{"gene":"VSIG8","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2018,"finding":"VSIG-8 does NOT bind to VISTA under the same ELISA binding screening conditions where VSIG-3/IGSF11 was shown to bind VISTA; this is a negative result for VSIG-8/VISTA interaction in this assay.","method":"Functional ELISA binding screening assay","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with explicit negative result for VSIG-8, single lab but clear experimental conditions described","pmids":["30220083"],"is_preprint":false},{"year":2022,"finding":"VSIG-8 binds to VISTA with a Kd of 1.58 ± 0.44 μM; mutation of the VISTA binding site to alanine abolished the interaction; VSIG-8 protein decreased IL-2 levels in VISTA-overexpressing cells but increased IL-2 in VISTA-/- cells, establishing VSIG-8 as a functional ligand of VISTA that inhibits T cell function in a VISTA-dependent manner.","method":"ELISA, Microscale Thermophoresis (MST), co-immunoprecipitation (Co-IP), alanine-scanning mutagenesis of VISTA binding site, IL-2 cytokine assay in VISTA-overexpressing and VISTA-knockout cells","journal":"Investigational new drugs","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal binding methods (ELISA, MST, Co-IP), mutagenesis validation, functional cytokine readout in genetic perturbation models, single lab but rigorous multi-method approach","pmids":["35404016"],"is_preprint":false}],"current_model":"VSIG-8 is a ligand of the immune checkpoint receptor VISTA (Kd ~1.58 µM), binding it at a defined amino-acid interface, and this interaction suppresses T cell function (reducing IL-2 production) in a VISTA-dependent manner, placing VSIG-8 as the receptor-side partner in the VSIG-8/VISTA co-inhibitory pathway."},"narrative":{"mechanistic_narrative":"VSIG8 is a functional ligand of the immune checkpoint receptor VISTA that operates in a co-inhibitory pathway suppressing T cell function [PMID:35404016]. VSIG8 binds VISTA directly with a Kd of ~1.58 µM through a defined interface, since alanine substitution of the VISTA binding site abolishes the interaction [PMID:35404016]. Engagement is functionally consequential: VSIG8 protein lowers IL-2 production in VISTA-overexpressing cells but raises IL-2 in VISTA-deficient cells, establishing that its T cell-inhibitory effect is strictly VISTA-dependent [PMID:35404016]. An earlier ELISA screen did not detect VSIG8/VISTA binding under conditions where VSIG-3/IGSF11 bound VISTA, indicating the interaction is assay-sensitive [PMID:30220083]. Beyond this VISTA interaction, no further mechanistic detail for VSIG8 has been characterized in the available corpus.","teleology":[{"year":2018,"claim":"Testing whether VSIG8 was among the VISTA-binding partners, an ELISA screen returned a negative result, leaving the question of a VSIG8/VISTA interaction unresolved under those conditions.","evidence":"Functional ELISA binding screening assay comparing VSIG8 to VSIG-3/IGSF11 for VISTA binding","pmids":["30220083"],"confidence":"Medium","gaps":["Single assay format may miss low-affinity or conformation-dependent binding","No orthogonal binding method or genetic validation","Did not test functional consequences"]},{"year":2022,"claim":"Establishing VSIG8 as a bona fide VISTA ligand resolved the earlier ambiguity by demonstrating direct micromolar-affinity binding through a defined interface and a VISTA-dependent suppression of T cell IL-2 output.","evidence":"ELISA, MST, Co-IP, alanine-scanning mutagenesis of the VISTA binding site, and IL-2 cytokine assays in VISTA-overexpressing and VISTA-knockout cells","pmids":["35404016"],"confidence":"High","gaps":["Work performed in a single lab without independent replication","Structural model of the VSIG8/VISTA interface not determined","Directionality of signaling (which partner transduces the inhibitory signal) not dissected in primary T cells"]},{"year":null,"claim":"Whether VSIG8 engages additional receptors, its expression pattern across cell types, and its role in vivo remain unaddressed in the available corpus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No in vivo or disease-model evidence for VSIG8/VISTA axis","No structural determination of the binding interface","No characterization of VSIG8 expression or regulation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1]}],"localization":[],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1]}],"complexes":[],"partners":["VISTA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P0DPA2","full_name":"V-set and immunoglobulin domain-containing protein 8","aliases":[],"length_aa":414,"mass_kda":43.9,"function":"","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P0DPA2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VSIG8","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VSIG8","total_profiled":1310},"omim":[{"mim_id":"621098","title":"V-SET AND IMMUNOGLOBULIN DOMAINS-CONTAINING PROTEIN 8; VSIG8","url":"https://www.omim.org/entry/621098"},{"mim_id":"615608","title":"V-SET IMMUNOREGULATORY RECEPTOR; VSIR","url":"https://www.omim.org/entry/615608"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":6.1},{"tissue":"skin 1","ntpm":23.6}],"url":"https://www.proteinatlas.org/search/VSIG8"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P0DPA2","domains":[{"cath_id":"2.60.40.10","chopping":"23-144","consensus_level":"high","plddt":88.8955,"start":23,"end":144},{"cath_id":"2.60.40.10","chopping":"150-193_217-255","consensus_level":"high","plddt":83.8719,"start":150,"end":255}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P0DPA2","model_url":"https://alphafold.ebi.ac.uk/files/AF-P0DPA2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P0DPA2-F1-predicted_aligned_error_v6.png","plddt_mean":69.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VSIG8","jax_strain_url":"https://www.jax.org/strain/search?query=VSIG8"},"sequence":{"accession":"P0DPA2","fasta_url":"https://rest.uniprot.org/uniprotkb/P0DPA2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P0DPA2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P0DPA2"}},"corpus_meta":[{"pmid":"30220083","id":"PMC_30220083","title":"VSIG-3 as a ligand of VISTA inhibits human T-cell function.","date":"2018","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30220083","citation_count":228,"is_preprint":false},{"pmid":"26959817","id":"PMC_26959817","title":"Comparative Transcriptome Analysis of Fetal Skin Reveals Key Genes Related to Hair Follicle Morphogenesis in Cashmere Goats.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26959817","citation_count":86,"is_preprint":false},{"pmid":"35404016","id":"PMC_35404016","title":"A small molecule inhibitor of VSIG-8 prevents its binding to VISTA.","date":"2022","source":"Investigational new drugs","url":"https://pubmed.ncbi.nlm.nih.gov/35404016","citation_count":26,"is_preprint":false},{"pmid":"37922010","id":"PMC_37922010","title":"Identification of genetic profile and biomarkers involved in acute respiratory distress syndrome.","date":"2023","source":"Intensive care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37922010","citation_count":21,"is_preprint":false},{"pmid":"39123357","id":"PMC_39123357","title":"VISTA Emerges as a Promising Target against Immune Evasion Mechanisms in Medulloblastoma.","date":"2024","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/39123357","citation_count":6,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5041,"output_tokens":607,"usd":0.012114,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6957,"output_tokens":1229,"usd":0.032755,"stage2_stop_reason":"end_turn"},"total_usd":0.044869,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"VSIG-8 does NOT bind to VISTA under the same ELISA binding screening conditions where VSIG-3/IGSF11 was shown to bind VISTA; this is a negative result for VSIG-8/VISTA interaction in this assay.\",\n      \"method\": \"Functional ELISA binding screening assay\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with explicit negative result for VSIG-8, single lab but clear experimental conditions described\",\n      \"pmids\": [\"30220083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VSIG-8 binds to VISTA with a Kd of 1.58 ± 0.44 μM; mutation of the VISTA binding site to alanine abolished the interaction; VSIG-8 protein decreased IL-2 levels in VISTA-overexpressing cells but increased IL-2 in VISTA-/- cells, establishing VSIG-8 as a functional ligand of VISTA that inhibits T cell function in a VISTA-dependent manner.\",\n      \"method\": \"ELISA, Microscale Thermophoresis (MST), co-immunoprecipitation (Co-IP), alanine-scanning mutagenesis of VISTA binding site, IL-2 cytokine assay in VISTA-overexpressing and VISTA-knockout cells\",\n      \"journal\": \"Investigational new drugs\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal binding methods (ELISA, MST, Co-IP), mutagenesis validation, functional cytokine readout in genetic perturbation models, single lab but rigorous multi-method approach\",\n      \"pmids\": [\"35404016\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VSIG-8 is a ligand of the immune checkpoint receptor VISTA (Kd ~1.58 µM), binding it at a defined amino-acid interface, and this interaction suppresses T cell function (reducing IL-2 production) in a VISTA-dependent manner, placing VSIG-8 as the receptor-side partner in the VSIG-8/VISTA co-inhibitory pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VSIG8 is a functional ligand of the immune checkpoint receptor VISTA that operates in a co-inhibitory pathway suppressing T cell function [#1]. VSIG8 binds VISTA directly with a Kd of ~1.58 µM through a defined interface, since alanine substitution of the VISTA binding site abolishes the interaction [#1]. Engagement is functionally consequential: VSIG8 protein lowers IL-2 production in VISTA-overexpressing cells but raises IL-2 in VISTA-deficient cells, establishing that its T cell-inhibitory effect is strictly VISTA-dependent [#1]. An earlier ELISA screen did not detect VSIG8/VISTA binding under conditions where VSIG-3/IGSF11 bound VISTA, indicating the interaction is assay-sensitive [#0]. Beyond this VISTA interaction, no further mechanistic detail for VSIG8 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Testing whether VSIG8 was among the VISTA-binding partners, an ELISA screen returned a negative result, leaving the question of a VSIG8/VISTA interaction unresolved under those conditions.\",\n      \"evidence\": \"Functional ELISA binding screening assay comparing VSIG8 to VSIG-3/IGSF11 for VISTA binding\",\n      \"pmids\": [\"30220083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single assay format may miss low-affinity or conformation-dependent binding\",\n        \"No orthogonal binding method or genetic validation\",\n        \"Did not test functional consequences\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Establishing VSIG8 as a bona fide VISTA ligand resolved the earlier ambiguity by demonstrating direct micromolar-affinity binding through a defined interface and a VISTA-dependent suppression of T cell IL-2 output.\",\n      \"evidence\": \"ELISA, MST, Co-IP, alanine-scanning mutagenesis of the VISTA binding site, and IL-2 cytokine assays in VISTA-overexpressing and VISTA-knockout cells\",\n      \"pmids\": [\"35404016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Work performed in a single lab without independent replication\",\n        \"Structural model of the VSIG8/VISTA interface not determined\",\n        \"Directionality of signaling (which partner transduces the inhibitory signal) not dissected in primary T cells\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether VSIG8 engages additional receptors, its expression pattern across cell types, and its role in vivo remain unaddressed in the available corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No in vivo or disease-model evidence for VSIG8/VISTA axis\",\n        \"No structural determination of the binding interface\",\n        \"No characterization of VSIG8 expression or regulation\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VISTA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":4,"faith_pct":75.0}}