{"gene":"TIGIT","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2015,"finding":"The Fap2 protein of Fusobacterium nucleatum directly binds human TIGIT (but not mouse TIGIT), leading to inhibition of NK cell cytotoxicity and T cell activity, identifying a bacterium-dependent tumor immune evasion mechanism via TIGIT.","method":"F. nucleatum mutant library screen, direct protein interaction assay, NK cell cytotoxicity assay","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction mapped with mutant library, functional NK/T cell readouts, replicated across multiple F. nucleatum strains","pmids":["25680274"],"is_preprint":false},{"year":2014,"finding":"TIGIT directly interacts with CD226 (DNAM-1) in cis on T cells, disrupting CD226 dimerization and thereby inhibiting CD226-mediated co-stimulation; antibody co-blockade of TIGIT and PD-L1 synergistically enhances CD8+ T cell effector function in tumor and chronic viral infection models.","method":"Co-IP for cis interaction, antibody blockade in vivo tumor and viral infection models, CD226 dimerization assay","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction demonstrated, multiple orthogonal methods (co-IP, in vivo models), replicated across cancer and viral infection contexts","pmids":["25465800"],"is_preprint":false},{"year":2018,"finding":"TIGIT is expressed on NK cells and its blockade prevents NK cell exhaustion, promotes NK cell-dependent tumor immunity, and enhances anti-PD-L1 therapy; TIGIT constitutes a checkpoint in NK cells distinct from CTLA-4 and PD-1.","method":"TIGIT blockade antibody in tumor-bearing mouse models, flow cytometry for NK exhaustion markers, in vivo tumor rechallenge","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple tumor models, NK cell depletion experiments to confirm NK-dependence, replicated functional readouts","pmids":["29915296"],"is_preprint":false},{"year":2011,"finding":"VSTM3/TIGIT is a CD28 family member whose ligands are CD155 and CD112 (also ligands for activating receptor CD226), forming a regulatory network analogous to CD28/CTLA-4/CD80/CD86; soluble VSTM3 attenuates T cell responses in vitro and in vivo, and VSTM3-deficient mice are more susceptible to autoimmune challenges.","method":"Ligand binding assays, soluble protein treatment in vitro and in vivo, VSTM3 knockout mice with autoimmune challenge","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO phenotype, soluble protein functional assays, ligand binding characterization, multiple orthogonal methods","pmids":["21416464"],"is_preprint":false},{"year":2023,"finding":"TIGIT ligation by CD155 causes TIGIT to reorganize into dense nanoclusters at immune synapses that coalesce with TCR-rich clusters; this directly inhibits T cell cytokine secretion via TIGIT's intracellular ITT-like signalling motif, independently of CD226 co-inhibition. TIGIT and CD226 co-expression is rare on tumor-infiltrating lymphocytes, making this cell-intrinsic signalling mechanism likely dominant in tumors.","method":"Super-resolution microscopy, matched tumor/blood lymphocyte analysis, ITT-motif mutagenesis, cytokine secretion assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — super-resolution structure, ITT-motif mutagenesis confirming signalling requirement, multiple orthogonal methods in single study","pmids":["37596248"],"is_preprint":false},{"year":2022,"finding":"TIGIT, upon binding to CD155 and being phosphorylated, inhibits NF-κB and ERK activation by recruiting SHIP-1, resulting in downregulation of cytokine production in CD8+ T cells; blocking TIGIT attenuates SHIP-1 inhibitory effect and restores NF-κB and ERK activation.","method":"Western blotting for NF-κB and ERK pathway components, TIGIT blockade in activated CD8+ T cells, in vivo antibody blockade","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined signaling pathway with western blot and in vivo validation, single lab, limited mechanistic depth on direct SHIP-1 recruitment","pmids":["35729552"],"is_preprint":false},{"year":2017,"finding":"TIGIT engagement by CD155 on NK cells contributes to NK cell education/functional maturation: TIGIT+ NK cells from CD155-deficient hosts show functional impairment, and TIGIT deficiency impairs NK cell-mediated missing-self recognition and rejection of CD155-negative targets in an MHC-I-independent and CD226-unrelated manner.","method":"TIGIT+ NK cell isolation, CD155-deficient mouse model, NK cell education assays, missing-self recognition assays","journal":"Journal of autoimmunity","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic mouse models (CD155 KO, TIGIT assessment), multiple functional readouts, mechanism separated from MHC-I pathway","pmids":["28438433"],"is_preprint":false},{"year":2017,"finding":"All PVR-like receptors are expressed on human NK cells, with TIGIT preferentially expressed on the CD16+ NK cell subset; TIGIT is upregulated upon NK cell activation via ADCC, and blockade of TIGIT or CD112R (separately or together) enhances trastuzumab-triggered antitumor NK cell responses.","method":"Flow cytometry for receptor expression, ADCC assays, antibody blockade of TIGIT and CD112R","journal":"Cancer immunology, immunotherapy : CII","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional NK cell assays, single lab, demonstrates subset-specific expression and functional blockade","pmids":["28623459"],"is_preprint":false},{"year":2022,"finding":"Crystal structure of anti-TIGIT monoclonal antibody MG1131 (scFv version) bound to TIGIT reveals the PVR-binding interface; MG1131 binds TIGIT more tightly than PVR and blocks the PVR-TIGIT interaction, inhibiting immunosuppressive signaling, enhancing NK cell tumor killing, and inhibiting Treg suppressive activity.","method":"Crystal structure determination, SPR binding assays, NK cell cytotoxicity assays, Treg functional assays","journal":"mAbs","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation, SPR affinity measurements, multiple cell-based functional assays","pmids":["35090381"],"is_preprint":false},{"year":2023,"finding":"Biophysical experiments demonstrate TIGIT recognizes the membrane-distal ectodomain of nectin-4; structure-guided mutagenesis maps the nectin-4 binding interface on TIGIT; the TIGIT:nectin-4 interaction is weaker than the well-characterized TIGIT:nectin-2 interaction and inhibits NK cell cytotoxicity.","method":"Surface plasmon resonance, structure-guided mutagenesis, NK cell cytotoxicity assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — SPR binding measurement, mutagenesis mapping of binding interface, functional NK assay confirming inhibitory consequence","pmids":["37542773"],"is_preprint":false},{"year":2023,"finding":"Mouse TIGIT interacts with and is inhibited by mPVR only (not by other nectin ligands); TIGIT-deficient mice generated by CRISPR-Cas9 show enhanced NK cell cytotoxicity and degranulation against tumors in vitro and slower in vivo tumor progression compared to wild-type mice.","method":"CRISPR-Cas9 knockout mice, ligand interaction assays, NK cell cytotoxicity/degranulation assays, in vivo tumor growth models","journal":"Oncoimmunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with CRISPR, multiple functional readouts, in vitro and in vivo validation","pmids":["37261087"],"is_preprint":false},{"year":2023,"finding":"TIGIT deficiency in CD4+ T cells promotes their differentiation into Th1 and Th17 cells via enhanced CD28-mediated PI3K/AKT/mTOR co-stimulatory pathway, promoting glucose oxidation, citrate production, and increased cytosolic acetyl-CoA levels, leading to epigenetic reprogramming via histone acetylation; TIGIT overexpression rescues this phenotype, and pharmacological histone acetylation inhibition suppresses Th1/Th17 differentiation.","method":"TIGIT knockout mouse model (EAM), CD4+ T cell differentiation assays, metabolic measurements, histone acetylation analysis, TIGIT overexpression rescue experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, overexpression rescue, metabolic-epigenetic mechanism defined with multiple orthogonal methods","pmids":["40374622"],"is_preprint":false},{"year":2023,"finding":"TIGIT mediates activation-induced cell death (AICD) of ILC2s during chronic airway allergy; CD155 expressed on macrophages enhances cell death in TIGIT+ ILC2s via TIGIT engagement; genetic ablation of Tigit or anti-TIGIT antagonistic antibodies promote ILC2 survival and worsen chronic allergic inflammation.","method":"TIGIT lineage tracer mice, Tigit genetic ablation, anti-TIGIT antibody blockade, chromatin accessibility analysis, co-culture with macrophages","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — lineage tracing, genetic KO, antibody blockade, cell-cell interaction mechanism, multiple orthogonal methods","pmids":["37036426"],"is_preprint":false},{"year":2022,"finding":"TIGIT blockade in AML shifts polarization of TIGIT+ M2 leukemia-associated macrophages toward the M1 phenotype, increases secretion of M1-associated cytokines, and augments anti-CD47-mediated phagocytosis of AML cells in vitro.","method":"Anti-TIGIT antibody blockade of primary LAMs and monocyte-derived M2 macrophages in vitro, cytokine profiling, phagocytosis assays","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional macrophage assays with blocking antibody, single lab, primary human cells","pmids":["36549780"],"is_preprint":false},{"year":2024,"finding":"CD155 on CTCs (circulating tumor cells) inhibits NK-cell cytotoxicity specifically through engagement with TIGIT (but not CD96 or DNAM-1/CD226); platelet adhesion to CTCs upregulates CD155 transcriptionally via the FAK/JNK/c-Jun cascade, and TIGIT antibody blockade restores NK-cell immunosurveillance on CTCs.","method":"Competition assays, cytotoxicity experiments with receptor-specific antibodies, FAK/JNK/c-Jun pathway western blotting, in vivo metastasis models","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — receptor-specific competition assays definitively identifying TIGIT (not CD96/DNAM1), signaling pathway characterization, in vivo validation","pmids":["38779918"],"is_preprint":false},{"year":2022,"finding":"TIGIT expression on B cells suppresses proliferation of IL-17-producing circulating follicular helper T cells (cTfh) via the TIGIT/CD155 axis; impaired TIGIT expression on MS-derived B cells (mediated by dysregulation of TCF4) leads to expansion of activated cTfh cells in multiple sclerosis.","method":"Co-culture of TIGIT+ B cells with CD155-expressing cTfh cells, TIGIT/CD155 axis blockade, TCF4 transcription factor analysis, flow cytometry","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional co-culture assays with axis blockade, transcription factor identified, single lab","pmids":["36250467"],"is_preprint":false},{"year":2023,"finding":"TIGIT-KO mice are significantly protected from ischemic and nephrotoxic AKI; TIGIT-expressing kidney T cells have effector/central memory phenotype and proinflammatory profile; scRNA-seq analysis shows enrichment of oxidative phosphorylation and mTORC1 signaling genes in Th17 cells from TIGIT-KO mice.","method":"TIGIT knockout mice in ischemia reperfusion and cisplatin AKI models, RNA-Seq, flow cytometry, scRNA-seq","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic KO with two injury models, single lab, scRNA-seq identifies downstream targets","pmids":["36747315"],"is_preprint":false},{"year":2022,"finding":"CD226 signals promote the early phase of human Tfh cell differentiation by driving proliferation of naive CD4+ T cells and Tfh precursors, while TIGIT (highly expressed on germinal center Tfh cells) attenuates CD226 signals post-GC Tfh maturation; blocking CD226 inhibits proliferation and Tfh marker expression at early stages but increases CXCR5, ICOS, and IL-21 in mature GC-Tfh.","method":"Artificial APC culture system with CD155, CD226 blocking antibody, flow cytometry for Tfh markers, cytokine measurement","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional co-culture assays with defined blocking, single lab, stage-dependent mechanistic finding","pmids":["35273617"],"is_preprint":false},{"year":2020,"finding":"TIGIT modulation alters the phenotype and cytokine profile of T cells during influenza and chronic LCMV infection and induces IL-10 expression, limiting immune pathology in peripheral organs; however, TIGIT does not affect virus control in vivo.","method":"TIGIT modulation in influenza and chronic LCMV mouse models, cytokine profiling, organ pathology assessment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — two distinct viral infection models, IL-10 mechanism identified, virus control specifically tested as negative (non-effect), multiple orthogonal readouts","pmids":["32152316"],"is_preprint":false},{"year":2018,"finding":"MEG3 (lncRNA) modulates TIGIT expression in CD4+ T cells by sponging miR-23a; MEG3 overexpression sequesters miR-23a, increasing TIGIT expression, which in turn suppresses Th1/Th17 differentiation and reduces IFN-γ and TNF-α in a mouse model of aplastic anemia.","method":"MEG3 overexpression, miR-23a sponging assay, TIGIT expression measurement, mouse aplastic anemia model","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — miRNA sponge mechanism demonstrated with overexpression and functional T cell assays, single lab","pmids":["30382432"],"is_preprint":false}],"current_model":"TIGIT is an inhibitory immune checkpoint receptor expressed on T cells, NK cells, and Tregs that suppresses immune responses through multiple mechanisms: (1) cell-intrinsic signaling via its ITT-like intracellular motif (recruiting SHIP-1, inhibiting NF-κB/ERK, forming inhibitory nanoclusters at the immune synapse upon CD155 ligation); (2) competition with the activating receptor CD226 for shared ligands CD155/CD112 and disruption of CD226 dimerization in cis; (3) engagement by bacterial Fap2 protein to mediate tumor immune evasion; (4) regulation of NK cell education via CD155-dependent functional maturation; and (5) control of ILC2 survival by inducing activation-induced cell death upon CD155 engagement, with TIGIT deficiency driving T cell-mediated pathology through a metabolic-epigenetic (PI3K/AKT/mTOR → histone acetylation) mechanism."},"narrative":{"mechanistic_narrative":"TIGIT (VSTM3) is a CD28-family inhibitory immune checkpoint receptor that restrains T cell, NK cell, and innate lymphoid responses by competing with the activating receptor CD226 for the shared nectin ligands CD155 and CD112, forming a CD28/CTLA-4-like regulatory network in which soluble TIGIT attenuates T cell responses and TIGIT-deficient animals become more susceptible to autoimmunity [PMID:21416464]. TIGIT engages CD226 in cis to disrupt CD226 dimerization and co-stimulation, but it also signals cell-intrinsically: upon CD155 ligation it reorganizes into dense nanoclusters that coalesce with TCR clusters at the immune synapse and, through its phosphorylated ITT-like motif, recruits SHIP-1 to inhibit NF-κB and ERK activation and suppress cytokine secretion independently of CD226 [PMID:25465800, PMID:37596248, PMID:35729552]. This receptor binds multiple nectin-family ligands beyond CD155, including nectin-4 with weaker affinity, all converging on inhibition of lymphocyte cytotoxicity [PMID:37542773]. In NK cells TIGIT acts as a distinct checkpoint whose blockade reverses exhaustion and enhances tumor immunity and ADCC-driven responses, while also contributing to NK cell education through CD155-dependent functional maturation [PMID:29915296, PMID:28438433, PMID:28623459]. Beyond cytotoxic effectors, TIGIT controls CD4+ T cell fate by limiting CD28-driven PI3K/AKT/mTOR co-stimulation, glucose oxidation, and acetyl-CoA-dependent histone acetylation, thereby restraining Th1/Th17 differentiation [PMID:40374622], and it triggers activation-induced cell death of ILC2s upon CD155 engagement to limit allergic inflammation [PMID:37036426]. TIGIT is also exploited for immune evasion: the Fusobacterium nucleatum Fap2 protein directly binds human TIGIT to suppress NK and T cell activity in tumors [PMID:25680274].","teleology":[{"year":2011,"claim":"Established TIGIT as an inhibitory CD28-family receptor by defining its ligands and demonstrating that its loss enhances autoimmune susceptibility, placing it in a CD28/CTLA-4-like regulatory network.","evidence":"Ligand binding assays, soluble protein treatment, and VSTM3 knockout mice under autoimmune challenge","pmids":["21416464"],"confidence":"High","gaps":["Did not define the intracellular signaling mechanism","Cis vs trans ligand engagement not distinguished"]},{"year":2014,"claim":"Showed that TIGIT inhibits T cells not only by ligand competition but by physically disrupting CD226 dimerization in cis, and that combined TIGIT/PD-L1 blockade synergistically restores CD8+ effector function.","evidence":"Co-IP for cis interaction, CD226 dimerization assays, and in vivo tumor and chronic viral infection blockade models","pmids":["25465800"],"confidence":"High","gaps":["Relative contribution of cis-disruption versus cell-intrinsic signaling not resolved","Did not address contexts where CD226 is absent"]},{"year":2015,"claim":"Revealed a pathogen-driven immune evasion route by showing Fusobacterium nucleatum Fap2 directly engages human TIGIT to suppress NK and T cell antitumor activity.","evidence":"F. nucleatum mutant library screen, direct protein interaction assay, and NK cytotoxicity assays","pmids":["25680274"],"confidence":"High","gaps":["Fap2 does not bind mouse TIGIT, limiting in vivo modeling","Downstream signaling triggered by Fap2 not mapped"]},{"year":2017,"claim":"Demonstrated that TIGIT contributes to NK cell education and missing-self recognition via CD155, defining a developmental role distinct from MHC-I and CD226 pathways, and that TIGIT is induced on activated CD16+ NK cells.","evidence":"CD155-deficient mouse models, NK education and missing-self recognition assays, and ADCC blockade experiments","pmids":["28438433","28623459"],"confidence":"High","gaps":["Molecular signaling underlying education not defined","How TIGIT discriminates education versus inhibition unresolved"]},{"year":2018,"claim":"Identified TIGIT as a checkpoint in NK cells distinct from PD-1 and CTLA-4 whose blockade prevents NK exhaustion and enhances anti-PD-L1 therapy.","evidence":"TIGIT blockade in multiple tumor models with NK depletion controls and exhaustion marker analysis","pmids":["29915296"],"confidence":"High","gaps":["Intracellular signaling driving NK exhaustion not detailed","Translation to human NK cells not directly tested here"]},{"year":2020,"claim":"Showed TIGIT limits immunopathology by inducing IL-10 and modulating T cell cytokine profiles during viral infection without affecting virus control, separating its tolerogenic role from antiviral clearance.","evidence":"TIGIT modulation in influenza and chronic LCMV mouse models with cytokine and organ pathology readouts","pmids":["32152316"],"confidence":"High","gaps":["Cellular source and induction mechanism of IL-10 not fully resolved","Whether IL-10 mediates protection causally not isolated"]},{"year":2022,"claim":"Defined the cell-intrinsic inhibitory signaling axis by showing CD155-engaged, phosphorylated TIGIT recruits SHIP-1 to suppress NF-κB and ERK and reduce cytokine output in CD8+ T cells.","evidence":"Western blotting of NF-κB/ERK components and TIGIT blockade in activated CD8+ T cells with in vivo validation","pmids":["35729552"],"confidence":"Medium","gaps":["Direct physical SHIP-1 recruitment to the ITT motif not structurally demonstrated","Single-lab finding with limited mechanistic depth"]},{"year":2022,"claim":"Provided structural and affinity definition of the TIGIT-PVR interface via an anti-TIGIT antibody, linking interface blockade to enhanced NK killing and reduced Treg suppression.","evidence":"Crystal structure of MG1131 scFv-TIGIT complex, SPR affinity, and NK/Treg functional assays","pmids":["35090381"],"confidence":"High","gaps":["Structure of native TIGIT-ligand engagement at the synapse not captured","In vivo efficacy of the antibody not reported here"]},{"year":2023,"claim":"Established that TIGIT signals cell-intrinsically through ITT-motif-dependent nanocluster formation at the immune synapse to inhibit cytokine secretion independently of CD226, likely the dominant mechanism in tumors where CD226 co-expression is rare.","evidence":"Super-resolution microscopy, ITT-motif mutagenesis, and matched tumor/blood lymphocyte cytokine analysis","pmids":["37596248"],"confidence":"High","gaps":["Proximal kinases phosphorylating the ITT motif not all defined","Quantitative balance between cis-CD226 and intrinsic signaling in vivo unresolved"]},{"year":2023,"claim":"Broadened the TIGIT ligand repertoire by demonstrating recognition of the membrane-distal nectin-4 ectodomain, a weaker interaction than nectin-2 that still inhibits NK cytotoxicity.","evidence":"SPR biophysics, structure-guided mutagenesis of the binding interface, and NK cytotoxicity assays","pmids":["37542773"],"confidence":"High","gaps":["Physiological contexts where nectin-4 engagement dominates not defined","In vivo relevance of the weak interaction untested"]},{"year":2023,"claim":"Defined a metabolic-epigenetic mechanism by which TIGIT restrains CD4+ T cell pathology, limiting CD28-driven PI3K/AKT/mTOR signaling, glucose oxidation, acetyl-CoA production, and histone-acetylation-dependent Th1/Th17 differentiation.","evidence":"TIGIT knockout EAM mice, T cell differentiation and metabolic assays, histone acetylation analysis, and overexpression rescue","pmids":["40374622"],"confidence":"High","gaps":["Direct link between TIGIT signaling and the metabolic switch not fully traced","Which histone marks and loci are reprogrammed not exhaustively mapped"]},{"year":2023,"claim":"Revealed a pro-apoptotic role for TIGIT in innate lymphocytes, showing CD155 on macrophages drives activation-induced cell death of TIGIT+ ILC2s to limit chronic allergic inflammation.","evidence":"TIGIT lineage-tracer and knockout mice, anti-TIGIT blockade, macrophage co-culture, and chromatin accessibility analysis","pmids":["37036426"],"confidence":"High","gaps":["Signaling pathway from TIGIT to AICD not delineated","Whether this AICD mechanism operates in other lymphocyte lineages unknown"]},{"year":2024,"claim":"Showed that TIGIT, but not CD96 or CD226, mediates CD155-dependent suppression of NK surveillance of circulating tumor cells, with platelet-induced CD155 upregulation via FAK/JNK/c-Jun.","evidence":"Receptor-specific competition and cytotoxicity assays, pathway western blotting, and in vivo metastasis models","pmids":["38779918"],"confidence":"High","gaps":["Receptor selectivity mechanism over CD96 not explained","Contribution to metastasis in patients not established"]},{"year":2023,"claim":"Extended TIGIT function beyond classical lymphocytes by implicating it in B cell suppression of Tfh cells, macrophage polarization, and renal injury, broadening its cellular reach.","evidence":"B cell/cTfh co-culture with axis blockade and TCF4 analysis, anti-TIGIT macrophage repolarization and phagocytosis assays, and TIGIT-knockout AKI mouse models with scRNA-seq","pmids":["36250467","36549780","36747315"],"confidence":"Medium","gaps":["Cell-intrinsic versus extrinsic effects in non-T/NK lineages not fully separated","Single-lab findings for each context"]},{"year":2018,"claim":"Identified an upstream regulatory layer controlling TIGIT abundance, showing the lncRNA MEG3 sponges miR-23a to raise TIGIT expression and suppress Th1/Th17 differentiation.","evidence":"MEG3 overexpression, miR-23a sponging assay, and TIGIT expression measurement in an aplastic anemia mouse model","pmids":["30382432"],"confidence":"Medium","gaps":["Direct miR-23a binding to TIGIT transcript not confirmed","Single-lab finding in one disease model"]},{"year":null,"claim":"How TIGIT integrates its multiple modes of action — cis-CD226 disruption, ITT/SHIP-1 intrinsic signaling, ligand-specific affinities, and metabolic-epigenetic control — into a quantitative hierarchy across cell types and disease contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model weighting cis versus intrinsic signaling in vivo","Proximal kinase(s) for the ITT motif not fully defined","Ligand-selectivity rules across the nectin family incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,4,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,4,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5]}],"complexes":[],"partners":["CD155","CD112","CD226","SHIP-1","FAP2","NECTIN-4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q495A1","full_name":"T-cell immunoreceptor with Ig and ITIM domains","aliases":["V-set and immunoglobulin domain-containing protein 9","V-set and transmembrane domain-containing protein 3"],"length_aa":244,"mass_kda":26.3,"function":"Inhibitory receptor that plays a role in the modulation of immune responses. Suppresses T-cell activation by promoting the generation of mature immunoregulatory dendritic cells (PubMed:19011627). Upon binding to its ligands PVR/CD155 or NECTIN2/CD112, which are expressed on antigen-presenting cells, sends inhibitory signals to the T-cell or NK cell. Mechanistically, interaction with ligand leads to phosphorylation of the cytoplasmic tail by Src family tyrosine kinases such as FYN or LCK, allowing subsequent binding to adapter GRB2 and SHIP1/INPP5D. In turn, inhibits PI3K and MAPK signaling cascades (PubMed:23154388). In addition, associates with beta-arrestin-2/ARRB2 to recruit SHIP1/INPP5D that suppresses autoubiquitination of TRAF6 and subsequently inhibits NF-kappa-B signaling pathway (PubMed:24817116). Also acts as a receptor for NECTIN4 to inhibit NK cell cytotoxicity (PubMed:32503945)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q495A1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TIGIT","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/TIGIT","total_profiled":1310},"omim":[{"mim_id":"612859","title":"T-CELL IMMUNORECEPTOR WITH IMMUNOGLOBULIN AND ITIM DOMAINS; TIGIT","url":"https://www.omim.org/entry/612859"},{"mim_id":"606863","title":"THYMOCYTE SELECTION-ASSOCIATED HIGH MOBILITY GROUP BOX; TOX","url":"https://www.omim.org/entry/606863"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":36.1}],"url":"https://www.proteinatlas.org/search/TIGIT"},"hgnc":{"alias_symbol":["FLJ39873","DKFZp667A205"],"prev_symbol":["VSIG9","VSTM3"]},"alphafold":{"accession":"Q495A1","domains":[{"cath_id":"2.60.40.10","chopping":"27-128","consensus_level":"high","plddt":96.8675,"start":27,"end":128},{"cath_id":"1.20.5","chopping":"134-181","consensus_level":"high","plddt":76.4206,"start":134,"end":181}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q495A1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q495A1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q495A1-F1-predicted_aligned_error_v6.png","plddt_mean":74.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TIGIT","jax_strain_url":"https://www.jax.org/strain/search?query=TIGIT"},"sequence":{"accession":"Q495A1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q495A1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q495A1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q495A1"}},"corpus_meta":[{"pmid":"27192565","id":"PMC_27192565","title":"Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation.","date":"2016","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/27192565","citation_count":1722,"is_preprint":false},{"pmid":"25680274","id":"PMC_25680274","title":"Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack.","date":"2015","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/25680274","citation_count":1148,"is_preprint":false},{"pmid":"25465800","id":"PMC_25465800","title":"The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function.","date":"2014","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/25465800","citation_count":982,"is_preprint":false},{"pmid":"29915296","id":"PMC_29915296","title":"Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity.","date":"2018","source":"Nature 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deficiency promotes autoreactive CD4+ T-cell responses through a metabolic‒epigenetic mechanism in autoimmune myositis.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40374622","citation_count":12,"is_preprint":false},{"pmid":"37359558","id":"PMC_37359558","title":"Self-delivery of TIGIT-blocking scFv enhances CAR-T immunotherapy in solid tumors.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37359558","citation_count":12,"is_preprint":false},{"pmid":"35413989","id":"PMC_35413989","title":"Increased expression of TIGIT and KLRG1 correlates with impaired CD56bright NK cell immunity in HPV16-related cervical intraepithelial neoplasia.","date":"2022","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/35413989","citation_count":12,"is_preprint":false},{"pmid":"38666504","id":"PMC_38666504","title":"CD155-TIGIT Axis as a Therapeutic Target for Cancer Immunotherapy.","date":"2024","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38666504","citation_count":11,"is_preprint":false},{"pmid":"37129788","id":"PMC_37129788","title":"Peptide-based PET imaging agent of tumor TIGIT expression.","date":"2023","source":"EJNMMI research","url":"https://pubmed.ncbi.nlm.nih.gov/37129788","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47322,"output_tokens":4841,"usd":0.10729,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13270,"output_tokens":4824,"usd":0.093475,"stage2_stop_reason":"end_turn"},"total_usd":0.200765,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"The Fap2 protein of Fusobacterium nucleatum directly binds human TIGIT (but not mouse TIGIT), leading to inhibition of NK cell cytotoxicity and T cell activity, identifying a bacterium-dependent tumor immune evasion mechanism via TIGIT.\",\n      \"method\": \"F. nucleatum mutant library screen, direct protein interaction assay, NK cell cytotoxicity assay\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction mapped with mutant library, functional NK/T cell readouts, replicated across multiple F. nucleatum strains\",\n      \"pmids\": [\"25680274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TIGIT directly interacts with CD226 (DNAM-1) in cis on T cells, disrupting CD226 dimerization and thereby inhibiting CD226-mediated co-stimulation; antibody co-blockade of TIGIT and PD-L1 synergistically enhances CD8+ T cell effector function in tumor and chronic viral infection models.\",\n      \"method\": \"Co-IP for cis interaction, antibody blockade in vivo tumor and viral infection models, CD226 dimerization assay\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction demonstrated, multiple orthogonal methods (co-IP, in vivo models), replicated across cancer and viral infection contexts\",\n      \"pmids\": [\"25465800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TIGIT is expressed on NK cells and its blockade prevents NK cell exhaustion, promotes NK cell-dependent tumor immunity, and enhances anti-PD-L1 therapy; TIGIT constitutes a checkpoint in NK cells distinct from CTLA-4 and PD-1.\",\n      \"method\": \"TIGIT blockade antibody in tumor-bearing mouse models, flow cytometry for NK exhaustion markers, in vivo tumor rechallenge\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple tumor models, NK cell depletion experiments to confirm NK-dependence, replicated functional readouts\",\n      \"pmids\": [\"29915296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"VSTM3/TIGIT is a CD28 family member whose ligands are CD155 and CD112 (also ligands for activating receptor CD226), forming a regulatory network analogous to CD28/CTLA-4/CD80/CD86; soluble VSTM3 attenuates T cell responses in vitro and in vivo, and VSTM3-deficient mice are more susceptible to autoimmune challenges.\",\n      \"method\": \"Ligand binding assays, soluble protein treatment in vitro and in vivo, VSTM3 knockout mice with autoimmune challenge\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO phenotype, soluble protein functional assays, ligand binding characterization, multiple orthogonal methods\",\n      \"pmids\": [\"21416464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TIGIT ligation by CD155 causes TIGIT to reorganize into dense nanoclusters at immune synapses that coalesce with TCR-rich clusters; this directly inhibits T cell cytokine secretion via TIGIT's intracellular ITT-like signalling motif, independently of CD226 co-inhibition. TIGIT and CD226 co-expression is rare on tumor-infiltrating lymphocytes, making this cell-intrinsic signalling mechanism likely dominant in tumors.\",\n      \"method\": \"Super-resolution microscopy, matched tumor/blood lymphocyte analysis, ITT-motif mutagenesis, cytokine secretion assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — super-resolution structure, ITT-motif mutagenesis confirming signalling requirement, multiple orthogonal methods in single study\",\n      \"pmids\": [\"37596248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TIGIT, upon binding to CD155 and being phosphorylated, inhibits NF-κB and ERK activation by recruiting SHIP-1, resulting in downregulation of cytokine production in CD8+ T cells; blocking TIGIT attenuates SHIP-1 inhibitory effect and restores NF-κB and ERK activation.\",\n      \"method\": \"Western blotting for NF-κB and ERK pathway components, TIGIT blockade in activated CD8+ T cells, in vivo antibody blockade\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined signaling pathway with western blot and in vivo validation, single lab, limited mechanistic depth on direct SHIP-1 recruitment\",\n      \"pmids\": [\"35729552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TIGIT engagement by CD155 on NK cells contributes to NK cell education/functional maturation: TIGIT+ NK cells from CD155-deficient hosts show functional impairment, and TIGIT deficiency impairs NK cell-mediated missing-self recognition and rejection of CD155-negative targets in an MHC-I-independent and CD226-unrelated manner.\",\n      \"method\": \"TIGIT+ NK cell isolation, CD155-deficient mouse model, NK cell education assays, missing-self recognition assays\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse models (CD155 KO, TIGIT assessment), multiple functional readouts, mechanism separated from MHC-I pathway\",\n      \"pmids\": [\"28438433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"All PVR-like receptors are expressed on human NK cells, with TIGIT preferentially expressed on the CD16+ NK cell subset; TIGIT is upregulated upon NK cell activation via ADCC, and blockade of TIGIT or CD112R (separately or together) enhances trastuzumab-triggered antitumor NK cell responses.\",\n      \"method\": \"Flow cytometry for receptor expression, ADCC assays, antibody blockade of TIGIT and CD112R\",\n      \"journal\": \"Cancer immunology, immunotherapy : CII\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional NK cell assays, single lab, demonstrates subset-specific expression and functional blockade\",\n      \"pmids\": [\"28623459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structure of anti-TIGIT monoclonal antibody MG1131 (scFv version) bound to TIGIT reveals the PVR-binding interface; MG1131 binds TIGIT more tightly than PVR and blocks the PVR-TIGIT interaction, inhibiting immunosuppressive signaling, enhancing NK cell tumor killing, and inhibiting Treg suppressive activity.\",\n      \"method\": \"Crystal structure determination, SPR binding assays, NK cell cytotoxicity assays, Treg functional assays\",\n      \"journal\": \"mAbs\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation, SPR affinity measurements, multiple cell-based functional assays\",\n      \"pmids\": [\"35090381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Biophysical experiments demonstrate TIGIT recognizes the membrane-distal ectodomain of nectin-4; structure-guided mutagenesis maps the nectin-4 binding interface on TIGIT; the TIGIT:nectin-4 interaction is weaker than the well-characterized TIGIT:nectin-2 interaction and inhibits NK cell cytotoxicity.\",\n      \"method\": \"Surface plasmon resonance, structure-guided mutagenesis, NK cell cytotoxicity assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SPR binding measurement, mutagenesis mapping of binding interface, functional NK assay confirming inhibitory consequence\",\n      \"pmids\": [\"37542773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mouse TIGIT interacts with and is inhibited by mPVR only (not by other nectin ligands); TIGIT-deficient mice generated by CRISPR-Cas9 show enhanced NK cell cytotoxicity and degranulation against tumors in vitro and slower in vivo tumor progression compared to wild-type mice.\",\n      \"method\": \"CRISPR-Cas9 knockout mice, ligand interaction assays, NK cell cytotoxicity/degranulation assays, in vivo tumor growth models\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with CRISPR, multiple functional readouts, in vitro and in vivo validation\",\n      \"pmids\": [\"37261087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TIGIT deficiency in CD4+ T cells promotes their differentiation into Th1 and Th17 cells via enhanced CD28-mediated PI3K/AKT/mTOR co-stimulatory pathway, promoting glucose oxidation, citrate production, and increased cytosolic acetyl-CoA levels, leading to epigenetic reprogramming via histone acetylation; TIGIT overexpression rescues this phenotype, and pharmacological histone acetylation inhibition suppresses Th1/Th17 differentiation.\",\n      \"method\": \"TIGIT knockout mouse model (EAM), CD4+ T cell differentiation assays, metabolic measurements, histone acetylation analysis, TIGIT overexpression rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, overexpression rescue, metabolic-epigenetic mechanism defined with multiple orthogonal methods\",\n      \"pmids\": [\"40374622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TIGIT mediates activation-induced cell death (AICD) of ILC2s during chronic airway allergy; CD155 expressed on macrophages enhances cell death in TIGIT+ ILC2s via TIGIT engagement; genetic ablation of Tigit or anti-TIGIT antagonistic antibodies promote ILC2 survival and worsen chronic allergic inflammation.\",\n      \"method\": \"TIGIT lineage tracer mice, Tigit genetic ablation, anti-TIGIT antibody blockade, chromatin accessibility analysis, co-culture with macrophages\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — lineage tracing, genetic KO, antibody blockade, cell-cell interaction mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"37036426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TIGIT blockade in AML shifts polarization of TIGIT+ M2 leukemia-associated macrophages toward the M1 phenotype, increases secretion of M1-associated cytokines, and augments anti-CD47-mediated phagocytosis of AML cells in vitro.\",\n      \"method\": \"Anti-TIGIT antibody blockade of primary LAMs and monocyte-derived M2 macrophages in vitro, cytokine profiling, phagocytosis assays\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional macrophage assays with blocking antibody, single lab, primary human cells\",\n      \"pmids\": [\"36549780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD155 on CTCs (circulating tumor cells) inhibits NK-cell cytotoxicity specifically through engagement with TIGIT (but not CD96 or DNAM-1/CD226); platelet adhesion to CTCs upregulates CD155 transcriptionally via the FAK/JNK/c-Jun cascade, and TIGIT antibody blockade restores NK-cell immunosurveillance on CTCs.\",\n      \"method\": \"Competition assays, cytotoxicity experiments with receptor-specific antibodies, FAK/JNK/c-Jun pathway western blotting, in vivo metastasis models\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific competition assays definitively identifying TIGIT (not CD96/DNAM1), signaling pathway characterization, in vivo validation\",\n      \"pmids\": [\"38779918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TIGIT expression on B cells suppresses proliferation of IL-17-producing circulating follicular helper T cells (cTfh) via the TIGIT/CD155 axis; impaired TIGIT expression on MS-derived B cells (mediated by dysregulation of TCF4) leads to expansion of activated cTfh cells in multiple sclerosis.\",\n      \"method\": \"Co-culture of TIGIT+ B cells with CD155-expressing cTfh cells, TIGIT/CD155 axis blockade, TCF4 transcription factor analysis, flow cytometry\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional co-culture assays with axis blockade, transcription factor identified, single lab\",\n      \"pmids\": [\"36250467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TIGIT-KO mice are significantly protected from ischemic and nephrotoxic AKI; TIGIT-expressing kidney T cells have effector/central memory phenotype and proinflammatory profile; scRNA-seq analysis shows enrichment of oxidative phosphorylation and mTORC1 signaling genes in Th17 cells from TIGIT-KO mice.\",\n      \"method\": \"TIGIT knockout mice in ischemia reperfusion and cisplatin AKI models, RNA-Seq, flow cytometry, scRNA-seq\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic KO with two injury models, single lab, scRNA-seq identifies downstream targets\",\n      \"pmids\": [\"36747315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD226 signals promote the early phase of human Tfh cell differentiation by driving proliferation of naive CD4+ T cells and Tfh precursors, while TIGIT (highly expressed on germinal center Tfh cells) attenuates CD226 signals post-GC Tfh maturation; blocking CD226 inhibits proliferation and Tfh marker expression at early stages but increases CXCR5, ICOS, and IL-21 in mature GC-Tfh.\",\n      \"method\": \"Artificial APC culture system with CD155, CD226 blocking antibody, flow cytometry for Tfh markers, cytokine measurement\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional co-culture assays with defined blocking, single lab, stage-dependent mechanistic finding\",\n      \"pmids\": [\"35273617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TIGIT modulation alters the phenotype and cytokine profile of T cells during influenza and chronic LCMV infection and induces IL-10 expression, limiting immune pathology in peripheral organs; however, TIGIT does not affect virus control in vivo.\",\n      \"method\": \"TIGIT modulation in influenza and chronic LCMV mouse models, cytokine profiling, organ pathology assessment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two distinct viral infection models, IL-10 mechanism identified, virus control specifically tested as negative (non-effect), multiple orthogonal readouts\",\n      \"pmids\": [\"32152316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MEG3 (lncRNA) modulates TIGIT expression in CD4+ T cells by sponging miR-23a; MEG3 overexpression sequesters miR-23a, increasing TIGIT expression, which in turn suppresses Th1/Th17 differentiation and reduces IFN-γ and TNF-α in a mouse model of aplastic anemia.\",\n      \"method\": \"MEG3 overexpression, miR-23a sponging assay, TIGIT expression measurement, mouse aplastic anemia model\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — miRNA sponge mechanism demonstrated with overexpression and functional T cell assays, single lab\",\n      \"pmids\": [\"30382432\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TIGIT is an inhibitory immune checkpoint receptor expressed on T cells, NK cells, and Tregs that suppresses immune responses through multiple mechanisms: (1) cell-intrinsic signaling via its ITT-like intracellular motif (recruiting SHIP-1, inhibiting NF-κB/ERK, forming inhibitory nanoclusters at the immune synapse upon CD155 ligation); (2) competition with the activating receptor CD226 for shared ligands CD155/CD112 and disruption of CD226 dimerization in cis; (3) engagement by bacterial Fap2 protein to mediate tumor immune evasion; (4) regulation of NK cell education via CD155-dependent functional maturation; and (5) control of ILC2 survival by inducing activation-induced cell death upon CD155 engagement, with TIGIT deficiency driving T cell-mediated pathology through a metabolic-epigenetic (PI3K/AKT/mTOR → histone acetylation) mechanism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TIGIT (VSTM3) is a CD28-family inhibitory immune checkpoint receptor that restrains T cell, NK cell, and innate lymphoid responses by competing with the activating receptor CD226 for the shared nectin ligands CD155 and CD112, forming a CD28/CTLA-4-like regulatory network in which soluble TIGIT attenuates T cell responses and TIGIT-deficient animals become more susceptible to autoimmunity [#3]. TIGIT engages CD226 in cis to disrupt CD226 dimerization and co-stimulation, but it also signals cell-intrinsically: upon CD155 ligation it reorganizes into dense nanoclusters that coalesce with TCR clusters at the immune synapse and, through its phosphorylated ITT-like motif, recruits SHIP-1 to inhibit NF-\\u03baB and ERK activation and suppress cytokine secretion independently of CD226 [#1, #4, #5]. This receptor binds multiple nectin-family ligands beyond CD155, including nectin-4 with weaker affinity, all converging on inhibition of lymphocyte cytotoxicity [#9]. In NK cells TIGIT acts as a distinct checkpoint whose blockade reverses exhaustion and enhances tumor immunity and ADCC-driven responses, while also contributing to NK cell education through CD155-dependent functional maturation [#2, #6, #7]. Beyond cytotoxic effectors, TIGIT controls CD4+ T cell fate by limiting CD28-driven PI3K/AKT/mTOR co-stimulation, glucose oxidation, and acetyl-CoA-dependent histone acetylation, thereby restraining Th1/Th17 differentiation [#11], and it triggers activation-induced cell death of ILC2s upon CD155 engagement to limit allergic inflammation [#12]. TIGIT is also exploited for immune evasion: the Fusobacterium nucleatum Fap2 protein directly binds human TIGIT to suppress NK and T cell activity in tumors [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established TIGIT as an inhibitory CD28-family receptor by defining its ligands and demonstrating that its loss enhances autoimmune susceptibility, placing it in a CD28/CTLA-4-like regulatory network.\",\n      \"evidence\": \"Ligand binding assays, soluble protein treatment, and VSTM3 knockout mice under autoimmune challenge\",\n      \"pmids\": [\"21416464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the intracellular signaling mechanism\", \"Cis vs trans ligand engagement not distinguished\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed that TIGIT inhibits T cells not only by ligand competition but by physically disrupting CD226 dimerization in cis, and that combined TIGIT/PD-L1 blockade synergistically restores CD8+ effector function.\",\n      \"evidence\": \"Co-IP for cis interaction, CD226 dimerization assays, and in vivo tumor and chronic viral infection blockade models\",\n      \"pmids\": [\"25465800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of cis-disruption versus cell-intrinsic signaling not resolved\", \"Did not address contexts where CD226 is absent\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a pathogen-driven immune evasion route by showing Fusobacterium nucleatum Fap2 directly engages human TIGIT to suppress NK and T cell antitumor activity.\",\n      \"evidence\": \"F. nucleatum mutant library screen, direct protein interaction assay, and NK cytotoxicity assays\",\n      \"pmids\": [\"25680274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Fap2 does not bind mouse TIGIT, limiting in vivo modeling\", \"Downstream signaling triggered by Fap2 not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that TIGIT contributes to NK cell education and missing-self recognition via CD155, defining a developmental role distinct from MHC-I and CD226 pathways, and that TIGIT is induced on activated CD16+ NK cells.\",\n      \"evidence\": \"CD155-deficient mouse models, NK education and missing-self recognition assays, and ADCC blockade experiments\",\n      \"pmids\": [\"28438433\", \"28623459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular signaling underlying education not defined\", \"How TIGIT discriminates education versus inhibition unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified TIGIT as a checkpoint in NK cells distinct from PD-1 and CTLA-4 whose blockade prevents NK exhaustion and enhances anti-PD-L1 therapy.\",\n      \"evidence\": \"TIGIT blockade in multiple tumor models with NK depletion controls and exhaustion marker analysis\",\n      \"pmids\": [\"29915296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling driving NK exhaustion not detailed\", \"Translation to human NK cells not directly tested here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed TIGIT limits immunopathology by inducing IL-10 and modulating T cell cytokine profiles during viral infection without affecting virus control, separating its tolerogenic role from antiviral clearance.\",\n      \"evidence\": \"TIGIT modulation in influenza and chronic LCMV mouse models with cytokine and organ pathology readouts\",\n      \"pmids\": [\"32152316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular source and induction mechanism of IL-10 not fully resolved\", \"Whether IL-10 mediates protection causally not isolated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the cell-intrinsic inhibitory signaling axis by showing CD155-engaged, phosphorylated TIGIT recruits SHIP-1 to suppress NF-\\u03baB and ERK and reduce cytokine output in CD8+ T cells.\",\n      \"evidence\": \"Western blotting of NF-\\u03baB/ERK components and TIGIT blockade in activated CD8+ T cells with in vivo validation\",\n      \"pmids\": [\"35729552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical SHIP-1 recruitment to the ITT motif not structurally demonstrated\", \"Single-lab finding with limited mechanistic depth\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided structural and affinity definition of the TIGIT-PVR interface via an anti-TIGIT antibody, linking interface blockade to enhanced NK killing and reduced Treg suppression.\",\n      \"evidence\": \"Crystal structure of MG1131 scFv-TIGIT complex, SPR affinity, and NK/Treg functional assays\",\n      \"pmids\": [\"35090381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of native TIGIT-ligand engagement at the synapse not captured\", \"In vivo efficacy of the antibody not reported here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that TIGIT signals cell-intrinsically through ITT-motif-dependent nanocluster formation at the immune synapse to inhibit cytokine secretion independently of CD226, likely the dominant mechanism in tumors where CD226 co-expression is rare.\",\n      \"evidence\": \"Super-resolution microscopy, ITT-motif mutagenesis, and matched tumor/blood lymphocyte cytokine analysis\",\n      \"pmids\": [\"37596248\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Proximal kinases phosphorylating the ITT motif not all defined\", \"Quantitative balance between cis-CD226 and intrinsic signaling in vivo unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened the TIGIT ligand repertoire by demonstrating recognition of the membrane-distal nectin-4 ectodomain, a weaker interaction than nectin-2 that still inhibits NK cytotoxicity.\",\n      \"evidence\": \"SPR biophysics, structure-guided mutagenesis of the binding interface, and NK cytotoxicity assays\",\n      \"pmids\": [\"37542773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts where nectin-4 engagement dominates not defined\", \"In vivo relevance of the weak interaction untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a metabolic-epigenetic mechanism by which TIGIT restrains CD4+ T cell pathology, limiting CD28-driven PI3K/AKT/mTOR signaling, glucose oxidation, acetyl-CoA production, and histone-acetylation-dependent Th1/Th17 differentiation.\",\n      \"evidence\": \"TIGIT knockout EAM mice, T cell differentiation and metabolic assays, histone acetylation analysis, and overexpression rescue\",\n      \"pmids\": [\"40374622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link between TIGIT signaling and the metabolic switch not fully traced\", \"Which histone marks and loci are reprogrammed not exhaustively mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a pro-apoptotic role for TIGIT in innate lymphocytes, showing CD155 on macrophages drives activation-induced cell death of TIGIT+ ILC2s to limit chronic allergic inflammation.\",\n      \"evidence\": \"TIGIT lineage-tracer and knockout mice, anti-TIGIT blockade, macrophage co-culture, and chromatin accessibility analysis\",\n      \"pmids\": [\"37036426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway from TIGIT to AICD not delineated\", \"Whether this AICD mechanism operates in other lymphocyte lineages unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed that TIGIT, but not CD96 or CD226, mediates CD155-dependent suppression of NK surveillance of circulating tumor cells, with platelet-induced CD155 upregulation via FAK/JNK/c-Jun.\",\n      \"evidence\": \"Receptor-specific competition and cytotoxicity assays, pathway western blotting, and in vivo metastasis models\",\n      \"pmids\": [\"38779918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor selectivity mechanism over CD96 not explained\", \"Contribution to metastasis in patients not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended TIGIT function beyond classical lymphocytes by implicating it in B cell suppression of Tfh cells, macrophage polarization, and renal injury, broadening its cellular reach.\",\n      \"evidence\": \"B cell/cTfh co-culture with axis blockade and TCF4 analysis, anti-TIGIT macrophage repolarization and phagocytosis assays, and TIGIT-knockout AKI mouse models with scRNA-seq\",\n      \"pmids\": [\"36250467\", \"36549780\", \"36747315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-intrinsic versus extrinsic effects in non-T/NK lineages not fully separated\", \"Single-lab findings for each context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified an upstream regulatory layer controlling TIGIT abundance, showing the lncRNA MEG3 sponges miR-23a to raise TIGIT expression and suppress Th1/Th17 differentiation.\",\n      \"evidence\": \"MEG3 overexpression, miR-23a sponging assay, and TIGIT expression measurement in an aplastic anemia mouse model\",\n      \"pmids\": [\"30382432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct miR-23a binding to TIGIT transcript not confirmed\", \"Single-lab finding in one disease model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TIGIT integrates its multiple modes of action — cis-CD226 disruption, ITT/SHIP-1 intrinsic signaling, ligand-specific affinities, and metabolic-epigenetic control — into a quantitative hierarchy across cell types and disease contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model weighting cis versus intrinsic signaling in vivo\", \"Proximal kinase(s) for the ITT motif not fully defined\", \"Ligand-selectivity rules across the nectin family incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 4, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD155\", \"CD112\", \"CD226\", \"SHIP-1\", \"Fap2\", \"nectin-4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}