{"gene":"IL12RB2","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2005,"finding":"Targeted inactivation (knockout) of Il12rb2 in mice leads to spontaneous autoimmunity (immune-complex mesangial glomerulonephritis, antinuclear antibodies, lymphoid infiltrates with vasculitis and Sjögren syndrome features), B-cell tumors (plasmacytoma), and lung carcinoma, associated with strong IL-6 upregulation in splenocytes and IFN-γ deficiency, establishing that IL-12Rβ2 signaling physiologically restrains aberrant B-cell activation and supports IFN-γ-dependent tumor surveillance.","method":"Il12rb2 knockout mouse model; histopathology, serum antibody assays, cytokine measurement in splenocytes","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple defined cellular phenotypes and pathway placement (IFN-γ deficiency secondary to loss of IL-12 signaling, IL-6 upregulation), single rigorous study with multiple orthogonal readouts","pmids":["16081683"],"is_preprint":false},{"year":2011,"finding":"In ex vivo-isolated murine Th17 cells, the Il12rb2 locus carries repressive H3K27 trimethylation marks that restrict its expression; in vitro activation or in vivo immunization removes these marks and allows IL-12Rβ2 upregulation. IL-12 stimulation then removes H3K27me3 at the Tbx21/T-bet locus, enhancing T-bet expression and enabling deviation of Th17 cells toward a Th1-like profile.","method":"ChIP for H3K27me3 and H3K4me3 at Il12rb2 and Tbx21 loci in purified ex vivo and in vitro Th17 cells; flow cytometry; in vitro IL-12 stimulation assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, flow cytometry, functional deviation assay), single lab","pmids":["21307296"],"is_preprint":false},{"year":2017,"finding":"During human naive CD4 T cell activation, H3K27me3 at the IL12RB2 promoter is dynamically removed (demethylated) predominantly within 1 day of activation; pharmacological inhibition of the H3K27 demethylase JMJD3 prevents this demethylation and impairs IL12RB2 expression, demonstrating that JMJD3-driven H3K27 demethylation is required for IL12RB2 upregulation during T cell activation.","method":"ChIP-seq for H3K27me3 at IL12RB2 promoter in naive and memory CD4 T cells; JMJD3 inhibitor treatment with quantification of IL12RB2 expression","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus inhibitor functional assay, single lab, two orthogonal methods","pmids":["28947543"],"is_preprint":false},{"year":2015,"finding":"SNPs in the promoter region of IL12RB2 (-1035 and -1023 positions; rs3762315 and rs3762316) create differential binding sites for the transcription factors JunB, GATA-3, and MEF-2; the -1023G polymorphism creates an AP-1 consensus site that enhances JunB binding. siRNA-mediated suppression of JunB eliminates haplotype-specific differences in IL12RB2 promoter activity in both Jurkat T cells and NK3.3 cells, establishing JunB as a key transcriptional regulator of IL12RB2.","method":"ELISA-based transcription factor binding assay; luciferase reporter assays; siRNA knockdown of JunB in Jurkat T and NK3.3 cells","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — reporter assay with mutagenesis-equivalent allele comparison plus siRNA functional validation, single lab, two orthogonal methods","pmids":["26552659"],"is_preprint":false},{"year":2008,"finding":"SNPs in the 5' flanking region of IL12RB2 (-1035A>G and -1023A>G) have differential effects on transcriptional activity depending on cell type: variant haplotypes show higher transcriptional activity in the NK cell line NK3.3 but lower activity in Jurkat T cells. Functionally, activated T cells from carriers of variant SNPs produce significantly less IFN-γ, while NK cells from carriers produce significantly more IFN-γ.","method":"Luciferase reporter gene assays in NK3.3 and Jurkat cells; IFN-γ ELISA in activated primary T cells and NK cells from genotyped donors","journal":"Journal of interferon & cytokine research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus functional cytokine readout in primary cells, single lab, two orthogonal methods","pmids":["18771340"],"is_preprint":false},{"year":2015,"finding":"IL-12-driven STAT4 phosphorylation in T cell blasts from healthy individuals correlates with specific IL12RB2 promoter SNP allele variants and haplotypes, indicating that genetically determined variation in IL12RB2 promoter region influences downstream IL-12 receptor signaling strength.","method":"STAT4 phosphorylation assay (presumably phospho-flow or ELISA) in T cell blasts from individuals stratified by IL12RB2 genotype","journal":"Immunobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single functional assay correlating genotype with signaling output, single lab, abstract lacks full methodological detail","pmids":["26547104"],"is_preprint":false},{"year":2016,"finding":"The AS-associated SNP rs11209032 in the IL23R-IL12RB2 intergenic region resides within a ~1.14 kb putative enhancer; the risk 'A' allele shows reduced luciferase reporter activity and reduced H3K4me1 methylation in CD4+ T cells from homozygous risk-allele carriers, and decreased binding of nuclear extract (~3.5-fold). Homozygosity for the risk allele is associated with increased proportions of IFN-γ+ (Th1) CD4+ T cells, but does not affect IL12RB2 mRNA levels.","method":"Luciferase reporter assay in HEK293T cells; EMSA (electrophoretic mobility gel shift assay); ChIP for H3K4me1; flow cytometry for IFN-γ+ CD4+ T cells; RT-qPCR for IL12RB2 mRNA","journal":"Annals of the rheumatic diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, EMSA, ChIP, flow cytometry), single lab","pmids":["26916345"],"is_preprint":false}],"current_model":"IL12RB2 encodes the IL-12 receptor β2 subunit, which is required for IL-12-driven IFN-γ production and Th1 differentiation; its expression is epigenetically regulated by JMJD3-mediated H3K27 demethylation during T cell activation and by promoter-region SNPs that differentially recruit transcription factors JunB, GATA-3, and MEF-2, with loss of IL-12Rβ2 signaling in vivo leading to deficient IFN-γ responses, spontaneous autoimmunity, and increased susceptibility to B-cell tumors and lung carcinoma."},"narrative":{"mechanistic_narrative":"IL12RB2 encodes the IL-12 receptor β2 subunit, a signaling component that transduces IL-12 stimulation into STAT4 phosphorylation and IFN-γ production, physiologically restraining aberrant B-cell activation and supporting IFN-γ-dependent tumor surveillance: its genetic inactivation in mice produces spontaneous autoimmunity, B-cell tumors, and lung carcinoma alongside IFN-γ deficiency and IL-6 upregulation [PMID:16081683]. IL12RB2 expression is epigenetically gated. In Th17 cells the locus carries repressive H3K27 trimethylation that is removed upon activation or immunization, permitting IL-12R β2 upregulation; subsequent IL-12 signaling demethylates the Tbx21/T-bet locus and deviates Th17 cells toward a Th1-like profile [PMID:21307296]. During human CD4 T cell activation this derepression depends on the H3K27 demethylase JMJD3, whose inhibition prevents promoter demethylation and impairs IL12RB2 induction [PMID:28947543]. Promoter and intergenic-enhancer polymorphisms further tune expression: SNPs at −1035/−1023 create differential binding sites for JunB, GATA-3, and MEF-2, with the −1023G allele forming an AP-1 site that enhances JunB binding, and JunB knockdown abolishes haplotype-specific promoter activity [PMID:26552659]. These variants act in a cell-type-specific manner, lowering transcriptional output and IFN-γ in T cells while raising both in NK cells [PMID:18771340], and an enhancer SNP in the IL23R–IL12RB2 intergenic region alters reporter activity, H3K4me1, and the proportion of Th1 cells [PMID:26916345].","teleology":[{"year":2005,"claim":"Established the in vivo physiological role of IL-12Rβ2 signaling, showing it is required to restrain B-cell activation and sustain IFN-γ-dependent tumor surveillance rather than merely being a cytokine receptor subunit.","evidence":"Il12rb2 knockout mouse with histopathology, serum autoantibody assays, and splenocyte cytokine measurement","pmids":["16081683"],"confidence":"High","gaps":["Does not resolve which downstream effectors mediate autoimmunity versus tumor phenotypes","IL-6 upregulation mechanism downstream of receptor loss not defined","Cell-intrinsic versus extrinsic contributions not dissected"]},{"year":2008,"claim":"Showed that IL12RB2 promoter SNPs functionally alter transcription and IFN-γ output in a cell-type-dependent manner, linking genetic variation to differential signaling capacity in T versus NK cells.","evidence":"Luciferase reporter assays in NK3.3 and Jurkat cells plus IFN-γ ELISA in primary cells from genotyped donors","pmids":["18771340"],"confidence":"Medium","gaps":["Transcription factors responsible for the cell-type difference not identified in this study","Reporter activity may not reflect endogenous chromatin context"]},{"year":2011,"claim":"Identified H3K27me3 as the repressive mark gating IL12RB2 expression in Th17 cells and connected its activation-dependent removal to IL-12-driven Th1 deviation.","evidence":"ChIP for H3K27me3/H3K4me3 at Il12rb2 and Tbx21 loci in ex vivo and in vitro Th17 cells with functional deviation assay","pmids":["21307296"],"confidence":"Medium","gaps":["Enzyme removing H3K27me3 not identified here","Single-lab finding","Stability of deviated phenotype not addressed"]},{"year":2015,"claim":"Defined JunB as a key transcriptional regulator of IL12RB2 and showed how the −1023G allele creates an AP-1 site that enhances JunB recruitment.","evidence":"TF-binding ELISA, luciferase reporter assays, and JunB siRNA knockdown in Jurkat and NK3.3 cells","pmids":["26552659"],"confidence":"Medium","gaps":["Roles of GATA-3 and MEF-2 not functionally validated","Endogenous gene-level effect of JunB not confirmed"]},{"year":2015,"claim":"Linked IL12RB2 promoter genotype to downstream IL-12 receptor signaling strength via STAT4 phosphorylation.","evidence":"STAT4 phosphorylation assay in T cell blasts stratified by IL12RB2 genotype","pmids":["26547104"],"confidence":"Low","gaps":["Single correlative functional assay without mechanistic dissection","Methodological detail limited","Causality from SNP to signaling not established"]},{"year":2016,"claim":"Mapped a disease-associated enhancer in the IL23R–IL12RB2 intergenic region whose risk allele alters chromatin state and Th1 proportions without changing IL12RB2 mRNA.","evidence":"Luciferase reporter, EMSA, H3K4me1 ChIP, flow cytometry, and RT-qPCR in CD4+ T cells from genotyped donors","pmids":["26916345"],"confidence":"Medium","gaps":["The trans-acting factor binding the enhancer not identified","Target gene of the enhancer ambiguous given unchanged IL12RB2 mRNA","Mechanism linking enhancer to Th1 skewing unresolved"]},{"year":2017,"claim":"Identified JMJD3 as the H3K27 demethylase required for IL12RB2 derepression during human T cell activation, providing the enzymatic basis for the activation-dependent epigenetic switch.","evidence":"H3K27me3 ChIP-seq in naive/memory CD4 T cells plus JMJD3 inhibitor with IL12RB2 expression quantification","pmids":["28947543"],"confidence":"Medium","gaps":["Recruitment mechanism of JMJD3 to the locus unknown","Inhibitor specificity not fully excluded","Single-lab finding"]},{"year":null,"claim":"How epigenetic gating (H3K27me3/JMJD3), SNP-driven transcription factor recruitment, and downstream STAT4 signaling integrate to set quantitative IL-12Rβ2 output in distinct lymphocyte lineages remains unresolved.","evidence":"No single study integrates chromatin, genetic, and signaling layers","pmids":[],"confidence":"Low","gaps":["No structural or biochemical characterization of the receptor itself in this corpus","No unified model linking promoter and intergenic-enhancer variants to in vivo phenotypes","Direct molecular partners of IL-12Rβ2 not defined in the timeline"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99665","full_name":"Interleukin-12 receptor subunit beta-2","aliases":[],"length_aa":862,"mass_kda":97.1,"function":"Receptor for interleukin-12. This subunit is the signaling component coupling to the JAK2/STAT4 pathway. Promotes the proliferation of T-cells as well as NK cells. Induces the promotion of T-cells towards the Th1 phenotype by strongly enhancing IFN-gamma production","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q99665/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL12RB2","classification":"Not Classified","n_dependent_lines":61,"n_total_lines":1208,"dependency_fraction":0.050496688741721855},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL12RB2","total_profiled":1310},"omim":[{"mim_id":"614221","title":"BILIARY CIRRHOSIS, PRIMARY, 5; PBC5","url":"https://www.omim.org/entry/614221"},{"mim_id":"614220","title":"BILIARY CIRRHOSIS, PRIMARY, 4; PBC4","url":"https://www.omim.org/entry/614220"},{"mim_id":"613008","title":"BILIARY CIRRHOSIS, PRIMARY, 3; PBC3","url":"https://www.omim.org/entry/613008"},{"mim_id":"613007","title":"BILIARY CIRRHOSIS, PRIMARY, 2; PBC2","url":"https://www.omim.org/entry/613007"},{"mim_id":"612599","title":"PSORIASIS 11, SUSCEPTIBILITY TO; PSORS11","url":"https://www.omim.org/entry/612599"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"placenta","ntpm":6.2},{"tissue":"skeletal muscle","ntpm":3.3}],"url":"https://www.proteinatlas.org/search/IL12RB2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q99665","domains":[{"cath_id":"2.60.40.10","chopping":"32-122","consensus_level":"high","plddt":86.9156,"start":32,"end":122},{"cath_id":"2.60.40.10","chopping":"129-223","consensus_level":"medium","plddt":89.8137,"start":129,"end":223},{"cath_id":"2.60.40.10","chopping":"225-316","consensus_level":"medium","plddt":89.4699,"start":225,"end":316},{"cath_id":"2.60.40.10","chopping":"328-414","consensus_level":"medium","plddt":89.4553,"start":328,"end":414},{"cath_id":"2.60.40.10","chopping":"421-515","consensus_level":"medium","plddt":87.118,"start":421,"end":515},{"cath_id":"2.60.40.10","chopping":"527-618","consensus_level":"high","plddt":88.0309,"start":527,"end":618}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99665","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99665-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99665-F1-predicted_aligned_error_v6.png","plddt_mean":72.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL12RB2","jax_strain_url":"https://www.jax.org/strain/search?query=IL12RB2"},"sequence":{"accession":"Q99665","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99665.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99665/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99665"}},"corpus_meta":[{"pmid":"20622878","id":"PMC_20622878","title":"Genome-wide 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1950)","url":"https://pubmed.ncbi.nlm.nih.gov/28947543","citation_count":32,"is_preprint":false},{"pmid":"21597988","id":"PMC_21597988","title":"Bovine IFNGR2, IL12RB1, IL12RB2, and IL23R polymorphisms and MAP infection status.","date":"2011","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/21597988","citation_count":18,"is_preprint":false},{"pmid":"18353079","id":"PMC_18353079","title":"Polymorphisms in the 5' flanking region of IL12RB2 are associated with susceptibility to periodontal diseases in the Japanese population.","date":"2008","source":"Journal of clinical periodontology","url":"https://pubmed.ncbi.nlm.nih.gov/18353079","citation_count":18,"is_preprint":false},{"pmid":"21285166","id":"PMC_21285166","title":"Role of rs1343151 IL23R and rs3790567 IL12RB2 polymorphisms in biopsy-proven giant cell arteritis.","date":"2011","source":"The Journal of 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spontaneous autoimmunity (immune-complex mesangial glomerulonephritis, antinuclear antibodies, lymphoid infiltrates with vasculitis and Sjögren syndrome features), B-cell tumors (plasmacytoma), and lung carcinoma, associated with strong IL-6 upregulation in splenocytes and IFN-γ deficiency, establishing that IL-12Rβ2 signaling physiologically restrains aberrant B-cell activation and supports IFN-γ-dependent tumor surveillance.\",\n      \"method\": \"Il12rb2 knockout mouse model; histopathology, serum antibody assays, cytokine measurement in splenocytes\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple defined cellular phenotypes and pathway placement (IFN-γ deficiency secondary to loss of IL-12 signaling, IL-6 upregulation), single rigorous study with multiple orthogonal readouts\",\n      \"pmids\": [\"16081683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In ex vivo-isolated murine Th17 cells, the Il12rb2 locus carries repressive H3K27 trimethylation marks that restrict its expression; in vitro activation or in vivo immunization removes these marks and allows IL-12Rβ2 upregulation. IL-12 stimulation then removes H3K27me3 at the Tbx21/T-bet locus, enhancing T-bet expression and enabling deviation of Th17 cells toward a Th1-like profile.\",\n      \"method\": \"ChIP for H3K27me3 and H3K4me3 at Il12rb2 and Tbx21 loci in purified ex vivo and in vitro Th17 cells; flow cytometry; in vitro IL-12 stimulation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, flow cytometry, functional deviation assay), single lab\",\n      \"pmids\": [\"21307296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"During human naive CD4 T cell activation, H3K27me3 at the IL12RB2 promoter is dynamically removed (demethylated) predominantly within 1 day of activation; pharmacological inhibition of the H3K27 demethylase JMJD3 prevents this demethylation and impairs IL12RB2 expression, demonstrating that JMJD3-driven H3K27 demethylation is required for IL12RB2 upregulation during T cell activation.\",\n      \"method\": \"ChIP-seq for H3K27me3 at IL12RB2 promoter in naive and memory CD4 T cells; JMJD3 inhibitor treatment with quantification of IL12RB2 expression\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus inhibitor functional assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"28947543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SNPs in the promoter region of IL12RB2 (-1035 and -1023 positions; rs3762315 and rs3762316) create differential binding sites for the transcription factors JunB, GATA-3, and MEF-2; the -1023G polymorphism creates an AP-1 consensus site that enhances JunB binding. siRNA-mediated suppression of JunB eliminates haplotype-specific differences in IL12RB2 promoter activity in both Jurkat T cells and NK3.3 cells, establishing JunB as a key transcriptional regulator of IL12RB2.\",\n      \"method\": \"ELISA-based transcription factor binding assay; luciferase reporter assays; siRNA knockdown of JunB in Jurkat T and NK3.3 cells\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reporter assay with mutagenesis-equivalent allele comparison plus siRNA functional validation, single lab, two orthogonal methods\",\n      \"pmids\": [\"26552659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SNPs in the 5' flanking region of IL12RB2 (-1035A>G and -1023A>G) have differential effects on transcriptional activity depending on cell type: variant haplotypes show higher transcriptional activity in the NK cell line NK3.3 but lower activity in Jurkat T cells. Functionally, activated T cells from carriers of variant SNPs produce significantly less IFN-γ, while NK cells from carriers produce significantly more IFN-γ.\",\n      \"method\": \"Luciferase reporter gene assays in NK3.3 and Jurkat cells; IFN-γ ELISA in activated primary T cells and NK cells from genotyped donors\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus functional cytokine readout in primary cells, single lab, two orthogonal methods\",\n      \"pmids\": [\"18771340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-12-driven STAT4 phosphorylation in T cell blasts from healthy individuals correlates with specific IL12RB2 promoter SNP allele variants and haplotypes, indicating that genetically determined variation in IL12RB2 promoter region influences downstream IL-12 receptor signaling strength.\",\n      \"method\": \"STAT4 phosphorylation assay (presumably phospho-flow or ELISA) in T cell blasts from individuals stratified by IL12RB2 genotype\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single functional assay correlating genotype with signaling output, single lab, abstract lacks full methodological detail\",\n      \"pmids\": [\"26547104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The AS-associated SNP rs11209032 in the IL23R-IL12RB2 intergenic region resides within a ~1.14 kb putative enhancer; the risk 'A' allele shows reduced luciferase reporter activity and reduced H3K4me1 methylation in CD4+ T cells from homozygous risk-allele carriers, and decreased binding of nuclear extract (~3.5-fold). Homozygosity for the risk allele is associated with increased proportions of IFN-γ+ (Th1) CD4+ T cells, but does not affect IL12RB2 mRNA levels.\",\n      \"method\": \"Luciferase reporter assay in HEK293T cells; EMSA (electrophoretic mobility gel shift assay); ChIP for H3K4me1; flow cytometry for IFN-γ+ CD4+ T cells; RT-qPCR for IL12RB2 mRNA\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, EMSA, ChIP, flow cytometry), single lab\",\n      \"pmids\": [\"26916345\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL12RB2 encodes the IL-12 receptor β2 subunit, which is required for IL-12-driven IFN-γ production and Th1 differentiation; its expression is epigenetically regulated by JMJD3-mediated H3K27 demethylation during T cell activation and by promoter-region SNPs that differentially recruit transcription factors JunB, GATA-3, and MEF-2, with loss of IL-12Rβ2 signaling in vivo leading to deficient IFN-γ responses, spontaneous autoimmunity, and increased susceptibility to B-cell tumors and lung carcinoma.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL12RB2 encodes the IL-12 receptor β2 subunit, a signaling component that transduces IL-12 stimulation into STAT4 phosphorylation and IFN-γ production, physiologically restraining aberrant B-cell activation and supporting IFN-γ-dependent tumor surveillance: its genetic inactivation in mice produces spontaneous autoimmunity, B-cell tumors, and lung carcinoma alongside IFN-γ deficiency and IL-6 upregulation [#0]. IL12RB2 expression is epigenetically gated. In Th17 cells the locus carries repressive H3K27 trimethylation that is removed upon activation or immunization, permitting IL-12R β2 upregulation; subsequent IL-12 signaling demethylates the Tbx21/T-bet locus and deviates Th17 cells toward a Th1-like profile [#1]. During human CD4 T cell activation this derepression depends on the H3K27 demethylase JMJD3, whose inhibition prevents promoter demethylation and impairs IL12RB2 induction [#2]. Promoter and intergenic-enhancer polymorphisms further tune expression: SNPs at −1035/−1023 create differential binding sites for JunB, GATA-3, and MEF-2, with the −1023G allele forming an AP-1 site that enhances JunB binding, and JunB knockdown abolishes haplotype-specific promoter activity [#3]. These variants act in a cell-type-specific manner, lowering transcriptional output and IFN-γ in T cells while raising both in NK cells [#4], and an enhancer SNP in the IL23R–IL12RB2 intergenic region alters reporter activity, H3K4me1, and the proportion of Th1 cells [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the in vivo physiological role of IL-12Rβ2 signaling, showing it is required to restrain B-cell activation and sustain IFN-γ-dependent tumor surveillance rather than merely being a cytokine receptor subunit.\",\n      \"evidence\": \"Il12rb2 knockout mouse with histopathology, serum autoantibody assays, and splenocyte cytokine measurement\",\n      \"pmids\": [\"16081683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve which downstream effectors mediate autoimmunity versus tumor phenotypes\", \"IL-6 upregulation mechanism downstream of receptor loss not defined\", \"Cell-intrinsic versus extrinsic contributions not dissected\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed that IL12RB2 promoter SNPs functionally alter transcription and IFN-γ output in a cell-type-dependent manner, linking genetic variation to differential signaling capacity in T versus NK cells.\",\n      \"evidence\": \"Luciferase reporter assays in NK3.3 and Jurkat cells plus IFN-γ ELISA in primary cells from genotyped donors\",\n      \"pmids\": [\"18771340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factors responsible for the cell-type difference not identified in this study\", \"Reporter activity may not reflect endogenous chromatin context\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified H3K27me3 as the repressive mark gating IL12RB2 expression in Th17 cells and connected its activation-dependent removal to IL-12-driven Th1 deviation.\",\n      \"evidence\": \"ChIP for H3K27me3/H3K4me3 at Il12rb2 and Tbx21 loci in ex vivo and in vitro Th17 cells with functional deviation assay\",\n      \"pmids\": [\"21307296\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzyme removing H3K27me3 not identified here\", \"Single-lab finding\", \"Stability of deviated phenotype not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined JunB as a key transcriptional regulator of IL12RB2 and showed how the −1023G allele creates an AP-1 site that enhances JunB recruitment.\",\n      \"evidence\": \"TF-binding ELISA, luciferase reporter assays, and JunB siRNA knockdown in Jurkat and NK3.3 cells\",\n      \"pmids\": [\"26552659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Roles of GATA-3 and MEF-2 not functionally validated\", \"Endogenous gene-level effect of JunB not confirmed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked IL12RB2 promoter genotype to downstream IL-12 receptor signaling strength via STAT4 phosphorylation.\",\n      \"evidence\": \"STAT4 phosphorylation assay in T cell blasts stratified by IL12RB2 genotype\",\n      \"pmids\": [\"26547104\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single correlative functional assay without mechanistic dissection\", \"Methodological detail limited\", \"Causality from SNP to signaling not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped a disease-associated enhancer in the IL23R–IL12RB2 intergenic region whose risk allele alters chromatin state and Th1 proportions without changing IL12RB2 mRNA.\",\n      \"evidence\": \"Luciferase reporter, EMSA, H3K4me1 ChIP, flow cytometry, and RT-qPCR in CD4+ T cells from genotyped donors\",\n      \"pmids\": [\"26916345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The trans-acting factor binding the enhancer not identified\", \"Target gene of the enhancer ambiguous given unchanged IL12RB2 mRNA\", \"Mechanism linking enhancer to Th1 skewing unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified JMJD3 as the H3K27 demethylase required for IL12RB2 derepression during human T cell activation, providing the enzymatic basis for the activation-dependent epigenetic switch.\",\n      \"evidence\": \"H3K27me3 ChIP-seq in naive/memory CD4 T cells plus JMJD3 inhibitor with IL12RB2 expression quantification\",\n      \"pmids\": [\"28947543\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Recruitment mechanism of JMJD3 to the locus unknown\", \"Inhibitor specificity not fully excluded\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How epigenetic gating (H3K27me3/JMJD3), SNP-driven transcription factor recruitment, and downstream STAT4 signaling integrate to set quantitative IL-12Rβ2 output in distinct lymphocyte lineages remains unresolved.\",\n      \"evidence\": \"No single study integrates chromatin, genetic, and signaling layers\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or biochemical characterization of the receptor itself in this corpus\", \"No unified model linking promoter and intergenic-enhancer variants to in vivo phenotypes\", \"Direct molecular partners of IL-12Rβ2 not defined in the timeline\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}