treg development, with CD8+CD122+ regulatory T cells suppressing immune responses through IL-10 secretion and Fas/FasL-mediated cytotoxicity in an MHC class I–TCR and CD28-dependent manner.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-2Rβ (CD122) is the shared β-chain subunit of the interleukin-2 and interleukin-15 receptors that transduces JAK1/STAT5 signals to control lymphocyte homeostasis, effector differentiation, and immune tolerance. Surface abundance of IL-2Rβ is the rate-limiting determinant of IL-2/IL-15 responsiveness: it is regulated post-translationally by ADAM17-mediated ectodomain shedding and FUT8-dependent core fucosylation, and transcriptionally by Runx3 and IL-27 signaling [PMID:38918390, PMID:40753573, PMID:18003603, PMID:41364763]. Graded CD122 signal strength specifies distinct cell fates—weak signaling supports CD8+ central-memory T cells while stronger signaling is required for effector-memory differentiation, and precise timing of CD122 expression governs iNKT subset and Treg development [PMID:21984699, PMID:34054809, PMID:21541329]. Homozygous hypomorphic IL2RB mutations in humans cause immune dysregulation with defective Treg development, impaired NK cell maturation, and expanded effector CD8+ T cells, establishing IL-2Rβ as essential for human immune tolerance [PMID:31040184, PMID:40570369].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Early expression mapping established that CD122 marks hematopoietic stem cells and the earliest lymphoid progenitors, suggesting a developmental role for IL-2Rβ signaling before mature lymphocyte differentiation.\",\n      \"evidence\": \"Flow cytometry and in situ mRNA localization on fetal liver and thymic progenitors with functional IL-2 proliferation assays\",\n      \"pmids\": [\"8547641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No loss-of-function evidence at the progenitor stage\", \"Relative contributions of IL-2 vs. IL-15 signaling through CD122 in progenitors undefined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The discovery that CD8+CD122+ T cells constitute a naturally occurring regulatory population capable of preventing autoimmune-like disease in CD122-deficient mice established a non-redundant immunosuppressive function for CD122-expressing CD8+ T cells.\",\n      \"evidence\": \"Adoptive transfer of CD8+CD122+ cells into CD122-knockout neonates; in vitro co-culture suppression assays\",\n      \"pmids\": [\"15520244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of suppression (soluble vs. contact) was unresolved\", \"Antigen specificity of recognition unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of IL-10 as the essential effector cytokine of CD8+CD122+ Tregs resolved the suppressive mechanism, showing it was soluble-factor-mediated rather than TGF-β-dependent.\",\n      \"evidence\": \"In vitro co-culture with neutralizing anti-IL-10 and anti-TGF-β antibodies; cells from IL-10 knockout mice\",\n      \"pmids\": [\"16301610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether contact-dependent killing also contributes was not addressed\", \"In vivo relevance of IL-10 production in Treg function not fully demonstrated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Two studies defined the recognition and costimulatory requirements of CD8+CD122+ Tregs: target recognition occurs via conventional MHC class I–αβTCR interaction, and activation requires CD28 costimulation through CD80/CD86, placing these Tregs within classical T cell activation paradigms.\",\n      \"evidence\": \"MHC-congenic mouse strains with blocking antibodies against MHC I, TCR, CD8, CD28, CD80, CD86; CD28-knockout mice\",\n      \"pmids\": [\"18495626\", \"18205792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific antigens recognized by these Tregs remain unidentified\", \"Whether CD28 signals directly drive IL-10 transcription or act indirectly was unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"PD-1 expression was shown to distinguish regulatory (PD-1+) from memory (PD-1−) cells within the CD8+CD122+ compartment, resolving the heterogeneity of this population and revealing that both CD28 and PD-1 signals cooperate for optimal IL-10 production.\",\n      \"evidence\": \"PD-1 subset sorting with in vitro suppression assays and in vivo transfer experiments; antibody blockade\",\n      \"pmids\": [\"20548035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Developmental origin of PD-1+ vs. PD-1− subsets unclear\", \"Whether PD-1 provides a costimulatory or survival signal to Tregs not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Engineered CD122 cytoplasmic-tail mutant mice demonstrated that graded signal strength through IL-2Rβ specifies CD8+ T cell memory fate: weak signaling sustains central-memory cells while stronger signaling is required for effector-memory differentiation independently of Bcl-2 survival.\",\n      \"evidence\": \"CD122 signaling-domain mutant knockin mice; Bcl-2 transgenic epistasis; OT-I adoptive transfer\",\n      \"pmids\": [\"21984699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific STAT5 target genes drive TEM vs. TCM fate not identified\", \"Contribution of IL-2 vs. IL-15 to each memory subset in vivo not fully dissected\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Continuous IL-15/CD122-driven STAT5 phosphorylation in Foxp3+ thymic Treg precursors was shown to exceed that in other CD4+ thymocytes and to correlate with CD122 rather than CD25 expression, placing CD122 signaling upstream of Treg lineage commitment.\",\n      \"evidence\": \"Ex vivo intracellular pSTAT5 flow cytometry in neonatal and adult murine thymus; IL-2/IL-15/IL-7 stimulation\",\n      \"pmids\": [\"21541329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal requirement (not just correlation) of CD122 for Treg thymic selection was not directly tested\", \"Whether IL-15 or IL-2 is the dominant ligand in vivo at this stage was unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A second, contact-dependent suppressive mechanism of CD8+CD122+ Tregs was uncovered: Fas/FasL-mediated cytotoxicity kills activated target T cells, operating independently of IL-10 secretion and refining the subset to CD49dlow cells.\",\n      \"evidence\": \"In vitro and in vivo suppression assays using lpr (Fas-deficient) and gld (FasL-deficient) mutant mice; CD49d fractionation\",\n      \"pmids\": [\"26869716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo contribution of IL-10 vs. Fas/FasL pathways not quantified\", \"Whether both mechanisms operate simultaneously or in distinct contexts is unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"CD122 was identified as the critical receptor enabling costimulation-independent recall of CD8+ memory T cells during allograft rejection, with IL-15R (not IL-2R) signaling through CD122 being the operative pathway—providing a therapeutic rationale for CD122 blockade in transplantation.\",\n      \"evidence\": \"Mouse and nonhuman primate transplant models with anti-CD122 antibody blockade; genetic dissection of IL-2 vs. IL-15 receptor contributions\",\n      \"pmids\": [\"30222140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise intracellular signaling differences between IL-2R and IL-15R through CD122 in memory recall not defined\", \"Long-term immunological consequences of CD122 blockade not assessed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A homozygous hypomorphic WSXWS-motif mutation in human IL2RB established the gene as essential for human immune tolerance and NK cell terminal maturation, directly linking reduced CD122 surface expression to diminished STAT5 phosphorylation, Treg deficiency, and CD56bright NK cell expansion.\",\n      \"evidence\": \"Human patient genetic analysis; flow cytometry; functional IL-2/IL-15 signaling assays\",\n      \"pmids\": [\"31040184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Only one family reported initially; broader mutational spectrum unknown\", \"Whether gene therapy or cytokine supplementation can rescue the phenotype not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Quantitative receptor-level control was demonstrated: naive CD4+ T cells express ~5-fold less CD122 than CD8+ T cells, and transgenic CD122 overexpression on CD4+ T cells conferred IL-15 responsiveness and lymphopenia-induced homeostatic proliferation, establishing surface CD122 abundance as the rate-limiting factor.\",\n      \"evidence\": \"Surface receptor quantification; transgenic CD122 overexpression on CD4+ T cells; in vivo lymphopenic proliferation assays\",\n      \"pmids\": [\"32393513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What controls the differential CD122 expression between CD4+ and CD8+ lineages at the transcriptional level was not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Precise timing and abundance of CD122 expression were shown to control iNKT cell development: premature expression was detrimental, CD122 was necessary for NKT1 but not NKT2/NKT17 generation, and supraphysiological CD122 paradoxically suppressed NKT1 differentiation—revealing a Goldilocks requirement.\",\n      \"evidence\": \"Genetic mouse models with altered IL-2Rβ expression timing and abundance; thymic iNKT subset flow cytometry\",\n      \"pmids\": [\"34054809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis for the biphasic dose-response (too much CD122 being inhibitory) not elucidated\", \"Whether IL-2 or IL-15 mediates the NKT1-promoting signal is not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ADAM17 was identified as the sheddase that cleaves membrane CD122, providing the first post-translational mechanism controlling CD122 surface abundance: T cell-specific ADAM17 deletion increased CD122 levels and enhanced IL-2/IL-15 responsiveness, boosting anti-tumor and anti-pathogen CD8+ T cell immunity.\",\n      \"evidence\": \"Conditional ADAM17 knockout in T cells; transcriptomic/proteomic analysis; human and mouse CD8+ T cell IL-2/IL-15 stimulation; CAR-T tumor models\",\n      \"pmids\": [\"38918390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific cleavage site on CD122 not mapped\", \"Whether soluble cleaved CD122 ectodomain has biological activity is unknown\", \"Regulation of ADAM17 activity toward CD122 during immune responses not characterized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Core fucosylation by FUT8 was identified as essential for CD122 surface stability and NK cell homeostasis: NK-specific Fut8 deletion caused severe NK lymphopenia with reduced CD122 surface expression and impaired IL-15-driven proliferation, tumor immunity, and antiviral defense.\",\n      \"evidence\": \"Genome-wide CRISPR screen in human NK cells validated by conditional NK-specific Fut8 knockout mouse; flow cytometry; in vivo functional assays\",\n      \"pmids\": [\"40753573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific fucosylation sites on CD122 not identified\", \"Whether FUT8 affects CD122 folding, trafficking, or protection from shedding is unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"IL-27 was placed upstream of CD122 in Treg homeostasis: IL-27 promotes CD122 expression on Tregs, and IL-27R-deficient Tregs were competitively disadvantaged and eroded with aging—phenocopied by CD122 blockade—establishing a cytokine–receptor cascade maintaining long-term Treg fitness.\",\n      \"evidence\": \"Mixed bone marrow chimeras with IL-27R-sufficient and -deficient Tregs; aging experiments; CD122 blockade; in vivo and in vitro IL-27 stimulation\",\n      \"pmids\": [\"41364763\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IL-27 directly drives IL2RB transcription or acts indirectly is not resolved\", \"Relevance of IL-27/CD122 axis in human Treg biology not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A hypomorphic IL2RB knockin mouse fully recapitulated human IL-2Rβ deficiency and demonstrated that Tregs and CD8+ T cells have distinct IL-2/IL-15 signaling thresholds through CD122, with WT Treg transfer alone being sufficient to normalize the T cell compartment—establishing a potential therapeutic principle.\",\n      \"evidence\": \"Homologous knockin mouse; mixed bone marrow chimeras; neonatal WT Treg adoptive transfer; STAT5 phosphorylation assays\",\n      \"pmids\": [\"40570369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the signaling threshold difference is cell-intrinsic to CD122 expression level or involves co-receptor differences is not fully resolved\", \"Long-term outcomes of Treg transfer therapy not assessed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the precise structural basis of the ADAM17 cleavage site and FUT8 fucosylation sites on CD122, whether soluble cleaved CD122 ectodomain has decoy-receptor activity, and the transcription factor network that establishes differential CD122 expression between CD4+ and CD8+ T cell lineages.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Structural mapping of ADAM17 cleavage site and FUT8-modified residues on CD122\", \"Function of soluble CD122 ectodomain\", \"Complete transcriptional regulatory network for IL2RB across lineages\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 7, 8, 9, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 12, 13, 14, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [7, 8, 11, 19, 20, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 5, 6, 8, 12, 14, 19]}\n    ],\n    \"complexes\": [\n      \"IL-2 receptor complex (IL-2Rα/IL-2Rβ/γc)\",\n      \"IL-15 receptor complex (IL-15Rα/IL-2Rβ/γc)\"\n    ],\n    \"partners\": [\n      \"IL2RG\",\n      \"IL2RA\",\n      \"IL15RA\",\n      \"JAK1\",\n      \"STAT5\",\n      \"ADAM17\",\n      \"FUT8\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}