{"gene":"ITGAE","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2000,"finding":"αE(CD103)β7 integrin binds E-cadherin on epithelial cells, mediating T cell localization to epithelial compartments; this interaction was characterized as the key adhesive mechanism for intraepithelial T cell retention.","method":"Review synthesizing binding studies and adhesion assays","journal":"Current opinion in cell biology","confidence":"Medium","confidence_rationale":"Tier 3 — review summarizing established binding data; E-cadherin identified as cognate ligand","pmids":["10978890"],"is_preprint":false},{"year":2004,"finding":"TGF-β signaling at the graft site is the dominant factor driving CD103 upregulation on CD8+ effector T cells after migration into renal allografts; CD8 cells expressing dominant-negative TGF-β receptor showed markedly deficient CD103 expression.","method":"Nonvascularized mouse renal allograft model, adoptive transfer of TCR-transgenic CD8 T cells expressing dominant-negative TGF-β receptor, three-color flow cytometry","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — clean genetic loss-of-function (dominant-negative receptor) combined with adoptive transfer and localization data","pmids":["14688328"],"is_preprint":false},{"year":2005,"finding":"The transcription factor Runx3 is necessary for CD103 (integrin αE) induction during development of CD8 single-positive thymocytes; Runx3 deletion reduces CD103 expression, and Runx3 overexpression upregulates CD103 on CD4 SP T cells.","method":"Runx3 knockout mice, Runx3 transgenic overexpression mice, flow cytometry analysis of thymocyte subsets","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal loss-of-function and gain-of-function genetic experiments with defined phenotypic readout","pmids":["16034110"],"is_preprint":false},{"year":2009,"finding":"Intratumoral co-engagement of TCR and TGF-β1 receptor triggers CD103 expression on CD8+ T cells, and CD103/E-cadherin interaction recruits CCR5 to the immunological synapse, inhibiting T cell sensitivity to CCL5 chemotactic gradient and promoting T cell retention at the tumor site.","method":"Adoptive transfer of PBL clone into NOD/SCID mice bearing cognate tumor, flow cytometry for CD103 induction, immunological synapse analysis for CCR5 recruitment","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — in vivo adoptive transfer plus mechanistic synapse imaging showing CCR5 recruitment dependent on αEβ7/E-cadherin but not LFA-1/ICAM-1","pmids":["19638592"],"is_preprint":false},{"year":2009,"finding":"TGF-β represses the transcriptional repressor Gfi-1, and Gfi-1 directly binds intron 1 of Cd103 to repress its expression; loss of Gfi-1 allows histone H3K4me3 marks at the Cd103 locus and promotes CD103+ iTreg differentiation.","method":"Gfi-1 knockout mice, ChIP showing Gfi-1-LSD1 complex binding to Cd103 intron 1, histone modification analysis, enforced Gfi-1 expression","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP demonstrating direct binding plus genetic KO/overexpression with epigenetic readout","pmids":["19188499"],"is_preprint":false},{"year":2014,"finding":"The transcription factors Smad2/3 and NFAT-1 cooperatively regulate ITGAE (CD103) gene transcription in human CD8 T cells; promoter and enhancer elements of the human ITGAE gene responsive to TGF-β1/TCR co-stimulation were identified.","method":"Human CTL clone model, reporter assays with ITGAE promoter/enhancer elements, Smad2/3 and NFAT-1 overexpression/knockdown","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — promoter/enhancer mapping combined with transcription factor functional studies in a defined human T cell system","pmids":["24477908"],"is_preprint":false},{"year":2017,"finding":"Paxillin (Pxn) binds the cytoplasmic tail of the αE/CD103 subunit upon engagement with E-cadherin; this triggers phosphorylation of Pxn and Pyk2, and serine residue S1163 of the αE chain intracellular domain is required for CD103 polarization and lysosome/Pxn recruitment at the contact zone, driving CD8+ T cell adhesion, spreading, and cytotoxic effector functions.","method":"Co-immunoprecipitation of Pxn with αE/CD103 cytoplasmic tail, shRNA knockdown of Pxn, Src inhibitor saracatinib, mutagenesis of S1163, Jurkat T cell model with rE-cadherin-Fc-coated beads, freshly isolated tumor-infiltrating lymphocytes","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 — binding identified by Co-IP, site-directed mutagenesis of key residue, multiple orthogonal functional assays in primary and cell-line models","pmids":["29021139"],"is_preprint":false},{"year":2020,"finding":"T cell factor 1 (Tcf1) directly binds the Itgae (CD103) locus and inhibits TGF-β-induced CD103 expression; T-cell-specific Tcf7 ablation enhances CD103 protein expression in TRM cells and increases TRM cell numbers, demonstrating reciprocal regulation between Tcf1 and CD103 in tissue residency programming.","method":"ChIP showing Tcf1 binding to Itgae locus, T-cell-specific Tcf7 conditional knockout mice, TGF-β signaling abrogation experiments, flow cytometry for CD103 expression","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP demonstrating direct locus binding plus genetic KO with defined phenotypic readout","pmids":["32268106"],"is_preprint":false},{"year":2019,"finding":"CD103+ cancer-specific CTLs express and secrete active TGF-β1 in an autocrine manner to continuously self-regulate CD103 expression, without relying on external TGF-β1-producing cells; CD103 expression on CTLs improves TCR antigen sensitivity enabling faster cancer recognition.","method":"TCR-matched CD103+ and CD103- cancer-specific CTL clones, in vitro TGF-β1 blocking, functional cytotoxicity assays, migration assays","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional assays with matched clones; autocrine TGF-β1 shown by blocking studies","pmids":["31771983"],"is_preprint":false},{"year":2021,"finding":"CD103 engagement by E-cadherin on enterocytes is required for γδ intraepithelial lymphocyte-mediated apoptotic cell shedding; CD103 ligation triggers extracellular granzyme A and B release from γδ IELs (without requiring perforin), and CD103 knockout or blockade significantly reduces LPS-induced epithelial cell shedding.","method":"Intravital microscopy in GFP γδ T cell reporter mice, CD103 knockout mice, anti-CD103 blocking antibody, granzyme A/B ELISA from ex vivo-stimulated γδ IELs, immunostaining for cleaved caspase-3","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO, antibody blockade, and ex vivo functional assays with multiple orthogonal methods demonstrating CD103/E-cadherin-dependent granzyme release","pmids":["34861219"],"is_preprint":false},{"year":2021,"finding":"Intraepithelial lymphocytes suppress intestinal tumor growth through CD103/E-cadherin-dependent cell-to-cell contact; genetic deletion of CD103 decreased IEL-epithelial cell interaction frequency and increased small intestinal tumor numbers, and wild-type IELs reduced viability of tumor organoids in a CD103-dependent manner.","method":"DPE-GFP × APCmin mice, CD103 knockout mice, in vivo live-imaging system, in vitro co-culture with intestinal tumor organoids, tumor counting","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with defined anti-tumor phenotype, in vivo imaging, and in vitro organoid co-culture confirming CD103 dependence","pmids":["33515805"],"is_preprint":false},{"year":2022,"finding":"NUDT1 promotes CD103+ TRM cell accumulation and longevity through PARP1-TGFβR axis-dependent DNA damage resistance; NUDT1-dependent signaling maintains TGF-β-Smad signaling required for tissue residency programming, and pharmacological blockade or genetic deletion of NUDT1 eliminates CD103+ TRM cells and alleviates cholangitis in mice.","method":"NUDT1 conditional knockout mice, NUDT1 overexpression in CD8+ T cells, PARP1 inhibition, 2OA-BSA murine immunization model, adoptive co-transfer, in vitro organoid co-culture cytotoxicity assay","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO/OE with pathway dissection (PARP1-TGFβR axis), multiple in vitro and in vivo models","pmids":["35753523"],"is_preprint":false},{"year":2023,"finding":"4-octyl itaconate (4-OI) inhibits CD103+ TRM induction and effector functions by blocking DNA demethylation of RUNX3 in CD8+ T cells, thereby suppressing tissue-residency programming; 4-OI administration reduced intrahepatic CD103+ TRM and ameliorated liver injury in murine PSC models.","method":"In vitro 4-OI treatment of CD8+ T cells with RUNX3 methylation analysis, murine PSC models with 4-OI administration and IRG1-deficient mice, flow cytometry, immunofluorescence","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2-3 — mechanistic link to RUNX3 demethylation shown in vitro; in vivo confirmation with genetic and pharmacological tools","pmids":["37505225"],"is_preprint":false},{"year":2023,"finding":"Retinoic acid signaling during T cell priming in mesenteric lymph nodes licenses intestinal CD103+ TRM cell differentiation in situ, independently of CCR9 expression/gut homing; T cells primed in the spleen are impaired in CD103+ TRM differentiation even after entering the intestine.","method":"Mesenteric lymph node vs. spleen priming comparison in mice, retinoic acid signaling blockade, CCR9 genetic studies, in vivo intestinal TRM differentiation assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic and pharmacological interventions demonstrating retinoic acid as a priming-stage regulator of CD103 TRM differentiation","pmids":["36809399"],"is_preprint":false},{"year":2024,"finding":"CD103+ CD8+ TRM cells in primary Sjögren's disease salivary glands produce granzyme B and IFN-γ contributing to tissue damage; intraglandular blockade of CD103 with monoclonal antibody in an experimental SS mouse model reduced TRM accumulation, reduced glandular damage and improved salivary flow.","method":"Anti-CD103 monoclonal antibody intraglandular blockade in ESS mouse model, flow cytometry, scRNAseq of salivary gland T cells, immunostaining for granzyme B/IFN-γ","journal":"Annals of the rheumatic diseases","confidence":"High","confidence_rationale":"Tier 2 — in vivo antibody blockade of CD103 with defined functional consequence (glandular damage and salivary flow) combined with transcriptomic characterization","pmids":["38777379"],"is_preprint":false}],"current_model":"ITGAE (CD103, αE integrin) forms the αEβ7 heterodimer that binds E-cadherin on epithelial cells, mediating tissue retention of CD8+ TRM cells and IELs; CD103 expression is transcriptionally induced by TGF-β/Smad2-3 and TCR/NFAT-1 co-signaling acting on the ITGAE promoter/enhancer, and repressed by Runx3-regulated Gfi-1 and Tcf1 binding to the Itgae locus; upon E-cadherin engagement, the CD103 cytoplasmic tail recruits paxillin via S1163-dependent signaling to drive outside-in integrin activation, T cell adhesion, CCR5 polarization to the immune synapse for tissue retention, and cytotoxic effector functions including granzyme release."},"narrative":{"teleology":[{"year":2000,"claim":"Establishing that αEβ7 integrin binds E-cadherin as its cognate ligand provided the molecular basis for how intraepithelial T cells are retained within epithelial tissues.","evidence":"Review synthesizing binding studies and adhesion assays characterizing αEβ7/E-cadherin interaction","pmids":["10978890"],"confidence":"Medium","gaps":["Mechanistic details of how E-cadherin engagement triggers intracellular signaling were unknown","No structural model of the αEβ7/E-cadherin interface"]},{"year":2004,"claim":"Demonstrating that TGF-β signaling at peripheral tissue sites is the dominant inducer of CD103 on CD8+ effector T cells resolved how tissue microenvironmental cues program integrin expression after T cell entry.","evidence":"Adoptive transfer of CD8 T cells expressing dominant-negative TGF-β receptor into mouse renal allografts with flow cytometric analysis","pmids":["14688328"],"confidence":"High","gaps":["Downstream transcription factors mediating TGF-β-driven CD103 induction not yet identified","Whether autocrine vs. paracrine TGF-β was responsible remained unclear"]},{"year":2005,"claim":"Identifying Runx3 as a transcription factor necessary for CD103 induction during thymic CD8 T cell development connected lineage-specific transcriptional programs to integrin αE expression.","evidence":"Runx3 knockout and transgenic overexpression mice with flow cytometric analysis of thymocyte CD103 expression","pmids":["16034110"],"confidence":"High","gaps":["Whether Runx3 binds the Itgae locus directly was not shown","Relationship between Runx3-dependent thymic induction and peripheral TGF-β-driven induction was unclear"]},{"year":2009,"claim":"Two parallel advances resolved both a transcriptional repression mechanism and a functional consequence of CD103 ligation: Gfi-1 was shown to directly repress Cd103 via intron 1 binding with LSD1-mediated histone demethylation, while CD103/E-cadherin engagement was found to recruit CCR5 to the immunological synapse, explaining how CD103 promotes T cell retention by desensitizing cells to chemotactic gradients.","evidence":"Gfi-1 KO mice and ChIP for Gfi-1/LSD1 at Cd103 intron 1 with histone modification analysis; in vivo adoptive transfer into NOD/SCID mice bearing tumors with synapse imaging for CCR5 polarization","pmids":["19188499","19638592"],"confidence":"High","gaps":["Whether CCR5 recruitment required cytoplasmic tail signaling or was adhesion-dependent remained unknown","Relative contribution of Gfi-1 repression vs. positive TGF-β induction in setting CD103 expression levels was not quantified"]},{"year":2014,"claim":"Mapping the human ITGAE promoter/enhancer and identifying cooperative Smad2/3-NFAT-1 transcription factor binding explained how TGF-β and TCR co-stimulation converge to activate CD103 transcription.","evidence":"Reporter assays with ITGAE regulatory elements, Smad2/3 and NFAT-1 overexpression/knockdown in human CTL clones","pmids":["24477908"],"confidence":"High","gaps":["Chromatin accessibility dynamics at the ITGAE locus during activation were not characterized","Whether additional co-activators participate in the Smad2/3-NFAT-1 complex was unknown"]},{"year":2017,"claim":"Identification of paxillin as a direct binding partner of the αE cytoplasmic tail, dependent on serine 1163, revealed the outside-in signaling pathway through which E-cadherin engagement drives T cell adhesion, spreading, and cytotoxic granule release.","evidence":"Co-immunoprecipitation of paxillin with αE tail, S1163 mutagenesis, shRNA knockdown of paxillin, functional assays in Jurkat cells and primary TILs","pmids":["29021139"],"confidence":"High","gaps":["Kinase responsible for S1163 phosphorylation not identified","Whether paxillin recruitment is sufficient or requires additional adaptor proteins was not resolved"]},{"year":2019,"claim":"Discovery that CD103+ CTLs produce autocrine TGF-β1 to self-maintain CD103 expression showed that tissue-resident T cells can sustain their own residency program independently of stromal TGF-β sources.","evidence":"TGF-β1 blocking studies on TCR-matched CD103+ vs. CD103− cancer-specific CTL clones with functional cytotoxicity assays","pmids":["31771983"],"confidence":"Medium","gaps":["Extent of autocrine vs. paracrine TGF-β contribution in vivo not quantified","Mechanism by which CD103 enhances TCR antigen sensitivity was not defined"]},{"year":2020,"claim":"Demonstrating that Tcf1 directly binds and represses the Itgae locus identified a second transcriptional repressor and established a reciprocal regulatory axis between Tcf1-dependent stemness and CD103-dependent tissue residency.","evidence":"ChIP for Tcf1 at Itgae locus, T-cell-specific Tcf7 conditional KO mice, flow cytometry for CD103 and TRM numbers","pmids":["32268106"],"confidence":"High","gaps":["Whether Tcf1 and Gfi-1 act on the same or distinct regulatory elements was not compared","Epigenetic state changes upon Tcf1 loss at the Itgae locus were not characterized"]},{"year":2021,"claim":"Genetic and antibody blockade studies in the intestine established that CD103/E-cadherin interaction is functionally required for both γδ IEL-mediated epithelial cell shedding via perforin-independent granzyme release and IEL-dependent suppression of intestinal tumorigenesis.","evidence":"CD103 KO mice, anti-CD103 blocking antibody, intravital microscopy, granzyme ELISA from γδ IELs, APCmin tumor model with organoid co-culture","pmids":["34861219","33515805"],"confidence":"High","gaps":["Molecular mechanism linking CD103 ligation to granzyme exocytosis (perforin-independent) was not elucidated","Whether CD103 signals differently in γδ vs. αβ IELs was not addressed"]},{"year":2022,"claim":"Linking NUDT1 to CD103+ TRM longevity through PARP1-TGFβR-dependent DNA damage resistance revealed a metabolic checkpoint that maintains TGF-β-Smad signaling and thereby sustains CD103 expression and tissue residency.","evidence":"NUDT1 conditional KO and overexpression in CD8+ T cells, PARP1 inhibition, adoptive co-transfer in murine cholangitis model","pmids":["35753523"],"confidence":"High","gaps":["Whether NUDT1 acts on the Itgae locus directly or exclusively through TGFβR maintenance was not resolved","Generalizability beyond hepatic TRM was not tested"]},{"year":2023,"claim":"Two studies expanded understanding of upstream signals: retinoic acid during mesenteric lymph node priming was shown to license intestinal CD103+ TRM differentiation independently of gut homing, and 4-octyl itaconate was found to suppress CD103+ TRM induction by blocking RUNX3 DNA demethylation.","evidence":"Retinoic acid blockade and MLN vs. spleen priming comparison in mice; 4-OI treatment with RUNX3 methylation analysis in CD8 T cells and murine PSC models","pmids":["36809399","37505225"],"confidence":"High","gaps":["Epigenetic regulation of Runx3 at the Itgae locus vs. Runx3 target genes was not distinguished","Whether retinoic acid acts on Itgae chromatin directly or indirectly through Runx3/Smad axis was not defined"]},{"year":2024,"claim":"Therapeutic blockade of CD103 in a Sjögren's disease model demonstrated that CD103+ TRM cells are pathogenic effectors in autoimmune glandular destruction, establishing CD103 as a potential therapeutic target in tissue-localized autoimmunity.","evidence":"Anti-CD103 monoclonal antibody intraglandular administration in ESS mouse model with functional salivary flow measurement, scRNAseq, granzyme B/IFN-γ immunostaining","pmids":["38777379"],"confidence":"High","gaps":["Whether CD103 blockade depletes TRM cells or merely disrupts retention was not mechanistically distinguished","Long-term consequences of CD103 blockade on mucosal immunity were not assessed"]},{"year":null,"claim":"Key unresolved questions include: the structural basis of the αEβ7/E-cadherin interface, the kinase(s) responsible for S1163 phosphorylation on the αE cytoplasmic tail, how CD103 ligation triggers perforin-independent granzyme release, and the integrated epigenetic logic governing Runx3/Gfi-1/Tcf1 at the Itgae locus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of αEβ7/E-cadherin complex","Kinase for S1163 phosphorylation unidentified","Mechanism of perforin-independent granzyme release downstream of CD103 unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,3,6,9,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,6,9,10]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,9,10,14]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,6,9,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4,5,7]}],"complexes":["αEβ7 integrin heterodimer"],"partners":["ITGB7","CDH1","PXN","PTK2B","CCR5","SMAD2","SMAD3","NFATC2"],"other_free_text":[]},"mechanistic_narrative":"ITGAE encodes the αE integrin subunit (CD103) that pairs with β7 to form the αEβ7 heterodimer, a key adhesion receptor on intraepithelial and tissue-resident memory (TRM) T cells that binds E-cadherin on epithelial cells to mediate lymphocyte retention within epithelial compartments [PMID:10978890, PMID:34861219]. CD103 expression is transcriptionally induced by TGF-β signaling through Smad2/3 cooperating with NFAT-1 at the ITGAE promoter/enhancer, positively regulated by Runx3, and repressed by Gfi-1 binding at intron 1 and by Tcf1 binding at the Itgae locus [PMID:14688328, PMID:24477908, PMID:16034110, PMID:19188499, PMID:32268106]. Upon E-cadherin engagement, the αE cytoplasmic tail recruits paxillin in an S1163-dependent manner, triggering Pyk2 phosphorylation, CCR5 polarization to the immunological synapse, and extracellular granzyme release that drives cytotoxic effector functions including epithelial cell shedding and tumor suppression [PMID:29021139, PMID:19638592, PMID:34861219, PMID:33515805]. CD103+ TRM cells contribute to tissue immunosurveillance and, when dysregulated, to autoimmune tissue damage in organs such as salivary glands, where anti-CD103 blockade reduces glandular injury [PMID:38777379]."},"prefetch_data":{"uniprot":{"accession":"P38570","full_name":"Integrin alpha-E","aliases":["HML-1 antigen","Integrin alpha-IEL","Mucosal lymphocyte 1 antigen"],"length_aa":1179,"mass_kda":130.2,"function":"Integrin ITGAE/ITGB7 (alpha-E/beta-7) is a receptor for E-cadherin. It mediates adhesion of intra-epithelial T-lymphocytes to epithelial cell monolayers","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P38570/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGAE","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITGAE","total_profiled":1310},"omim":[{"mim_id":"609240","title":"HISTONE H3-ASSOCIATED PROTEIN KINASE; HASPIN","url":"https://www.omim.org/entry/609240"},{"mim_id":"606065","title":"ATYPICAL CHEMOKINE RECEPTOR 4; ACKR4","url":"https://www.omim.org/entry/606065"},{"mim_id":"605984","title":"EMBRYONIC ECTODERM DEVELOPMENT; EED","url":"https://www.omim.org/entry/605984"},{"mim_id":"604874","title":"KILLER CELL LECTIN-LIKE RECEPTOR, SUBFAMILY G, MEMBER 1; KLRG1","url":"https://www.omim.org/entry/604874"},{"mim_id":"604682","title":"INTEGRIN, ALPHA-E; ITGAE","url":"https://www.omim.org/entry/604682"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":6.1},{"tissue":"intestine","ntpm":5.5},{"tissue":"lung","ntpm":6.2}],"url":"https://www.proteinatlas.org/search/ITGAE"},"hgnc":{"alias_symbol":["CD103","HUMINAE"],"prev_symbol":[]},"alphafold":{"accession":"P38570","domains":[{"cath_id":"2.130.10.130","chopping":"22-142_403-677","consensus_level":"medium","plddt":87.0028,"start":22,"end":677},{"cath_id":"3.40.50.410","chopping":"202-387","consensus_level":"high","plddt":89.9552,"start":202,"end":387},{"cath_id":"2.60.40.1460","chopping":"680-818","consensus_level":"high","plddt":78.8378,"start":680,"end":818},{"cath_id":"2.60.40.1510","chopping":"834-964","consensus_level":"high","plddt":85.6619,"start":834,"end":964},{"cath_id":"2.60.40.1530","chopping":"971-1118","consensus_level":"high","plddt":80.063,"start":971,"end":1118}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P38570","model_url":"https://alphafold.ebi.ac.uk/files/AF-P38570-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P38570-F1-predicted_aligned_error_v6.png","plddt_mean":80.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGAE","jax_strain_url":"https://www.jax.org/strain/search?query=ITGAE"},"sequence":{"accession":"P38570","fasta_url":"https://rest.uniprot.org/uniprotkb/P38570.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P38570/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P38570"}},"corpus_meta":[{"pmid":"24162776","id":"PMC_24162776","title":"The 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Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/37505225","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50620,"output_tokens":3866,"usd":0.104925},"stage2":{"model":"claude-opus-4-6","input_tokens":7413,"output_tokens":3435,"usd":0.18441},"total_usd":0.289335,"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\": 2000,\n      \"finding\": \"αE(CD103)β7 integrin binds E-cadherin on epithelial cells, mediating T cell localization to epithelial compartments; this interaction was characterized as the key adhesive mechanism for intraepithelial T cell retention.\",\n      \"method\": \"Review synthesizing binding studies and adhesion assays\",\n      \"journal\": \"Current opinion in cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review summarizing established binding data; E-cadherin identified as cognate ligand\",\n      \"pmids\": [\"10978890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TGF-β signaling at the graft site is the dominant factor driving CD103 upregulation on CD8+ effector T cells after migration into renal allografts; CD8 cells expressing dominant-negative TGF-β receptor showed markedly deficient CD103 expression.\",\n      \"method\": \"Nonvascularized mouse renal allograft model, adoptive transfer of TCR-transgenic CD8 T cells expressing dominant-negative TGF-β receptor, three-color flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic loss-of-function (dominant-negative receptor) combined with adoptive transfer and localization data\",\n      \"pmids\": [\"14688328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The transcription factor Runx3 is necessary for CD103 (integrin αE) induction during development of CD8 single-positive thymocytes; Runx3 deletion reduces CD103 expression, and Runx3 overexpression upregulates CD103 on CD4 SP T cells.\",\n      \"method\": \"Runx3 knockout mice, Runx3 transgenic overexpression mice, flow cytometry analysis of thymocyte subsets\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal loss-of-function and gain-of-function genetic experiments with defined phenotypic readout\",\n      \"pmids\": [\"16034110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Intratumoral co-engagement of TCR and TGF-β1 receptor triggers CD103 expression on CD8+ T cells, and CD103/E-cadherin interaction recruits CCR5 to the immunological synapse, inhibiting T cell sensitivity to CCL5 chemotactic gradient and promoting T cell retention at the tumor site.\",\n      \"method\": \"Adoptive transfer of PBL clone into NOD/SCID mice bearing cognate tumor, flow cytometry for CD103 induction, immunological synapse analysis for CCR5 recruitment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo adoptive transfer plus mechanistic synapse imaging showing CCR5 recruitment dependent on αEβ7/E-cadherin but not LFA-1/ICAM-1\",\n      \"pmids\": [\"19638592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TGF-β represses the transcriptional repressor Gfi-1, and Gfi-1 directly binds intron 1 of Cd103 to repress its expression; loss of Gfi-1 allows histone H3K4me3 marks at the Cd103 locus and promotes CD103+ iTreg differentiation.\",\n      \"method\": \"Gfi-1 knockout mice, ChIP showing Gfi-1-LSD1 complex binding to Cd103 intron 1, histone modification analysis, enforced Gfi-1 expression\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP demonstrating direct binding plus genetic KO/overexpression with epigenetic readout\",\n      \"pmids\": [\"19188499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The transcription factors Smad2/3 and NFAT-1 cooperatively regulate ITGAE (CD103) gene transcription in human CD8 T cells; promoter and enhancer elements of the human ITGAE gene responsive to TGF-β1/TCR co-stimulation were identified.\",\n      \"method\": \"Human CTL clone model, reporter assays with ITGAE promoter/enhancer elements, Smad2/3 and NFAT-1 overexpression/knockdown\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — promoter/enhancer mapping combined with transcription factor functional studies in a defined human T cell system\",\n      \"pmids\": [\"24477908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Paxillin (Pxn) binds the cytoplasmic tail of the αE/CD103 subunit upon engagement with E-cadherin; this triggers phosphorylation of Pxn and Pyk2, and serine residue S1163 of the αE chain intracellular domain is required for CD103 polarization and lysosome/Pxn recruitment at the contact zone, driving CD8+ T cell adhesion, spreading, and cytotoxic effector functions.\",\n      \"method\": \"Co-immunoprecipitation of Pxn with αE/CD103 cytoplasmic tail, shRNA knockdown of Pxn, Src inhibitor saracatinib, mutagenesis of S1163, Jurkat T cell model with rE-cadherin-Fc-coated beads, freshly isolated tumor-infiltrating lymphocytes\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — binding identified by Co-IP, site-directed mutagenesis of key residue, multiple orthogonal functional assays in primary and cell-line models\",\n      \"pmids\": [\"29021139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"T cell factor 1 (Tcf1) directly binds the Itgae (CD103) locus and inhibits TGF-β-induced CD103 expression; T-cell-specific Tcf7 ablation enhances CD103 protein expression in TRM cells and increases TRM cell numbers, demonstrating reciprocal regulation between Tcf1 and CD103 in tissue residency programming.\",\n      \"method\": \"ChIP showing Tcf1 binding to Itgae locus, T-cell-specific Tcf7 conditional knockout mice, TGF-β signaling abrogation experiments, flow cytometry for CD103 expression\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP demonstrating direct locus binding plus genetic KO with defined phenotypic readout\",\n      \"pmids\": [\"32268106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD103+ cancer-specific CTLs express and secrete active TGF-β1 in an autocrine manner to continuously self-regulate CD103 expression, without relying on external TGF-β1-producing cells; CD103 expression on CTLs improves TCR antigen sensitivity enabling faster cancer recognition.\",\n      \"method\": \"TCR-matched CD103+ and CD103- cancer-specific CTL clones, in vitro TGF-β1 blocking, functional cytotoxicity assays, migration assays\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional assays with matched clones; autocrine TGF-β1 shown by blocking studies\",\n      \"pmids\": [\"31771983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD103 engagement by E-cadherin on enterocytes is required for γδ intraepithelial lymphocyte-mediated apoptotic cell shedding; CD103 ligation triggers extracellular granzyme A and B release from γδ IELs (without requiring perforin), and CD103 knockout or blockade significantly reduces LPS-induced epithelial cell shedding.\",\n      \"method\": \"Intravital microscopy in GFP γδ T cell reporter mice, CD103 knockout mice, anti-CD103 blocking antibody, granzyme A/B ELISA from ex vivo-stimulated γδ IELs, immunostaining for cleaved caspase-3\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO, antibody blockade, and ex vivo functional assays with multiple orthogonal methods demonstrating CD103/E-cadherin-dependent granzyme release\",\n      \"pmids\": [\"34861219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Intraepithelial lymphocytes suppress intestinal tumor growth through CD103/E-cadherin-dependent cell-to-cell contact; genetic deletion of CD103 decreased IEL-epithelial cell interaction frequency and increased small intestinal tumor numbers, and wild-type IELs reduced viability of tumor organoids in a CD103-dependent manner.\",\n      \"method\": \"DPE-GFP × APCmin mice, CD103 knockout mice, in vivo live-imaging system, in vitro co-culture with intestinal tumor organoids, tumor counting\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined anti-tumor phenotype, in vivo imaging, and in vitro organoid co-culture confirming CD103 dependence\",\n      \"pmids\": [\"33515805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NUDT1 promotes CD103+ TRM cell accumulation and longevity through PARP1-TGFβR axis-dependent DNA damage resistance; NUDT1-dependent signaling maintains TGF-β-Smad signaling required for tissue residency programming, and pharmacological blockade or genetic deletion of NUDT1 eliminates CD103+ TRM cells and alleviates cholangitis in mice.\",\n      \"method\": \"NUDT1 conditional knockout mice, NUDT1 overexpression in CD8+ T cells, PARP1 inhibition, 2OA-BSA murine immunization model, adoptive co-transfer, in vitro organoid co-culture cytotoxicity assay\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO/OE with pathway dissection (PARP1-TGFβR axis), multiple in vitro and in vivo models\",\n      \"pmids\": [\"35753523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"4-octyl itaconate (4-OI) inhibits CD103+ TRM induction and effector functions by blocking DNA demethylation of RUNX3 in CD8+ T cells, thereby suppressing tissue-residency programming; 4-OI administration reduced intrahepatic CD103+ TRM and ameliorated liver injury in murine PSC models.\",\n      \"method\": \"In vitro 4-OI treatment of CD8+ T cells with RUNX3 methylation analysis, murine PSC models with 4-OI administration and IRG1-deficient mice, flow cytometry, immunofluorescence\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mechanistic link to RUNX3 demethylation shown in vitro; in vivo confirmation with genetic and pharmacological tools\",\n      \"pmids\": [\"37505225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Retinoic acid signaling during T cell priming in mesenteric lymph nodes licenses intestinal CD103+ TRM cell differentiation in situ, independently of CCR9 expression/gut homing; T cells primed in the spleen are impaired in CD103+ TRM differentiation even after entering the intestine.\",\n      \"method\": \"Mesenteric lymph node vs. spleen priming comparison in mice, retinoic acid signaling blockade, CCR9 genetic studies, in vivo intestinal TRM differentiation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacological interventions demonstrating retinoic acid as a priming-stage regulator of CD103 TRM differentiation\",\n      \"pmids\": [\"36809399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD103+ CD8+ TRM cells in primary Sjögren's disease salivary glands produce granzyme B and IFN-γ contributing to tissue damage; intraglandular blockade of CD103 with monoclonal antibody in an experimental SS mouse model reduced TRM accumulation, reduced glandular damage and improved salivary flow.\",\n      \"method\": \"Anti-CD103 monoclonal antibody intraglandular blockade in ESS mouse model, flow cytometry, scRNAseq of salivary gland T cells, immunostaining for granzyme B/IFN-γ\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo antibody blockade of CD103 with defined functional consequence (glandular damage and salivary flow) combined with transcriptomic characterization\",\n      \"pmids\": [\"38777379\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGAE (CD103, αE integrin) forms the αEβ7 heterodimer that binds E-cadherin on epithelial cells, mediating tissue retention of CD8+ TRM cells and IELs; CD103 expression is transcriptionally induced by TGF-β/Smad2-3 and TCR/NFAT-1 co-signaling acting on the ITGAE promoter/enhancer, and repressed by Runx3-regulated Gfi-1 and Tcf1 binding to the Itgae locus; upon E-cadherin engagement, the CD103 cytoplasmic tail recruits paxillin via S1163-dependent signaling to drive outside-in integrin activation, T cell adhesion, CCR5 polarization to the immune synapse for tissue retention, and cytotoxic effector functions including granzyme release.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ITGAE encodes the αE integrin subunit (CD103) that pairs with β7 to form the αEβ7 heterodimer, a key adhesion receptor on intraepithelial and tissue-resident memory (TRM) T cells that binds E-cadherin on epithelial cells to mediate lymphocyte retention within epithelial compartments [PMID:10978890, PMID:34861219]. CD103 expression is transcriptionally induced by TGF-β signaling through Smad2/3 cooperating with NFAT-1 at the ITGAE promoter/enhancer, positively regulated by Runx3, and repressed by Gfi-1 binding at intron 1 and by Tcf1 binding at the Itgae locus [PMID:14688328, PMID:24477908, PMID:16034110, PMID:19188499, PMID:32268106]. Upon E-cadherin engagement, the αE cytoplasmic tail recruits paxillin in an S1163-dependent manner, triggering Pyk2 phosphorylation, CCR5 polarization to the immunological synapse, and extracellular granzyme release that drives cytotoxic effector functions including epithelial cell shedding and tumor suppression [PMID:29021139, PMID:19638592, PMID:34861219, PMID:33515805]. CD103+ TRM cells contribute to tissue immunosurveillance and, when dysregulated, to autoimmune tissue damage in organs such as salivary glands, where anti-CD103 blockade reduces glandular injury [PMID:38777379].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that αEβ7 integrin binds E-cadherin as its cognate ligand provided the molecular basis for how intraepithelial T cells are retained within epithelial tissues.\",\n      \"evidence\": \"Review synthesizing binding studies and adhesion assays characterizing αEβ7/E-cadherin interaction\",\n      \"pmids\": [\"10978890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic details of how E-cadherin engagement triggers intracellular signaling were unknown\", \"No structural model of the αEβ7/E-cadherin interface\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that TGF-β signaling at peripheral tissue sites is the dominant inducer of CD103 on CD8+ effector T cells resolved how tissue microenvironmental cues program integrin expression after T cell entry.\",\n      \"evidence\": \"Adoptive transfer of CD8 T cells expressing dominant-negative TGF-β receptor into mouse renal allografts with flow cytometric analysis\",\n      \"pmids\": [\"14688328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcription factors mediating TGF-β-driven CD103 induction not yet identified\", \"Whether autocrine vs. paracrine TGF-β was responsible remained unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying Runx3 as a transcription factor necessary for CD103 induction during thymic CD8 T cell development connected lineage-specific transcriptional programs to integrin αE expression.\",\n      \"evidence\": \"Runx3 knockout and transgenic overexpression mice with flow cytometric analysis of thymocyte CD103 expression\",\n      \"pmids\": [\"16034110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Runx3 binds the Itgae locus directly was not shown\", \"Relationship between Runx3-dependent thymic induction and peripheral TGF-β-driven induction was unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Two parallel advances resolved both a transcriptional repression mechanism and a functional consequence of CD103 ligation: Gfi-1 was shown to directly repress Cd103 via intron 1 binding with LSD1-mediated histone demethylation, while CD103/E-cadherin engagement was found to recruit CCR5 to the immunological synapse, explaining how CD103 promotes T cell retention by desensitizing cells to chemotactic gradients.\",\n      \"evidence\": \"Gfi-1 KO mice and ChIP for Gfi-1/LSD1 at Cd103 intron 1 with histone modification analysis; in vivo adoptive transfer into NOD/SCID mice bearing tumors with synapse imaging for CCR5 polarization\",\n      \"pmids\": [\"19188499\", \"19638592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CCR5 recruitment required cytoplasmic tail signaling or was adhesion-dependent remained unknown\", \"Relative contribution of Gfi-1 repression vs. positive TGF-β induction in setting CD103 expression levels was not quantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapping the human ITGAE promoter/enhancer and identifying cooperative Smad2/3-NFAT-1 transcription factor binding explained how TGF-β and TCR co-stimulation converge to activate CD103 transcription.\",\n      \"evidence\": \"Reporter assays with ITGAE regulatory elements, Smad2/3 and NFAT-1 overexpression/knockdown in human CTL clones\",\n      \"pmids\": [\"24477908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin accessibility dynamics at the ITGAE locus during activation were not characterized\", \"Whether additional co-activators participate in the Smad2/3-NFAT-1 complex was unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of paxillin as a direct binding partner of the αE cytoplasmic tail, dependent on serine 1163, revealed the outside-in signaling pathway through which E-cadherin engagement drives T cell adhesion, spreading, and cytotoxic granule release.\",\n      \"evidence\": \"Co-immunoprecipitation of paxillin with αE tail, S1163 mutagenesis, shRNA knockdown of paxillin, functional assays in Jurkat cells and primary TILs\",\n      \"pmids\": [\"29021139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for S1163 phosphorylation not identified\", \"Whether paxillin recruitment is sufficient or requires additional adaptor proteins was not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that CD103+ CTLs produce autocrine TGF-β1 to self-maintain CD103 expression showed that tissue-resident T cells can sustain their own residency program independently of stromal TGF-β sources.\",\n      \"evidence\": \"TGF-β1 blocking studies on TCR-matched CD103+ vs. CD103− cancer-specific CTL clones with functional cytotoxicity assays\",\n      \"pmids\": [\"31771983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Extent of autocrine vs. paracrine TGF-β contribution in vivo not quantified\", \"Mechanism by which CD103 enhances TCR antigen sensitivity was not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that Tcf1 directly binds and represses the Itgae locus identified a second transcriptional repressor and established a reciprocal regulatory axis between Tcf1-dependent stemness and CD103-dependent tissue residency.\",\n      \"evidence\": \"ChIP for Tcf1 at Itgae locus, T-cell-specific Tcf7 conditional KO mice, flow cytometry for CD103 and TRM numbers\",\n      \"pmids\": [\"32268106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Tcf1 and Gfi-1 act on the same or distinct regulatory elements was not compared\", \"Epigenetic state changes upon Tcf1 loss at the Itgae locus were not characterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic and antibody blockade studies in the intestine established that CD103/E-cadherin interaction is functionally required for both γδ IEL-mediated epithelial cell shedding via perforin-independent granzyme release and IEL-dependent suppression of intestinal tumorigenesis.\",\n      \"evidence\": \"CD103 KO mice, anti-CD103 blocking antibody, intravital microscopy, granzyme ELISA from γδ IELs, APCmin tumor model with organoid co-culture\",\n      \"pmids\": [\"34861219\", \"33515805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking CD103 ligation to granzyme exocytosis (perforin-independent) was not elucidated\", \"Whether CD103 signals differently in γδ vs. αβ IELs was not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linking NUDT1 to CD103+ TRM longevity through PARP1-TGFβR-dependent DNA damage resistance revealed a metabolic checkpoint that maintains TGF-β-Smad signaling and thereby sustains CD103 expression and tissue residency.\",\n      \"evidence\": \"NUDT1 conditional KO and overexpression in CD8+ T cells, PARP1 inhibition, adoptive co-transfer in murine cholangitis model\",\n      \"pmids\": [\"35753523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NUDT1 acts on the Itgae locus directly or exclusively through TGFβR maintenance was not resolved\", \"Generalizability beyond hepatic TRM was not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two studies expanded understanding of upstream signals: retinoic acid during mesenteric lymph node priming was shown to license intestinal CD103+ TRM differentiation independently of gut homing, and 4-octyl itaconate was found to suppress CD103+ TRM induction by blocking RUNX3 DNA demethylation.\",\n      \"evidence\": \"Retinoic acid blockade and MLN vs. spleen priming comparison in mice; 4-OI treatment with RUNX3 methylation analysis in CD8 T cells and murine PSC models\",\n      \"pmids\": [\"36809399\", \"37505225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Epigenetic regulation of Runx3 at the Itgae locus vs. Runx3 target genes was not distinguished\", \"Whether retinoic acid acts on Itgae chromatin directly or indirectly through Runx3/Smad axis was not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Therapeutic blockade of CD103 in a Sjögren's disease model demonstrated that CD103+ TRM cells are pathogenic effectors in autoimmune glandular destruction, establishing CD103 as a potential therapeutic target in tissue-localized autoimmunity.\",\n      \"evidence\": \"Anti-CD103 monoclonal antibody intraglandular administration in ESS mouse model with functional salivary flow measurement, scRNAseq, granzyme B/IFN-γ immunostaining\",\n      \"pmids\": [\"38777379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD103 blockade depletes TRM cells or merely disrupts retention was not mechanistically distinguished\", \"Long-term consequences of CD103 blockade on mucosal immunity were not assessed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis of the αEβ7/E-cadherin interface, the kinase(s) responsible for S1163 phosphorylation on the αE cytoplasmic tail, how CD103 ligation triggers perforin-independent granzyme release, and the integrated epigenetic logic governing Runx3/Gfi-1/Tcf1 at the Itgae locus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of αEβ7/E-cadherin complex\", \"Kinase for S1163 phosphorylation unidentified\", \"Mechanism of perforin-independent granzyme release downstream of CD103 unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 3, 6, 9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 6, 9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 9, 10, 14]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 6, 9, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4, 5, 7]}\n    ],\n    \"complexes\": [\n      \"αEβ7 integrin heterodimer\"\n    ],\n    \"partners\": [\n      \"ITGB7\",\n      \"CDH1\",\n      \"PXN\",\n      \"PTK2B\",\n      \"CCR5\",\n      \"SMAD2\",\n      \"SMAD3\",\n      \"NFATC2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}