{"gene":"CRTAM","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2000,"finding":"CRTAM was identified as a new immunoglobulin superfamily member expressed on activated mouse alphabetaTCR+ CD4-CD8- NKT cells, with restricted expression in class I-MHC-restricted T cells, suggesting a gene expression program common to this T cell subset.","method":"cDNA library subtraction, expression pattern analysis","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — original identification by cDNA subtraction with expression characterization across T cell subsets, single lab","pmids":["10811014"],"is_preprint":false},{"year":2005,"finding":"CRTAM functions as a receptor on NK cells and CD8+ T cells that binds tumor suppressor Necl-2 (TSLC1/CADM1); CRTAM-Necl-2 interaction promotes NK cell cytotoxicity and IFN-gamma secretion by CD8+ T cells in vitro, and NK cell-mediated tumor rejection in vivo.","method":"Receptor-ligand binding assays, in vitro cytotoxicity assays, IFN-gamma secretion assays, in vivo tumor rejection model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (in vitro cytotoxicity, cytokine secretion, in vivo tumor model), replicated concept across two independent 2005 papers","pmids":["15811952"],"is_preprint":false},{"year":2005,"finding":"CRTAM is expressed as a dimer on the cell surface of activated NK cells and CD8+ T cells; CRTAM binds Necl-2 heterotypically (not homotypically), and this interaction mediates tight cell-cell adhesion between CRTAM+ lymphocytes and Necl-2+ target cells, which can be blocked by soluble CRTAM-Ig fusion protein.","method":"Expression cloning, CRTAM-Ig fusion protein binding assays, cell adhesion/aggregation assays, inhibition with soluble CRTAM-Ig","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — expression cloning to identify ligand, functional blocking experiments, replicated in same year by independent group (PMID:15811952)","pmids":["16091383"],"is_preprint":false},{"year":2008,"finding":"CRTAM coordinates a signaling complex anchored by the Scrib polarity protein to establish a late phase (>6 hours post-activation) of T cell polarity on a subset of CD4+ T cells; this late polarity selectively enables CD4+CRTAM+ T cells to produce more IFN-gamma and IL-22.","method":"Immunological synapse imaging, signaling complex analysis, cytokine production assays in CRTAM+ vs CRTAM- CD4+ T cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — published in Cell with multiple orthogonal methods demonstrating complex formation, polarity establishment, and functional cytokine output","pmids":["18329370"],"is_preprint":false},{"year":2009,"finding":"CRTAM mediates retention of activated CD8+ T cells within the draining lymph node by binding Necl-2 on CD8+ dendritic cells in the T cell area in an antigen-independent fashion at late-stage activation; CRTAM-/- mice show reduced CD8+ T cell numbers in draining lymph nodes, impaired protective immunity against viral infection, and impaired autoimmune diabetes induction.","method":"CRTAM-/- mouse generation, in vivo viral infection model, autoimmune diabetes model, lymph node retention assays, DC binding assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple in vivo phenotypic readouts and mechanistic cell-binding experiments","pmids":["19752223"],"is_preprint":false},{"year":2009,"finding":"CRTAM gene expression in human CD8+ T cells is driven by an AP-1 binding site located 1.4 kb upstream of the ATG codon, activated via the JNK-AP-1 signaling pathway; mutation of the AP-1 site abolishes CRTAM promoter activity in activated but not resting T cells.","method":"Luciferase reporter assays, EMSA, supershift assays, JNK inhibitor (SP600125) treatment, site-directed mutagenesis of AP-1 element","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — promoter mutagenesis combined with EMSA and reporter assays in a single lab with multiple orthogonal methods","pmids":["19695707"],"is_preprint":false},{"year":2009,"finding":"CRTAM is constitutively expressed in adult thymocytes throughout all stages of thymocyte development (restricted to CD8 and DN subpopulations from E13.5 to adult); blocking CRTAM-CADM1 interaction impairs thymus growth and thymocyte maturation.","method":"Flow cytometry of thymic subsets, developmental time-course analysis, CADM1 blocking experiments in thymus","journal":"Developmental and comparative immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — blocking experiments establish functional role, but single lab without genetic knockout confirmation","pmids":["19799932"],"is_preprint":false},{"year":2010,"finding":"CRTAM is expressed in epithelial cells at the lateral membrane and participates in both homotypic and heterotypic cell adhesion; treatment with soluble CRTAM enhances cell-cell dissociation and lowers transepithelial electrical resistance; anti-CRTAM antibody decreases cell aggregate formation and promotes cell detachment.","method":"Immunofluorescence localization, transepithelial electrical resistance measurement, soluble CRTAM treatment, anti-CRTAM antibody blocking, co-culture binding assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple functional assays in epithelial cells, single lab, no genetic knockout","pmids":["20556794"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of the Necl-2/CRTAM complex shows that Necl-2 occupies the CRTAM homodimer interface, making CRTAM homodimerization impossible; mutational analysis identified key 'lock-and-key' amino acids responsible for binding; Necl-2 binding to CRTAM competes with CRTAM dimerization.","method":"X-ray crystallography of Necl-2/CRTAM complex, site-directed mutagenesis, functional binding assays","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with mutagenesis and functional validation in a single study","pmids":["23871486"],"is_preprint":false},{"year":2013,"finding":"CRTAM engagement by Necl-2 on tumor cells triggers cell death of activated Vgamma9Vdelta2 T cells via an autophagic process (not apoptosis or necroptosis); CRTAM is acquired at the tumor cell surface through membrane capture from Vgamma9Vdelta2 T cells upon contact.","method":"Co-culture experiments, autophagy/apoptosis/necroptosis marker analysis, specific pathway inhibitors, flow cytometry for CRTAM membrane transfer","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific inhibitor blocking experiments with multiple cell death pathway markers, single lab","pmids":["23530148"],"is_preprint":false},{"year":2014,"finding":"CRTAM-CADM1 (Necl-2) interactions are required for residency of CD4+CD8+ T cells in the intestinal epithelium; CRTAM is expressed on activated intraepithelial T cells while CADM1 is expressed on gut CD103+ DCs; Crtam-/- and Cadm1-/- mice both lose intestinal CD4+CD8+ T cells; during T. gondii infection, loss of CRTAM results in markedly reduced Th17 cells in the intestinal mucosa.","method":"Crtam-/- and Cadm1-/- mouse phenotyping, flow cytometry of intestinal T cell populations, T. gondii infection model, expression analysis of ligand/receptor on specific cell types","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — dual genetic knockout (both receptor and ligand KO), multiple in vivo models, and ligand-receptor pairing on specific cell types","pmids":["24687959"],"is_preprint":false},{"year":2015,"finding":"CRTAM expression marks a precursor population for CD4+ cytotoxic T lymphocytes (CD4+CTL); ectopic expression of CRTAM in T cells induces IFN-gamma production, CTL-related gene expression (Eomes, Granzyme B, perforin), and cytotoxic activity; CRTAM-mediated intracellular signaling is required for CD4+CTL induction.","method":"Ectopic CRTAM expression, gene expression profiling, IFN-gamma and cytokine assays, cytotoxicity assays, signaling mutant analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function ectopic expression with multiple functional readouts plus signaling requirement established","pmids":["26694968"],"is_preprint":false},{"year":2015,"finding":"ZEB1 (zinc finger E-box-binding protein) functions as a transcriptional repressor of CRTAM in T cells; ZEB1 overexpression represses CRTAM promoter activity and endogenous CRTAM levels; ZEB1-mediated repression is abolished when E-box-like elements in the CRTAM promoter are mutated; STAT3 controls ZEB1 expression downstream of IL-6 and IL-27 signaling.","method":"Luciferase reporter assays, site-directed mutagenesis of E-box elements, ZEB1 overexpression, endogenous CRTAM protein measurement","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis and gain-of-function ZEB1 overexpression with endogenous protein measurement, single lab","pmids":["25910959"],"is_preprint":false},{"year":2019,"finding":"In leukemic bone marrow (ALL), CRTAM/Necl-2 interaction drives NK cells into an exhaustion-like phenotype with suppressive functions (IL-10 and TGF-beta production in vitro); preactivated CD56high NK cells expressing CRTAM are enriched in leukemic bone marrow.","method":"Flow cytometry of bone marrow NK populations, in vitro cytokine production assays (IL-10, TGF-beta), phenotypic characterization of exhaustion markers","journal":"Journal of leukocyte biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, in vitro functional assay without genetic proof of CRTAM causality","pmids":["30791148"],"is_preprint":false},{"year":2020,"finding":"The IgC constant domain of CRTAM forms a homodimer in solution via hydrophobic interactions and is essential for high-affinity binding to Necl-2; the IgV domain mediates ligand recognition but requires the IgC domain for high-affinity interaction (Kd = 2.16 nM by SPR); recombinant CRTAM recognizes Necl-2 in a cell-free system only when the stalk region is included.","method":"Recombinant protein purification, surface plasmon resonance (SPR), cell-free binding assay, domain deletion analysis","journal":"The protein journal / Biochemistry and biophysics reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — SPR affinity measurement combined with domain mutagenesis/deletion and cell-free reconstitution in two complementary studies","pmids":["32300914","39263316"],"is_preprint":false},{"year":2026,"finding":"CRTAM acts as a T cell checkpoint for immune-related adverse events (irAEs) during immune checkpoint blockade; CRTAM+ T cells preferentially infiltrate normal tissues over tumors via CRTAM-CADM1 interaction and promote IL-23-centered type 3 immunity; Crtam knockout or T cell lineage-specific Crtam ablation impairs irAE induction without affecting antitumor efficacy.","method":"Crtam knockout mice, T cell lineage-specific Crtam ablation, preclinical irAE models, tumor-bearing irAE models, transcriptome and pharmacovigilance data integration","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout and cell-type-specific ablation with mechanistic pathway identification (CRTAM-CADM1-IL-23 axis) in multiple preclinical models","pmids":["41786980"],"is_preprint":false},{"year":2024,"finding":"IL-6 and IL-27 negatively regulate CRTAM expression on activated naïve CD4+ T cells; this regulation operates through STAT3-mediated control of the CRTAM transcriptional repressor ZEB1.","method":"Ex vivo T cell activation with IL-6/IL-27, STAT3 pathway analysis, ZEB1 expression measurement, flow cytometry","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, cytokine treatment experiments without genetic proof of STAT3-ZEB1 causality for CRTAM repression","pmids":[],"is_preprint":true}],"current_model":"CRTAM is an immunoglobulin superfamily transmembrane receptor expressed on activated NK cells, CD8+ T cells, NKT cells, and a subset of CD4+ T cells that binds its ligand Necl-2/CADM1 with high affinity (Kd ~2 nM) through its IgV domain, with the IgC domain forming a homodimer essential for this interaction; upon Necl-2 engagement, CRTAM assembles a Scrib-anchored polarity complex to establish late-phase T cell polarity, promotes IFN-gamma and IL-22 production, drives CD4+ CTL differentiation through Eomes induction, mediates lymphocyte adhesion and retention in lymph nodes and gut mucosa via CRTAM-CADM1 on dendritic cells, and its transcription is induced by the JNK-AP-1 pathway and repressed by ZEB1 downstream of IL-6/IL-27-STAT3 signaling."},"narrative":{"mechanistic_narrative":"CRTAM is an immunoglobulin-superfamily transmembrane receptor expressed on activated NK cells, CD8+ T cells, NKT cells, and a subset of CD4+ T cells that orchestrates late-phase lymphocyte activation, polarity, and tissue retention through engagement of its ligand Necl-2/CADM1 [PMID:15811952, PMID:16091383, PMID:18329370]. CRTAM is displayed as a cell-surface dimer and binds Necl-2 heterotypically with high affinity (Kd ~2 nM), driving tight cell-cell adhesion that can be competed by soluble CRTAM-Ig [PMID:16091383, PMID:32300914, PMID:39263316]; structural and domain analyses show that Necl-2 occupies the CRTAM homodimer interface and that the IgC constant domain mediates the homodimerization required for high-affinity IgV-dependent ligand recognition, so ligand binding and self-dimerization are mutually exclusive [PMID:23871486, PMID:32300914, PMID:39263316]. Functionally, Necl-2 engagement promotes NK cytotoxicity and CD8+ T cell IFN-gamma secretion and tumor rejection [PMID:15811952], and recruits a Scrib-anchored polarity complex to establish a late (>6 h) phase of T cell polarity that selectively enhances IFN-gamma and IL-22 output [PMID:18329370]. CRTAM marks and instructs CD4+ cytotoxic T lymphocyte differentiation, with its intracellular signaling inducing Eomes, granzyme B, and perforin [PMID:26694968]. Through CRTAM-CADM1 contacts with dendritic cells, CRTAM mediates antigen-independent retention of activated CD8+ T cells in draining lymph nodes and residency of CD4+CD8+ T cells in the intestinal epithelium, shaping protective and autoimmune responses in vivo [PMID:19752223, PMID:24687959]. CRTAM transcription is induced via a JNK-AP-1 element in activated T cells and repressed by ZEB1 [PMID:19695707, PMID:25910959]. Recent genetic work establishes CRTAM as a T cell checkpoint that directs CRTAM+ T cells into normal tissues to drive IL-23-centered type 3 immunity, such that its ablation impairs immune-related adverse events without compromising antitumor efficacy [PMID:41786980].","teleology":[{"year":2000,"claim":"Established CRTAM as a novel IgSF gene with expression restricted to class I-MHC-restricted T cell subsets, framing it as part of a shared activation program of these lineages.","evidence":"cDNA library subtraction and expression profiling across mouse T cell subsets","pmids":["10811014"],"confidence":"Medium","gaps":["No ligand or molecular function identified","Expression pattern only, no functional assay"]},{"year":2005,"claim":"Identified Necl-2/CADM1 as the CRTAM ligand and defined CRTAM as a surface-dimeric adhesion receptor whose heterotypic engagement drives NK/CD8 effector function and target adhesion.","evidence":"Expression cloning, CRTAM-Ig binding/blocking, cytotoxicity and IFN-gamma assays, in vivo tumor rejection","pmids":["15811952","16091383"],"confidence":"High","gaps":["Intracellular signaling mechanism downstream of CRTAM unresolved","Structural basis of dimerization vs ligand binding not yet defined"]},{"year":2008,"claim":"Showed CRTAM couples ligand engagement to a Scrib-anchored polarity complex producing a late phase of T cell polarity, linking the receptor to cytokine output (IFN-gamma, IL-22).","evidence":"Immunological synapse imaging, signaling-complex analysis, and cytokine assays in CRTAM+ vs CRTAM- CD4+ T cells","pmids":["18329370"],"confidence":"High","gaps":["Direct CRTAM-Scrib biochemical interaction not detailed","Signaling intermediates between CRTAM cytoplasmic tail and polarity machinery unknown"]},{"year":2009,"claim":"Demonstrated in vivo that CRTAM-Necl-2 contacts with dendritic cells retain activated CD8+ T cells in lymph nodes and that an AP-1 element drives CRTAM transcription, connecting activation signaling to receptor expression and tissue positioning.","evidence":"CRTAM-/- mice with viral and autoimmune diabetes models plus LN retention assays; luciferase/EMSA/JNK-inhibitor promoter analysis","pmids":["19752223","19695707"],"confidence":"High","gaps":["Mechanism of antigen-independent late retention incompletely defined","How JNK-AP-1 integrates with later repressors not addressed"]},{"year":2010,"claim":"Extended CRTAM beyond lymphocytes by showing epithelial CRTAM at lateral membranes participates in homotypic and heterotypic adhesion controlling barrier integrity.","evidence":"Immunofluorescence localization, TEER measurement, soluble CRTAM and antibody blocking in epithelial cultures","pmids":["20556794"],"confidence":"Medium","gaps":["No genetic knockout in epithelium","Physiological relevance of epithelial CRTAM in vivo unclear"]},{"year":2013,"claim":"Resolved the structural logic of the receptor: Necl-2 binds the CRTAM homodimer interface so ligand engagement and self-dimerization are mutually exclusive, and defined CRTAM-triggered autophagic death of gammadelta T cells via membrane capture.","evidence":"X-ray crystallography of Necl-2/CRTAM with mutagenesis; co-culture with autophagy/apoptosis/necroptosis markers and inhibitors","pmids":["23871486","23530148"],"confidence":"High","gaps":["Functional consequence of dimer-to-monomer switching during signaling not established","Mechanism linking CRTAM engagement to autophagy machinery unknown"]},{"year":2014,"claim":"Established CRTAM-CADM1 as the receptor-ligand pair required for residency of CD4+CD8+ intestinal intraepithelial T cells and mucosal Th17 responses, using both receptor and ligand knockouts.","evidence":"Crtam-/- and Cadm1-/- phenotyping, intestinal T cell flow cytometry, T. gondii infection model","pmids":["24687959"],"confidence":"High","gaps":["Signaling driving residency vs migration not dissected","Whether CRTAM acts on the lymphocyte or via ligand-bearing DC dominates is partially open"]},{"year":2015,"claim":"Defined CRTAM as a marker and driver of CD4+ cytotoxic T lymphocyte differentiation through intracellular signaling that induces Eomes/granzyme B/perforin, and identified ZEB1 (STAT3-controlled) as a transcriptional repressor of CRTAM.","evidence":"Ectopic CRTAM expression with gene-expression profiling and cytotoxicity assays; ZEB1 overexpression with E-box promoter mutagenesis","pmids":["26694968","25910959"],"confidence":"High","gaps":["Identity of CRTAM cytoplasmic signaling adaptors driving Eomes still unknown","Direct vs indirect role of STAT3 on ZEB1 not fully causally tested"]},{"year":2019,"claim":"Linked CRTAM/Necl-2 to NK cell dysfunction by associating the interaction with an exhaustion-like, suppressive NK phenotype in leukemic bone marrow.","evidence":"Flow cytometry of BM NK subsets and in vitro IL-10/TGF-beta cytokine assays","pmids":["30791148"],"confidence":"Low","gaps":["No genetic proof of CRTAM causality in the exhaustion phenotype","In vitro association only, not validated in vivo"]},{"year":2026,"claim":"Positioned CRTAM as a T cell checkpoint for immune-related adverse events, showing CRTAM+ T cells traffic to normal tissue via CRTAM-CADM1 to drive IL-23 type 3 immunity, separable from antitumor activity.","evidence":"Crtam global and T-cell-specific knockouts in preclinical irAE and tumor models with transcriptome and pharmacovigilance integration","pmids":["41786980"],"confidence":"High","gaps":["Mechanism by which CRTAM-CADM1 biases tissue over tumor infiltration not fully resolved","Direct link from CRTAM signaling to IL-23 induction not mapped"]},{"year":null,"claim":"The intracellular signaling cascade linking CRTAM's cytoplasmic tail to its diverse outputs (polarity, Eomes induction, retention, IL-23) remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No characterized proximal signaling adaptors of the CRTAM tail","Unclear how a single receptor produces adhesion, polarity, differentiation, and cytokine programs in different contexts"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,7,10]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,3,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,7]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,3,4,10,15]}],"complexes":[],"partners":["CADM1","SCRIB","ZEB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95727","full_name":"Cytotoxic and regulatory T-cell molecule","aliases":["Class-I MHC-restricted T-cell-associated molecule"],"length_aa":393,"mass_kda":44.6,"function":"Mediates heterophilic cell-cell adhesion which regulates the activation, differentiation and tissue retention of various T-cell subsets (By similarity). Interaction with CADM1 promotes natural killer (NK) cell cytotoxicity and IFNG/interferon-gamma secretion by CD8+ T-cells in vitro as well as NK cell-mediated rejection of tumors expressing CADM1 in vivo (PubMed:15811952). Regulates CD8+ T-cell proliferation in response to T-cell receptor (TCR) activation (By similarity). Appears to be dispensable for CD8+ T-cell-mediated cytotoxicity (By similarity). Interaction with SCRIB promotes the late phase of cellular polarization of a subset of CD4+ T-cells, which in turn regulates TCR-mediated proliferation and IFNG, IL17 and IL22 production (By similarity). By interacting with CADM1 on CD8+ dendritic cells, regulates the retention of activated CD8+ T-cells within the draining lymph node (By similarity). Required for the intestinal retention of intraepithelial CD4+ CD8+ T-cells and, to a lesser extent, intraepithelial and lamina propria CD8+ T-cells and CD4+ T-cells (By similarity). Interaction with CADM1 promotes the adhesion to gut-associated CD103+ dendritic cells, which may facilitate the expression of gut-homing and adhesion molecules on T-cells and the conversion of CD4+ T-cells into CD4+ CD8+ T-cells (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O95727/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CRTAM","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CRTAM","total_profiled":1310},"omim":[{"mim_id":"612597","title":"CYTOTOXIC AND REGULATORY T-CELL MOLECULE; CRTAM","url":"https://www.omim.org/entry/612597"},{"mim_id":"605686","title":"CELL ADHESION MOLECULE 1; CADM1","url":"https://www.omim.org/entry/605686"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":128.2}],"url":"https://www.proteinatlas.org/search/CRTAM"},"hgnc":{"alias_symbol":["CD355"],"prev_symbol":[]},"alphafold":{"accession":"O95727","domains":[{"cath_id":"2.60.40.10","chopping":"24-116","consensus_level":"high","plddt":94.7498,"start":24,"end":116},{"cath_id":"2.60.40.10","chopping":"120-218","consensus_level":"high","plddt":93.7056,"start":120,"end":218}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95727","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95727-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95727-F1-predicted_aligned_error_v6.png","plddt_mean":73.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CRTAM","jax_strain_url":"https://www.jax.org/strain/search?query=CRTAM"},"sequence":{"accession":"O95727","fasta_url":"https://rest.uniprot.org/uniprotkb/O95727.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95727/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95727"}},"corpus_meta":[{"pmid":"26694968","id":"PMC_26694968","title":"CRTAM 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/10811014","citation_count":68,"is_preprint":false},{"pmid":"16091383","id":"PMC_16091383","title":"Heterotypic interaction of CRTAM with Necl2 induces cell adhesion on activated NK cells and CD8+ T cells.","date":"2005","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16091383","citation_count":63,"is_preprint":false},{"pmid":"19752223","id":"PMC_19752223","title":"CRTAM confers late-stage activation of CD8+ T cells to regulate retention within lymph node.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19752223","citation_count":56,"is_preprint":false},{"pmid":"24687959","id":"PMC_24687959","title":"CRTAM controls residency of gut CD4+CD8+ T cells in the steady state and maintenance of gut CD4+ Th17 during parasitic infection.","date":"2014","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24687959","citation_count":50,"is_preprint":false},{"pmid":"21572449","id":"PMC_21572449","title":"Trichosanthin enhances anti-tumor immune response in a murine Lewis lung cancer model by boosting the interaction between TSLC1 and CRTAM.","date":"2011","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21572449","citation_count":42,"is_preprint":false},{"pmid":"22051697","id":"PMC_22051697","title":"Genome-wide association study reveals class I MHC-restricted T cell-associated molecule gene (CRTAM) variants interact with vitamin D levels to affect asthma exacerbations.","date":"2011","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22051697","citation_count":37,"is_preprint":false},{"pmid":"30791148","id":"PMC_30791148","title":"CRTAM+ NK cells endowed with suppressor properties arise in leukemic bone marrow.","date":"2019","source":"Journal of leukocyte 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1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23530148","citation_count":13,"is_preprint":false},{"pmid":"23871486","id":"PMC_23871486","title":"Competition of cell adhesion and immune recognition: insights into the interaction between CRTAM and nectin-like 2.","date":"2013","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/23871486","citation_count":13,"is_preprint":false},{"pmid":"19413645","id":"PMC_19413645","title":"Ethanol-responsive genes (Crtam, Zbtb16, and Mobp) located in the alcohol-QTL region of chromosome 9 are associated with alcohol preference in mice.","date":"2009","source":"Alcoholism, clinical and experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/19413645","citation_count":13,"is_preprint":false},{"pmid":"19799932","id":"PMC_19799932","title":"Role of CRTAM during mouse early T lymphocytes development.","date":"2009","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19799932","citation_count":12,"is_preprint":false},{"pmid":"31312200","id":"PMC_31312200","title":"CRTAM Protects Against Intestinal Dysbiosis During Pathogenic Parasitic Infection by Enabling Th17 Maturation.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31312200","citation_count":12,"is_preprint":false},{"pmid":"31142601","id":"PMC_31142601","title":"CRTAM Shapes the Gut Microbiota and Enhances the Severity of Infection.","date":"2019","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/31142601","citation_count":11,"is_preprint":false},{"pmid":"38354509","id":"PMC_38354509","title":"CRTAM promotes antitumor immune response in triple negative breast cancer by enhancing CD8+ T cell infiltration.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38354509","citation_count":9,"is_preprint":false},{"pmid":"24939541","id":"PMC_24939541","title":"[Nectins and nectin-like receptors DNAM-1 and CRTAM: new ways for tumor escape].","date":"2014","source":"Medecine sciences : M/S","url":"https://pubmed.ncbi.nlm.nih.gov/24939541","citation_count":8,"is_preprint":false},{"pmid":"25910959","id":"PMC_25910959","title":"CRTAM is negatively regulated by ZEB1 in T cells.","date":"2015","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25910959","citation_count":8,"is_preprint":false},{"pmid":"36720375","id":"PMC_36720375","title":"Molecular characterization of the cytotoxic and regulatory T cell coreceptor (CRTAM), and its ligand CADM1, in the European seabass and gilthead seabream.","date":"2023","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36720375","citation_count":4,"is_preprint":false},{"pmid":"32300914","id":"PMC_32300914","title":"Prokaryotic Expression of the Immunoglobulin's Domains of CRTAM to Characterize a Monoclonal Antibody.","date":"2020","source":"The protein journal","url":"https://pubmed.ncbi.nlm.nih.gov/32300914","citation_count":3,"is_preprint":false},{"pmid":"24339981","id":"PMC_24339981","title":"Chicken CRTAM binds nectin-like 2 ligand and is upregulated on CD8+ αβ and γδ T lymphocytes with different kinetics.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24339981","citation_count":3,"is_preprint":false},{"pmid":"38931955","id":"PMC_38931955","title":"Single-Cell Transcriptomic and Targeted Genomic Profiling Adjusted for Inflammation and Therapy Bias Reveal CRTAM and PLCB1 as Novel Hub Genes for Anti-Tumor Necrosis Factor Alpha Therapy Response in Crohn's Disease.","date":"2024","source":"Pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/38931955","citation_count":2,"is_preprint":false},{"pmid":"39263316","id":"PMC_39263316","title":"The constant domain of CRTAM is essential for high-affinity interaction with Nectin-like 2.","date":"2024","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/39263316","citation_count":1,"is_preprint":false},{"pmid":"41786980","id":"PMC_41786980","title":"CRTAM inhibition mitigates toxicity of immune checkpoint inhibitors without antitumor efficacy trade-off.","date":"2026","source":"Nature cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41786980","citation_count":0,"is_preprint":false},{"pmid":"33233764","id":"PMC_33233764","title":"Short Disordered Epitope of CRTAM Ig-Like V Domain as a Potential Target for Blocking Antibodies.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33233764","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.12.675787","title":"The proteomics and phosphoproteomics landscape of melanoma under T cell attack","date":"2025-09-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.12.675787","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.09.652839","title":"IFNγ expression correlates with enhanced cytotoxicity in CD8  <sup>+</sup>  T cells","date":"2025-05-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.09.652839","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.01.651731","title":"Enhancement of activation-induced T cell proliferation by SIRPG in a CD47-independent manner","date":"2025-05-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.01.651731","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.23.25328231","title":"Neonatal methylation-based predictors of childhood cognition","date":"2025-05-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.23.25328231","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.03.610972","title":"IL-6 and IL-27 negatively regulate CRTAM-expressing CD4  <sup>+</sup>  T-cells associated with lymphoid-driven synovitis","date":"2024-09-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.03.610972","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18219,"output_tokens":4237,"usd":0.059106,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12145,"output_tokens":3811,"usd":0.078,"stage2_stop_reason":"end_turn"},"total_usd":0.137106,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"CRTAM was identified as a new immunoglobulin superfamily member expressed on activated mouse alphabetaTCR+ CD4-CD8- NKT cells, with restricted expression in class I-MHC-restricted T cells, suggesting a gene expression program common to this T cell subset.\",\n      \"method\": \"cDNA library subtraction, expression pattern analysis\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — original identification by cDNA subtraction with expression characterization across T cell subsets, single lab\",\n      \"pmids\": [\"10811014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CRTAM functions as a receptor on NK cells and CD8+ T cells that binds tumor suppressor Necl-2 (TSLC1/CADM1); CRTAM-Necl-2 interaction promotes NK cell cytotoxicity and IFN-gamma secretion by CD8+ T cells in vitro, and NK cell-mediated tumor rejection in vivo.\",\n      \"method\": \"Receptor-ligand binding assays, in vitro cytotoxicity assays, IFN-gamma secretion assays, in vivo tumor rejection model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (in vitro cytotoxicity, cytokine secretion, in vivo tumor model), replicated concept across two independent 2005 papers\",\n      \"pmids\": [\"15811952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CRTAM is expressed as a dimer on the cell surface of activated NK cells and CD8+ T cells; CRTAM binds Necl-2 heterotypically (not homotypically), and this interaction mediates tight cell-cell adhesion between CRTAM+ lymphocytes and Necl-2+ target cells, which can be blocked by soluble CRTAM-Ig fusion protein.\",\n      \"method\": \"Expression cloning, CRTAM-Ig fusion protein binding assays, cell adhesion/aggregation assays, inhibition with soluble CRTAM-Ig\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — expression cloning to identify ligand, functional blocking experiments, replicated in same year by independent group (PMID:15811952)\",\n      \"pmids\": [\"16091383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CRTAM coordinates a signaling complex anchored by the Scrib polarity protein to establish a late phase (>6 hours post-activation) of T cell polarity on a subset of CD4+ T cells; this late polarity selectively enables CD4+CRTAM+ T cells to produce more IFN-gamma and IL-22.\",\n      \"method\": \"Immunological synapse imaging, signaling complex analysis, cytokine production assays in CRTAM+ vs CRTAM- CD4+ T cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — published in Cell with multiple orthogonal methods demonstrating complex formation, polarity establishment, and functional cytokine output\",\n      \"pmids\": [\"18329370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRTAM mediates retention of activated CD8+ T cells within the draining lymph node by binding Necl-2 on CD8+ dendritic cells in the T cell area in an antigen-independent fashion at late-stage activation; CRTAM-/- mice show reduced CD8+ T cell numbers in draining lymph nodes, impaired protective immunity against viral infection, and impaired autoimmune diabetes induction.\",\n      \"method\": \"CRTAM-/- mouse generation, in vivo viral infection model, autoimmune diabetes model, lymph node retention assays, DC binding assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple in vivo phenotypic readouts and mechanistic cell-binding experiments\",\n      \"pmids\": [\"19752223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRTAM gene expression in human CD8+ T cells is driven by an AP-1 binding site located 1.4 kb upstream of the ATG codon, activated via the JNK-AP-1 signaling pathway; mutation of the AP-1 site abolishes CRTAM promoter activity in activated but not resting T cells.\",\n      \"method\": \"Luciferase reporter assays, EMSA, supershift assays, JNK inhibitor (SP600125) treatment, site-directed mutagenesis of AP-1 element\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter mutagenesis combined with EMSA and reporter assays in a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19695707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRTAM is constitutively expressed in adult thymocytes throughout all stages of thymocyte development (restricted to CD8 and DN subpopulations from E13.5 to adult); blocking CRTAM-CADM1 interaction impairs thymus growth and thymocyte maturation.\",\n      \"method\": \"Flow cytometry of thymic subsets, developmental time-course analysis, CADM1 blocking experiments in thymus\",\n      \"journal\": \"Developmental and comparative immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — blocking experiments establish functional role, but single lab without genetic knockout confirmation\",\n      \"pmids\": [\"19799932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CRTAM is expressed in epithelial cells at the lateral membrane and participates in both homotypic and heterotypic cell adhesion; treatment with soluble CRTAM enhances cell-cell dissociation and lowers transepithelial electrical resistance; anti-CRTAM antibody decreases cell aggregate formation and promotes cell detachment.\",\n      \"method\": \"Immunofluorescence localization, transepithelial electrical resistance measurement, soluble CRTAM treatment, anti-CRTAM antibody blocking, co-culture binding assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple functional assays in epithelial cells, single lab, no genetic knockout\",\n      \"pmids\": [\"20556794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of the Necl-2/CRTAM complex shows that Necl-2 occupies the CRTAM homodimer interface, making CRTAM homodimerization impossible; mutational analysis identified key 'lock-and-key' amino acids responsible for binding; Necl-2 binding to CRTAM competes with CRTAM dimerization.\",\n      \"method\": \"X-ray crystallography of Necl-2/CRTAM complex, site-directed mutagenesis, functional binding assays\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with mutagenesis and functional validation in a single study\",\n      \"pmids\": [\"23871486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CRTAM engagement by Necl-2 on tumor cells triggers cell death of activated Vgamma9Vdelta2 T cells via an autophagic process (not apoptosis or necroptosis); CRTAM is acquired at the tumor cell surface through membrane capture from Vgamma9Vdelta2 T cells upon contact.\",\n      \"method\": \"Co-culture experiments, autophagy/apoptosis/necroptosis marker analysis, specific pathway inhibitors, flow cytometry for CRTAM membrane transfer\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific inhibitor blocking experiments with multiple cell death pathway markers, single lab\",\n      \"pmids\": [\"23530148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CRTAM-CADM1 (Necl-2) interactions are required for residency of CD4+CD8+ T cells in the intestinal epithelium; CRTAM is expressed on activated intraepithelial T cells while CADM1 is expressed on gut CD103+ DCs; Crtam-/- and Cadm1-/- mice both lose intestinal CD4+CD8+ T cells; during T. gondii infection, loss of CRTAM results in markedly reduced Th17 cells in the intestinal mucosa.\",\n      \"method\": \"Crtam-/- and Cadm1-/- mouse phenotyping, flow cytometry of intestinal T cell populations, T. gondii infection model, expression analysis of ligand/receptor on specific cell types\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dual genetic knockout (both receptor and ligand KO), multiple in vivo models, and ligand-receptor pairing on specific cell types\",\n      \"pmids\": [\"24687959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CRTAM expression marks a precursor population for CD4+ cytotoxic T lymphocytes (CD4+CTL); ectopic expression of CRTAM in T cells induces IFN-gamma production, CTL-related gene expression (Eomes, Granzyme B, perforin), and cytotoxic activity; CRTAM-mediated intracellular signaling is required for CD4+CTL induction.\",\n      \"method\": \"Ectopic CRTAM expression, gene expression profiling, IFN-gamma and cytokine assays, cytotoxicity assays, signaling mutant analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function ectopic expression with multiple functional readouts plus signaling requirement established\",\n      \"pmids\": [\"26694968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ZEB1 (zinc finger E-box-binding protein) functions as a transcriptional repressor of CRTAM in T cells; ZEB1 overexpression represses CRTAM promoter activity and endogenous CRTAM levels; ZEB1-mediated repression is abolished when E-box-like elements in the CRTAM promoter are mutated; STAT3 controls ZEB1 expression downstream of IL-6 and IL-27 signaling.\",\n      \"method\": \"Luciferase reporter assays, site-directed mutagenesis of E-box elements, ZEB1 overexpression, endogenous CRTAM protein measurement\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis and gain-of-function ZEB1 overexpression with endogenous protein measurement, single lab\",\n      \"pmids\": [\"25910959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In leukemic bone marrow (ALL), CRTAM/Necl-2 interaction drives NK cells into an exhaustion-like phenotype with suppressive functions (IL-10 and TGF-beta production in vitro); preactivated CD56high NK cells expressing CRTAM are enriched in leukemic bone marrow.\",\n      \"method\": \"Flow cytometry of bone marrow NK populations, in vitro cytokine production assays (IL-10, TGF-beta), phenotypic characterization of exhaustion markers\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, in vitro functional assay without genetic proof of CRTAM causality\",\n      \"pmids\": [\"30791148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The IgC constant domain of CRTAM forms a homodimer in solution via hydrophobic interactions and is essential for high-affinity binding to Necl-2; the IgV domain mediates ligand recognition but requires the IgC domain for high-affinity interaction (Kd = 2.16 nM by SPR); recombinant CRTAM recognizes Necl-2 in a cell-free system only when the stalk region is included.\",\n      \"method\": \"Recombinant protein purification, surface plasmon resonance (SPR), cell-free binding assay, domain deletion analysis\",\n      \"journal\": \"The protein journal / Biochemistry and biophysics reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SPR affinity measurement combined with domain mutagenesis/deletion and cell-free reconstitution in two complementary studies\",\n      \"pmids\": [\"32300914\", \"39263316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CRTAM acts as a T cell checkpoint for immune-related adverse events (irAEs) during immune checkpoint blockade; CRTAM+ T cells preferentially infiltrate normal tissues over tumors via CRTAM-CADM1 interaction and promote IL-23-centered type 3 immunity; Crtam knockout or T cell lineage-specific Crtam ablation impairs irAE induction without affecting antitumor efficacy.\",\n      \"method\": \"Crtam knockout mice, T cell lineage-specific Crtam ablation, preclinical irAE models, tumor-bearing irAE models, transcriptome and pharmacovigilance data integration\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout and cell-type-specific ablation with mechanistic pathway identification (CRTAM-CADM1-IL-23 axis) in multiple preclinical models\",\n      \"pmids\": [\"41786980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-6 and IL-27 negatively regulate CRTAM expression on activated naïve CD4+ T cells; this regulation operates through STAT3-mediated control of the CRTAM transcriptional repressor ZEB1.\",\n      \"method\": \"Ex vivo T cell activation with IL-6/IL-27, STAT3 pathway analysis, ZEB1 expression measurement, flow cytometry\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, cytokine treatment experiments without genetic proof of STAT3-ZEB1 causality for CRTAM repression\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CRTAM is an immunoglobulin superfamily transmembrane receptor expressed on activated NK cells, CD8+ T cells, NKT cells, and a subset of CD4+ T cells that binds its ligand Necl-2/CADM1 with high affinity (Kd ~2 nM) through its IgV domain, with the IgC domain forming a homodimer essential for this interaction; upon Necl-2 engagement, CRTAM assembles a Scrib-anchored polarity complex to establish late-phase T cell polarity, promotes IFN-gamma and IL-22 production, drives CD4+ CTL differentiation through Eomes induction, mediates lymphocyte adhesion and retention in lymph nodes and gut mucosa via CRTAM-CADM1 on dendritic cells, and its transcription is induced by the JNK-AP-1 pathway and repressed by ZEB1 downstream of IL-6/IL-27-STAT3 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CRTAM is an immunoglobulin-superfamily transmembrane receptor expressed on activated NK cells, CD8+ T cells, NKT cells, and a subset of CD4+ T cells that orchestrates late-phase lymphocyte activation, polarity, and tissue retention through engagement of its ligand Necl-2/CADM1 [#1, #2, #3]. CRTAM is displayed as a cell-surface dimer and binds Necl-2 heterotypically with high affinity (Kd ~2 nM), driving tight cell-cell adhesion that can be competed by soluble CRTAM-Ig [#2, #14]; structural and domain analyses show that Necl-2 occupies the CRTAM homodimer interface and that the IgC constant domain mediates the homodimerization required for high-affinity IgV-dependent ligand recognition, so ligand binding and self-dimerization are mutually exclusive [#8, #14]. Functionally, Necl-2 engagement promotes NK cytotoxicity and CD8+ T cell IFN-gamma secretion and tumor rejection [#1], and recruits a Scrib-anchored polarity complex to establish a late (>6 h) phase of T cell polarity that selectively enhances IFN-gamma and IL-22 output [#3]. CRTAM marks and instructs CD4+ cytotoxic T lymphocyte differentiation, with its intracellular signaling inducing Eomes, granzyme B, and perforin [#11]. Through CRTAM-CADM1 contacts with dendritic cells, CRTAM mediates antigen-independent retention of activated CD8+ T cells in draining lymph nodes and residency of CD4+CD8+ T cells in the intestinal epithelium, shaping protective and autoimmune responses in vivo [#4, #10]. CRTAM transcription is induced via a JNK-AP-1 element in activated T cells and repressed by ZEB1 [#5, #12]. Recent genetic work establishes CRTAM as a T cell checkpoint that directs CRTAM+ T cells into normal tissues to drive IL-23-centered type 3 immunity, such that its ablation impairs immune-related adverse events without compromising antitumor efficacy [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established CRTAM as a novel IgSF gene with expression restricted to class I-MHC-restricted T cell subsets, framing it as part of a shared activation program of these lineages.\",\n      \"evidence\": \"cDNA library subtraction and expression profiling across mouse T cell subsets\",\n      \"pmids\": [\"10811014\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No ligand or molecular function identified\", \"Expression pattern only, no functional assay\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified Necl-2/CADM1 as the CRTAM ligand and defined CRTAM as a surface-dimeric adhesion receptor whose heterotypic engagement drives NK/CD8 effector function and target adhesion.\",\n      \"evidence\": \"Expression cloning, CRTAM-Ig binding/blocking, cytotoxicity and IFN-gamma assays, in vivo tumor rejection\",\n      \"pmids\": [\"15811952\", \"16091383\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Intracellular signaling mechanism downstream of CRTAM unresolved\", \"Structural basis of dimerization vs ligand binding not yet defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed CRTAM couples ligand engagement to a Scrib-anchored polarity complex producing a late phase of T cell polarity, linking the receptor to cytokine output (IFN-gamma, IL-22).\",\n      \"evidence\": \"Immunological synapse imaging, signaling-complex analysis, and cytokine assays in CRTAM+ vs CRTAM- CD4+ T cells\",\n      \"pmids\": [\"18329370\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct CRTAM-Scrib biochemical interaction not detailed\", \"Signaling intermediates between CRTAM cytoplasmic tail and polarity machinery unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated in vivo that CRTAM-Necl-2 contacts with dendritic cells retain activated CD8+ T cells in lymph nodes and that an AP-1 element drives CRTAM transcription, connecting activation signaling to receptor expression and tissue positioning.\",\n      \"evidence\": \"CRTAM-/- mice with viral and autoimmune diabetes models plus LN retention assays; luciferase/EMSA/JNK-inhibitor promoter analysis\",\n      \"pmids\": [\"19752223\", \"19695707\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism of antigen-independent late retention incompletely defined\", \"How JNK-AP-1 integrates with later repressors not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended CRTAM beyond lymphocytes by showing epithelial CRTAM at lateral membranes participates in homotypic and heterotypic adhesion controlling barrier integrity.\",\n      \"evidence\": \"Immunofluorescence localization, TEER measurement, soluble CRTAM and antibody blocking in epithelial cultures\",\n      \"pmids\": [\"20556794\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No genetic knockout in epithelium\", \"Physiological relevance of epithelial CRTAM in vivo unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the structural logic of the receptor: Necl-2 binds the CRTAM homodimer interface so ligand engagement and self-dimerization are mutually exclusive, and defined CRTAM-triggered autophagic death of gammadelta T cells via membrane capture.\",\n      \"evidence\": \"X-ray crystallography of Necl-2/CRTAM with mutagenesis; co-culture with autophagy/apoptosis/necroptosis markers and inhibitors\",\n      \"pmids\": [\"23871486\", \"23530148\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional consequence of dimer-to-monomer switching during signaling not established\", \"Mechanism linking CRTAM engagement to autophagy machinery unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established CRTAM-CADM1 as the receptor-ligand pair required for residency of CD4+CD8+ intestinal intraepithelial T cells and mucosal Th17 responses, using both receptor and ligand knockouts.\",\n      \"evidence\": \"Crtam-/- and Cadm1-/- phenotyping, intestinal T cell flow cytometry, T. gondii infection model\",\n      \"pmids\": [\"24687959\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Signaling driving residency vs migration not dissected\", \"Whether CRTAM acts on the lymphocyte or via ligand-bearing DC dominates is partially open\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined CRTAM as a marker and driver of CD4+ cytotoxic T lymphocyte differentiation through intracellular signaling that induces Eomes/granzyme B/perforin, and identified ZEB1 (STAT3-controlled) as a transcriptional repressor of CRTAM.\",\n      \"evidence\": \"Ectopic CRTAM expression with gene-expression profiling and cytotoxicity assays; ZEB1 overexpression with E-box promoter mutagenesis\",\n      \"pmids\": [\"26694968\", \"25910959\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Identity of CRTAM cytoplasmic signaling adaptors driving Eomes still unknown\", \"Direct vs indirect role of STAT3 on ZEB1 not fully causally tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked CRTAM/Necl-2 to NK cell dysfunction by associating the interaction with an exhaustion-like, suppressive NK phenotype in leukemic bone marrow.\",\n      \"evidence\": \"Flow cytometry of BM NK subsets and in vitro IL-10/TGF-beta cytokine assays\",\n      \"pmids\": [\"30791148\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No genetic proof of CRTAM causality in the exhaustion phenotype\", \"In vitro association only, not validated in vivo\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Positioned CRTAM as a T cell checkpoint for immune-related adverse events, showing CRTAM+ T cells traffic to normal tissue via CRTAM-CADM1 to drive IL-23 type 3 immunity, separable from antitumor activity.\",\n      \"evidence\": \"Crtam global and T-cell-specific knockouts in preclinical irAE and tumor models with transcriptome and pharmacovigilance integration\",\n      \"pmids\": [\"41786980\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which CRTAM-CADM1 biases tissue over tumor infiltration not fully resolved\", \"Direct link from CRTAM signaling to IL-23 induction not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intracellular signaling cascade linking CRTAM's cytoplasmic tail to its diverse outputs (polarity, Eomes induction, retention, IL-23) remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No characterized proximal signaling adaptors of the CRTAM tail\", \"Unclear how a single receptor produces adhesion, polarity, differentiation, and cytokine programs in different contexts\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 7, 10]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 3, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 3, 4, 10, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CADM1\", \"SCRIB\", \"ZEB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}