{"gene":"VSIR","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2019,"finding":"VISTA binds to PSGL-1 selectively at acidic pH (as found in tumor microenvironments), mediated by multiple histidine residues along the rim of the VISTA extracellular domain. Antibodies engineered to block this interaction specifically at acidic pH reversed VISTA-mediated immune suppression in vivo.","method":"Binding assays, mutagenesis of histidine residues, pH-selective antibody engineering, in vivo tumor models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of active-site residues combined with in vivo functional validation; replicated structurally in subsequent structural paper (PMID:31919279)","pmids":["31645726"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of human PD-1H (VISTA) extracellular domain at 1.9 Å resolution reveals an elongated CC' loop, a striking concentration of surface-exposed histidine clusters in the CDR-like proximal region, a noncanonical IgV-like topology with an extra 'H' β-strand and a 'clamping' disulfide absent in known IgV-like structures. Surface-exposed histidine clusters are essential for robust inhibition of T cell activation, as shown by mutagenesis.","method":"X-ray crystallography (1.9 Å), site-directed mutagenesis, T cell activation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus functional mutagenesis in one rigorous study","pmids":["31919279"],"is_preprint":false},{"year":2018,"finding":"VSIG-3/IGSF11 is a binding ligand for VISTA; VSIG-3 binds VISTA (but not other B7 family members) and inhibits human T cell proliferation and cytokine production (IFN-γ, IL-2, IL-17, CCL5, CCL3, CXCL11). Anti-VISTA neutralizing antibodies block the VSIG-3/VISTA interaction and reverse VSIG-3-induced T cell inhibition.","method":"Functional ELISA binding screening, T cell proliferation assays, cytokine production assays, neutralizing antibody blockade","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays in single lab; binding confirmed by ELISA with specificity controls","pmids":["30220083"],"is_preprint":false},{"year":2021,"finding":"Crystal structure of the VSIG3 extracellular domain at 2.64 Å resolution determined; VISTA–VSIG3 protein–protein interaction confirmed by Co-IP. Protein–protein docking identified the binding interface, enabling identification of a small-molecule inhibitor K284-3046 of VSIG3.","method":"X-ray crystallography (2.64 Å), co-immunoprecipitation, protein-protein docking, small-molecule inhibitor assay","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus reciprocal Co-IP in single lab with functional inhibitor validation","pmids":["33841409"],"is_preprint":false},{"year":2014,"finding":"PD-1H (VISTA) functions as a coinhibitory receptor on CD4+ T cells (in addition to its known ligand role on APCs). PD-1H-deficient CD4+ T cells show dramatically increased responses to antigen stimulation; agonist mAb delivery directly inhibits CD4+ T cell activation in vitro and in vivo. In a glioma model, PD-1H-deficient animals were highly resistant to tumor induction and this effect was reversed by CD4+ T cell depletion but not CD8+ T cell depletion.","method":"Genetic knockout mice, agonistic mAb treatment, in vitro T cell activation assays, in vivo tumor model, CD4/CD8 T cell depletion","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse phenotype plus agonist mAb rescue plus specific cell-depletion experiments; replicated by other labs","pmids":["24743150"],"is_preprint":false},{"year":2015,"finding":"VISTA and PD-1 are nonredundant immune checkpoint proteins: VISTA-KO and PD-1-KO mice both show spontaneous T cell activation and chronic inflammation, but double-KO mice show synergistically higher phenotypes. VISTA/PD-1 double KO mice on 2D2 TCR transgenic background show markedly higher CNS autoimmune disease penetrance. Combinatorial blockade with anti-VISTA and anti-PD-L1 mAbs achieves optimal tumor-clearing efficacy.","method":"Single and double genetic knockout mice, 2D2 TCR transgenic crosses, T cell response assays, combination antibody treatment in tumor models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double KO mice plus orthogonal combination antibody therapy experiments","pmids":["25964334"],"is_preprint":false},{"year":2015,"finding":"PD-1H (VISTA) acts as a coinhibitory receptor on alloreactive T cells via two distinct mechanisms: (1) signaling via PD-1H potently arrests alloreactive donor T cells from activation and expansion in the initiation phase; (2) donor regulatory T cells are subsequently expanded to maintain long-term tolerance and GVHD suppression.","method":"PD-1H agonistic mAb treatment in murine GVHD model, flow cytometric analysis of T cell activation and Treg expansion","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined two-phase mechanism by in vivo model with agonist mAb; single lab","pmids":["25917101"],"is_preprint":false},{"year":2019,"finding":"VISTA modulates TLR signaling in myeloid cells by regulating the polyubiquitination and protein expression of TRAF6, consequently dampening TLR-mediated activation of MAPK/AP-1 and IKK/NF-κB signaling cascades. VISTA deficiency augments myeloid-derived suppressor cell and tolerogenic DC effector functions, and VISTA blockade promotes proinflammatory mediator production while diminishing T cell-suppressive functions of these myeloid cells.","method":"VISTA KO myeloid cells, TRAF6 polyubiquitination assay, MAPK/NF-κB signaling assays, MDSC/DC functional assays, in vivo tumor model","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical pathway analysis with KO cells plus in vivo model; single lab but multiple orthogonal methods","pmids":["31340983"],"is_preprint":false},{"year":2020,"finding":"VISTA is expressed on naïve T cells and maintains a major quiescent naïve T cell subset. Loss of VISTA disrupts naïve T cell quiescence and enhances self-reactivity. Agonistic VISTA engagement increases T cell tolerance by promoting antigen-induced peripheral T cell deletion. VISTA's ability to restrain naïve T cell responses is lost under inflammatory conditions.","method":"Vsir-/- mouse model, naïve T cell subset characterization by flow cytometry, agonistic VISTA engagement, peripheral tolerance assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO phenotype plus agonistic engagement experiment; high-quality journal with multiple orthogonal methods","pmids":["31949051"],"is_preprint":false},{"year":2010,"finding":"GI24 (VSIR) promotes tumor invasiveness by regulating cell-surface levels of MT1-MMP. Co-expression of GI24 with MT1-MMP increases cell-surface MT1-MMP concomitant with cleavage of GI24 at the juxtamembrane site to shed the extracellular domain. MT1-MMP-mediated cleavage of GI24 was blocked by MMP inhibitor BB94 or MT1-MMP siRNA. GI24 knockdown in HSC-4 oral squamous carcinoma cells reduced MT1-MMP expression and invasive growth in collagen matrix.","method":"Overexpression in HEK293T cells, MMP inhibitor treatment, MT1-MMP siRNA, GI24 siRNA knockdown, collagen invasion assay","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (overexpression, siRNA, inhibitor, invasion assay); single lab","pmids":["20666777"],"is_preprint":false},{"year":2017,"finding":"VISTA deficiency in dendritic cells leads to hyper-activation of Erk1/2 and Jnk1/2 upon TLR7 stimulation and augmented production of IL-23, which promotes IL-17A expression in both TCRγδ+ T cells and CD4+ Th17 cells. VISTA also regulates peripheral homeostasis of CD27- γδ T cells and their activation upon TCR or cytokine stimulation.","method":"Vsir-/- mice, IMQ-induced psoriasis model, signaling pathway analysis (Erk1/2, Jnk1/2), IL-23/IL-17 cytokine assays, γδ T cell flow cytometry","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with defined signaling pathway analysis; single lab with multiple orthogonal measurements","pmids":["28469254"],"is_preprint":false},{"year":2024,"finding":"LRIG1 (leucine-rich repeats and immunoglobulin-like domains 1) is a VISTA binding partner that acts as an inhibitory receptor on T cells by engaging VISTA and suppressing TCR signaling pathways. T cell-specific LRIG1 deletion in mice led to expansion of tumor-specific CTLs with increased effector function and superior antitumor responses.","method":"Co-immunoprecipitation/binding partner identification, T cell-specific conditional KO mice, tumor models, TCR signaling assays, flow cytometry of CTL subsets","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding partner identification plus conditional KO with defined downstream signaling and tumor phenotype; single lab multiple orthogonal methods","pmids":["38758807"],"is_preprint":false},{"year":2024,"finding":"VISTA promotes MDSC differentiation and expansion through STAT3 activation and STAT3-dependent polyamine biosynthesis, which supports mitochondrial respiration. VISTA deficiency reduced STAT3 activation and polyamine production, impairing MDSC expansion. In mixed bone marrow chimera and myeloid-specific VISTA conditional KO mice, VISTA deficiency reduced tumor-associated MDSCs and expanded monocyte-derived DCs.","method":"Myeloid-specific conditional KO mice, bone marrow chimera assays, STAT3 activation assays, polyamine biosynthesis measurements, mitochondrial respiration assays, flow cytometry","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO plus multiple orthogonal mechanistic readouts (STAT3, polyamine, mitochondria); single lab but rigorous","pmids":["38175754"],"is_preprint":false},{"year":2023,"finding":"PD-1H (VISTA) is the bona fide receptor for MMP-13 on osteoclasts. Silencing PD-1H or using Pd-1h-/- bone marrow cells abrogates MMP-13-enhanced osteoclast fusion and bone-resorptive activity. PD-1H interacts with the actin cytoskeleton and plays a necessary role in supporting c-Src activation and sealing zone formation in osteoclasts.","method":"PD-1H siRNA silencing, Pd-1h-/- bone marrow cells, Pd-1h-/-/Rag2-/- myeloma bone disease mouse model, osteoclast fusion assay, c-Src activation assay, sealing zone formation analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor identification confirmed by KO model plus multiple downstream mechanistic readouts (actin cytoskeleton, c-Src, sealing zone) in in vivo bone disease model","pmids":["37460553"],"is_preprint":false},{"year":2023,"finding":"VISTA expression on endothelial cells in tumors selectively prevents T cell transmigration over endothelial layers under physiologic flow conditions, without affecting migration of other immune cell types. Endothelial VISTA is present on the plasma membrane and in recycling endosomes, and its expression is upregulated by cancer cell-secreted factors in a VEGF-A-dependent manner.","method":"Ex vivo human vasculature model, T cell transmigration assay under physiologic flow, immunofluorescence/confocal localization, VEGF-A blockade experiments, flow cytometry","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ex vivo functional model with specific cell-type selectivity and upstream VEGF-A mechanism; single lab","pmids":["37695550"],"is_preprint":false},{"year":2021,"finding":"VISTA functions as an activating receptor in human monocytes. Novel VISTA antibodies agonized VISTA in an Fc-functional manner to elicit transcriptional and functional changes in monocytes consistent with activation. Pentameric VISTA identified Syndecan-2 and heparan sulfate proteoglycan synthesis genes as novel regulators of VISTA interactions with monocytic cells, providing evidence of bidirectional signaling.","method":"Novel VISTA antibody development, scRNA/CITE-seq of human PBMCs, pentameric VISTA pulldown/binding assays","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNA-seq plus novel antibody functional assay plus pentameric VISTA binding; single lab, multiple orthogonal methods","pmids":["34106206"],"is_preprint":false},{"year":2017,"finding":"A stable pentameric VISTA construct (VISTA.COMP), but not dimeric VISTA-Fc, functions as a checkpoint receptor agonist in vivo without requiring surface immobilization, suppressing T cell-mediated immune responses. VISTA.COMP prolonged skin allograft survival and rescued mice from acute concanavalin-A-induced hepatitis, demonstrating engagement of a putative VISTA receptor.","method":"Pentameric VISTA.COMP construct design, in vitro T cell proliferation assay, murine skin allograft model, ConA-induced hepatitis model","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — engineered agonist with multiple in vivo models; single lab","pmids":["28931757"],"is_preprint":false},{"year":2019,"finding":"VISTA deficiency dramatically impacts macrophage cytokine and chemokine production (CCL2, CCL3, CCL4, CCL5 strikingly elevated in VISTA KO macrophages) and alters chemokine receptor recycling, profoundly disrupting myeloid chemotaxis. VISTA-deficient macrophages and MDSCs show reduced ability to migrate to the tumor microenvironment in vivo.","method":"VISTA KO macrophages, cytokine/chemokine measurement in culture supernatants, chemokine receptor recycling assay, in vivo tumor migration assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model with multiple functional readouts (cytokines, receptor recycling, chemotaxis) in single lab","pmids":["31803182"],"is_preprint":false},{"year":2022,"finding":"VSIG-8 binds to VISTA with a Kd of 1.58 ± 0.44 μM (measured by MST). When relevant VISTA amino acid binding sites were mutated to alanine, the interaction disappeared. VSIG-8 protein induced decreased IL-2 in VISTA-overexpressing cells but increased IL-2 in VISTA-/- cells, demonstrating VISTA-dependent inhibitory signaling through the VSIG-8/VISTA interaction.","method":"ELISA binding assay, Microscale Thermophoresis (MST), Co-IP, VISTA alanine mutagenesis, IL-2 cytokine assay in VISTA-KO vs. overexpressing cells","journal":"Investigational new drugs","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — MST affinity measurement plus mutagenesis of binding site plus functional readout; single lab","pmids":["35404016"],"is_preprint":false},{"year":2020,"finding":"VISTA interacts with galectin-9 as a ligand. Galectin-9 secreted by AML cells is recognized by VISTA expressed on T cells. Soluble VISTA released by AML cells enhances galectin-9 effects, likely forming multiprotein complexes on T cell surfaces, causing plasma membrane potential changes, activating granzyme B inside cytotoxic T cells, and inducing apoptosis.","method":"Binding assays, soluble VISTA experiments, membrane potential measurements, granzyme B activation assay, T cell apoptosis assay","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, binding assay plus downstream functional readout without full mechanistic characterization of the interaction","pmids":["33329552"],"is_preprint":false},{"year":2022,"finding":"VISTA deletion in Cx3Cr1-expressing microglia induces a more amoeboid morphology and increased expression of cell cycle and immune-activation genes. VISTA KO in microglia in vitro decreased myelin phagocytic uptake, demonstrating a role for VISTA in microglial function and myelin phagocytosis.","method":"Cx3Cr1-Cre VISTA conditional KO mice, microglia morphology analysis, transcriptional profiling, myelin phagocytosis assay in vitro","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with morphological, transcriptional, and functional phagocytosis readouts; single lab","pmids":["34006329"],"is_preprint":false},{"year":2022,"finding":"VISTA deficiency in kidney macrophages leads to increased contact frequency of macrophages with infiltrated T cells, altered T cell immunometabolism (elevated oxidative phosphorylation and fatty acid metabolism), and overproduction of IFN-γ. This altered milieu causes increased IL-9 production by parenchymal cells, augmenting tubulointerstitial fibrosis. Blocking antibodies against IFN-γ and IL-9 protected against this pathological process in VISTA-depleted conditions.","method":"Vsir-/- mouse nephrotoxic serum model, macrophage-T cell contact frequency analysis, T cell metabolic profiling, IFN-γ/IL-9 measurements, blocking antibody treatment","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model plus cytokine blocking rescue plus metabolic profiling; single lab with multiple orthogonal methods","pmids":["34752423"],"is_preprint":false},{"year":2016,"finding":"Dies1/VISTA expression loss in gastric cancer is caused by promoter methylation and/or miR-125a-5p overexpression. VISTA also regulates BMP-pathway downstream effectors, though this relationship is cell-context-dependent. VISTA expression is controlled by epigenetic mechanisms including promoter methylation in a TGFβ1-induced EMT model and cancer cell lines.","method":"Promoter methylation analysis, miR-125a-5p overexpression, TGFβ1-induced EMT model, cancer cell line analysis, primary gastric cancer sample analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter methylation and miRNA regulation demonstrated by multiple methods in cell lines and primary samples; single lab","pmids":["27721458"],"is_preprint":false},{"year":2020,"finding":"FOXD3 transcription factor regulates VISTA transcript levels in melanoma. BRAF inhibition upregulates FOXD3 expression, which in turn reduces VISTA expression. Tumor cell-specific VISTA expression promotes tumor onset in vivo, associated with increased intratumoral T regulatory cells and enhanced PDL-1 expression on tumor-infiltrating macrophages.","method":"FOXD3 modulation experiments, BRAF inhibitor treatment, in vivo syngeneic tumor model, flow cytometry of TILs","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FOXD3 transcriptional regulation plus in vivo tumor model with defined immune phenotype; single lab","pmids":["31940493"],"is_preprint":false},{"year":2023,"finding":"STAT3 functions as a transcriptional regulator of VISTA expression by directly binding to a DNA response element in the VISTA gene. High VISTA expression is positively associated with hyperactive STAT3 in AML. A STAT3 inhibitor down-regulates VISTA expression and enhances the efficacy of anti-VISTA mAb.","method":"ChIP/STAT3 binding to VISTA promoter, STAT3 inhibitor treatment, co-treatment with anti-VISTA mAb in AML models in vitro and in vivo","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct STAT3-VISTA promoter binding plus functional rescue; single lab","pmids":["36849939"],"is_preprint":false},{"year":2023,"finding":"ALDH2-mediated aldehyde metabolism drives VISTA expression via the NOD/NF-κB signaling pathway. Inhibiting ALDH2 downregulates VISTA expression through inactivation of NOD/NF-κB signaling, revitalizing CD8+ T cell cytotoxic function. Mechanism confirmed by RNA sequencing, flow cytometry, Western blot, ChIP assay, and luciferase reporter assays.","method":"CRISPR KO of ALDH2, RNA sequencing, flow cytometry, Western blot, ChIP assay, luciferase reporter, immunocompetent tumor models","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal mechanistic methods establishing NOD/NF-κB/VISTA axis; single lab","pmids":["38088186"],"is_preprint":false},{"year":2023,"finding":"Chemotherapy promotes VISTA expression in tumor cells via HIF-2α. VISTA overexpression on melanoma cells promotes immune evasion, and this is reversible by VISTA-blocking antibody in combination with carboplatin.","method":"HIF-2α pathway analysis, VISTA expression after chemotherapy treatment, VISTA-blocking antibody in combination with carboplatin in melanoma model","journal":"Biochemical pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, HIF-2α link shown but mechanistic detail on the HIF-2α–VISTA transcriptional axis is limited in the abstract","pmids":["36898416"],"is_preprint":false},{"year":2025,"finding":"VISTA interacts intracellularly with galectin-9, facilitating its interaction with TGF-β-activated kinase 1 (TAK1), a process required for lysosomal protection. VISTA expression is differentially regulated by TGF-β (via TGF-β–Smad3 pathway), hypoxic signaling, TAK1/ASK1-induced activation of ATF-2, and other TME factors. Five critical functions of VISTA were determined through these regulatory networks.","method":"Co-IP of intracellular VISTA with galectin-9 and TAK1, TGF-β and hypoxia treatment, pathway inhibitor experiments, lysosomal protection assay","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — intracellular interaction shown by Co-IP; full mechanistic characterization limited in abstract; single lab","pmids":["39983894"],"is_preprint":false},{"year":2025,"finding":"VISTA stimulation in ILC2s activates FOXO1, leading to modulation of ILC2 proliferation and function. VISTA-deficient ILC2s show enhanced fatty acid oxidation and oxidative phosphorylation and increased type 2 cytokine production, exacerbating airway hyperreactivity. VISTA agonist treatment reduces ILC2 function ex vivo and in vivo, alleviating ILC2-driven airway hyperreactivity.","method":"Vsir-/- mice and VISTA-deficient ILC2 transfer, FOXO1 inhibitors/activators, metabolic profiling (FAO and OXPHOS), ILC2 cytokine assays, AHR model, humanized mouse model","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model plus pharmacological FOXO1 manipulation plus metabolic profiling plus in vivo therapeutic model; single lab but multiple orthogonal methods","pmids":["39745792"],"is_preprint":false},{"year":2019,"finding":"PD-1H (VISTA) on both T cells and myeloid cells (including neutrophils and plasmacytoid dendritic cells) transmits inhibitory signals, resulting in reduced activation and function. Agonistic mAb in MRL/lpr lupus mice reduces cutaneous disease, autoantibodies, inflammatory cytokines, and immune cell expansion.","method":"PD-1H KO mice on BALB/c background (spontaneous lupus model), mass cytometry, agonistic mAb treatment in MRL/lpr mice, cell-type-specific inhibitory signaling assays","journal":"Science translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple KO mouse models plus mass cytometry plus agonist mAb therapeutic experiments; single lab","pmids":["31826980"],"is_preprint":false},{"year":2024,"finding":"VISTA expression in macrophages drives M2-like differentiation, strongly downregulates SIRPα (a 'don't eat me' signal), augments phagocytic activity against cancer cells, and reduces IL-1β while elevating IL-10 secretion. VISTA interacts with MHC-I and downregulates its surface expression, leading to diminished T cell activation. Expression of VISTA's extracellular domain alone was sufficient to trigger phagocytosis in ~50% of cell lines.","method":"VISTA overexpression in THP-1 and primary monocytes, macrophage polarization assays (qRT-PCR, flow cytometry, ELISA), phagocytosis assay with Rituximab-opsonized target cells, SIRPα expression analysis, MHC-I surface expression analysis, T cell co-culture","journal":"Experimental hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression in cell line and primary cells plus multiple functional readouts; single lab","pmids":["38553748"],"is_preprint":false},{"year":2022,"finding":"VISTA agonist (VISTA.COMP) treatment of LPS-stimulated macrophages and neutrophils ex vivo downregulates pro-inflammatory cytokines and increases expression of immunoregulatory genes. In vivo administration of VISTA.COMP attenuated circulating TNFα, IL-6, and IL-12p40 in LPS-treated mice. A VISTA receptor is rapidly expressed on the surface of macrophages and neutrophils upon LPS exposure.","method":"Ex vivo LPS stimulation of macrophages/neutrophils, VISTA.COMP agonist treatment, cytokine measurement, in vivo LPS model with VISTA.COMP","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional agonist experiments in ex vivo and in vivo models; single lab","pmids":["35933919"],"is_preprint":false},{"year":2025,"finding":"The transcription factor SP1 physically interacts with and stabilizes the YAP/TEAD4 complex at VISTA regulatory genomic loci in colorectal cancer. PKCζ phosphorylates SP1, enhancing its interaction with TEAD4 and coregulating VISTA expression. VISTA was identified as a direct transcriptional target of the SP1-YAP/TEAD4 complex. YAP-induced VISTA upregulation in CRC cells strongly suppresses CD8+ T cell antitumor function.","method":"SP1-YAP/TEAD4 Co-IP, ChIP assay, PKCζ phosphorylation assay, VISTA promoter reporter assay, VISTA KD/OE in CRC cells, CD8+ T cell co-culture functional assay","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, reporter) establishing transcriptional regulation plus functional T cell suppression assay; single lab","pmids":["39875519"],"is_preprint":false}],"current_model":"VISTA (VSIR/PD-1H) is a dual-function immune checkpoint protein that acts as both a ligand on myeloid cells and a coinhibitory receptor on T cells and other immune cells; its extracellular IgV domain contains a distinctive histidine-rich region and noncanonical topology (established by crystal structure) that mediates pH-dependent binding to PSGL-1 and pH-independent interactions with VSIG-3, VSIG-8, galectin-9, and LRIG1, suppressing T cell activation through multiple downstream pathways including FOXO1 and TCR signaling; on myeloid cells, VISTA controls TLR/TRAF6/NF-κB and MAPK signaling, STAT3-dependent polyamine biosynthesis supporting MDSC differentiation, chemokine production and receptor recycling, macrophage polarization towards M2-like states with SIRPα downregulation and augmented phagocytosis, and MHC-I surface levels; VISTA transcription is directly regulated by STAT3, FOXD3, the SP1-YAP/TEAD4 complex, HIF-2α, and epigenetic promoter methylation; in osteoclasts, PD-1H serves as the MMP-13 receptor and supports c-Src activation and sealing zone formation; and in endothelial cells, VISTA selectively blocks T cell transmigration in a VEGF-A-dependent manner."},"narrative":{"mechanistic_narrative":"VSIR (VISTA/PD-1H) is a dual-function immune checkpoint protein that operates both as an inhibitory ligand on myeloid cells and as a coinhibitory receptor on T cells, enforcing immune quiescence and peripheral tolerance [PMID:24743150, PMID:31949051]. Its extracellular IgV-like domain has a noncanonical topology—an elongated CC' loop, an extra 'H' β-strand, a clamping disulfide, and surface-exposed histidine clusters that are essential for T cell inhibition [PMID:31919279]; these histidine residues confer selective binding to PSGL-1 at the acidic pH of the tumor microenvironment, and pH-selective antibodies blocking this interaction reverse VISTA-mediated suppression [PMID:31645726]. VISTA additionally engages a panel of binding partners—VSIG-3/IGSF11, VSIG-8, and LRIG1—that suppress TCR signaling and T cell proliferation and cytokine production [PMID:30220083, PMID:35404016, PMID:38758807]. Genetically, VISTA acts nonredundantly with PD-1, with double-knockout mice showing synergistic autoimmunity and combination blockade achieving optimal tumor clearance [PMID:25964334]. As a receptor on naive and regulatory T cells, agonistic engagement arrests T cell activation and promotes tolerance, in part through FOXO1-dependent control of innate lymphoid cell metabolism and function [PMID:31949051, PMID:39745792]. On myeloid cells, VISTA restrains TLR signaling by regulating TRAF6 polyubiquitination to dampen MAPK/AP-1 and NF-κB cascades [PMID:31340983], drives MDSC differentiation through STAT3-dependent polyamine biosynthesis [PMID:38175754], controls chemokine production and receptor recycling to enable myeloid chemotaxis [PMID:31803182], and promotes M2-like macrophage polarization with SIRPα downregulation, augmented phagocytosis, and reduced surface MHC-I [PMID:38553748]. VISTA transcription is directly controlled by STAT3, FOXD3, and an SP1-stabilized YAP/TEAD4 complex, and is modulated by promoter methylation and aldehyde/NOD/NF-κB signaling [PMID:36849939, PMID:31940493, PMID:39875519, PMID:27721458, PMID:38088186]. Beyond immune regulation, PD-1H serves as the osteoclast receptor for MMP-13, supporting c-Src activation and sealing zone formation [PMID:37460553], and on tumor endothelium selectively blocks T cell transmigration in a VEGF-A-dependent manner [PMID:37695550].","teleology":[{"year":2010,"claim":"Established an early, non-immune cellular function for VSIR (GI24) in tumor invasion, before its checkpoint role was recognized.","evidence":"Overexpression, siRNA knockdown, MMP inhibitor treatment, and collagen invasion assay in oral squamous carcinoma cells","pmids":["20666777"],"confidence":"Medium","gaps":["Did not connect this MT1-MMP cell-surface regulation to immune checkpoint signaling","Single cell-line context"]},{"year":2014,"claim":"Resolved whether VISTA acts only as a ligand by showing it also functions as a coinhibitory receptor on CD4+ T cells, broadening its mechanistic identity.","evidence":"Genetic knockout mice, agonistic mAb, in vitro T cell assays, glioma model with CD4/CD8 depletion","pmids":["24743150"],"confidence":"High","gaps":["The receptor counter-ligand on T cells was not identified","Downstream signaling pathway undefined"]},{"year":2015,"claim":"Determined that VISTA operates nonredundantly with PD-1, establishing it as a distinct checkpoint axis amenable to combination blockade.","evidence":"Single and double knockout mice, 2D2 TCR transgenic crosses, combination antibody tumor therapy","pmids":["25964334","25917101"],"confidence":"High","gaps":["Molecular basis of nonredundancy with PD-1 not resolved","Whether the two phases of T cell suppression use the same receptor unclear"]},{"year":2016,"claim":"Identified transcriptional/epigenetic control of VISTA, addressing how its expression is silenced or induced in cancer.","evidence":"Promoter methylation analysis, miR-125a-5p overexpression, TGFβ1-EMT model in gastric cancer","pmids":["27721458"],"confidence":"Medium","gaps":["BMP-pathway relationship described as cell-context dependent","Direct transcription factors not identified here"]},{"year":2017,"claim":"Showed multimeric VISTA acts as a soluble agonist of a T cell receptor, and that VISTA controls Th17/γδ T cell responses via myeloid signaling.","evidence":"Pentameric VISTA.COMP construct in allograft and hepatitis models; Vsir-/- mice in psoriasis model with Erk/Jnk and IL-23/IL-17 readouts","pmids":["28931757","28469254"],"confidence":"Medium","gaps":["The putative T cell receptor engaged by VISTA.COMP was not molecularly identified","Avidity requirements not fully defined"]},{"year":2018,"claim":"Identified VSIG-3/IGSF11 as the first defined VISTA ligand mediating T cell suppression.","evidence":"Functional ELISA binding screen, T cell proliferation/cytokine assays, neutralizing antibody blockade","pmids":["30220083"],"confidence":"Medium","gaps":["No structural definition of the interface in this study","Downstream T cell signaling not mapped"]},{"year":2019,"claim":"Defined the structural and pH-dependent basis of VISTA binding and established myeloid-intrinsic mechanisms of suppression.","evidence":"Histidine mutagenesis with pH-selective antibodies and tumor models (PSGL-1); TRAF6 polyubiquitination and NF-κB/MAPK assays in myeloid cells; chemokine/receptor-recycling assays; mass cytometry in lupus models","pmids":["31645726","31340983","31803182","31826980"],"confidence":"High","gaps":["How acidic-pH PSGL-1 binding integrates with pH-independent ligands unresolved","Mechanism linking VISTA to TRAF6 ubiquitination machinery not detailed"]},{"year":2020,"claim":"Provided atomic structure of the VISTA ectodomain and established its role in maintaining naive T cell quiescence and in galectin-9 engagement.","evidence":"1.9 Å crystal structure with functional mutagenesis; Vsir-/- naive T cell quiescence and tolerance assays; FOXD3/BRAF inhibitor transcriptional studies; galectin-9 binding and granzyme B/apoptosis assays","pmids":["31919279","31949051","31940493","33329552"],"confidence":"High","gaps":["Galectin-9 interaction (Low confidence) lacks full mechanistic characterization","Structural basis of pH-independent partner binding not solved"]},{"year":2021,"claim":"Solved the VSIG3 ectodomain structure to enable small-molecule inhibition and revealed VISTA can function as an activating receptor on monocytes.","evidence":"2.64 Å VSIG3 crystal structure, Co-IP, docking, and inhibitor assay; scRNA/CITE-seq with Fc-functional agonist antibodies and pentameric VISTA pulldowns identifying Syndecan-2","pmids":["33841409","34106206"],"confidence":"High","gaps":["How VISTA toggles between inhibitory and activating signaling on monocytes unresolved","Syndecan-2/heparan sulfate role not functionally dissected"]},{"year":2022,"claim":"Extended VISTA mechanism into tissue-specific macrophage/microglia biology and quantified the VSIG-8 interaction.","evidence":"Cx3Cr1-Cre conditional KO microglia phagocytosis; Vsir-/- kidney macrophage T cell contact and immunometabolism with IFN-γ/IL-9 blockade; MST-measured VSIG-8 affinity with alanine mutagenesis and IL-2 readout; VISTA.COMP in LPS sepsis models","pmids":["34006329","34752423","35404016","35933919"],"confidence":"Medium","gaps":["Tissue-specific receptors mediating these effects not all identified","Whether VSIG-8 is a physiologically dominant ligand unclear"]},{"year":2023,"claim":"Identified VISTA as the osteoclast MMP-13 receptor, the tumor endothelial gatekeeper of T cell transmigration, and a direct STAT3 transcriptional target.","evidence":"Pd-1h-/- osteoclast fusion/c-Src/sealing zone assays; ex vivo vasculature transmigration under flow with VEGF-A blockade; ChIP/STAT3 promoter binding with inhibitor rescue; HIF-2α chemotherapy-induced expression","pmids":["37460553","37695550","36849939","36898416"],"confidence":"High","gaps":["How a single ectodomain serves both immune-ligand and MMP-13-receptor roles unresolved","HIF-2α transcriptional axis (Low confidence) mechanistically thin"]},{"year":2024,"claim":"Defined LRIG1 as a VISTA-engaging T cell inhibitory receptor and established the STAT3-polyamine axis for MDSC differentiation plus VISTA-driven macrophage reprogramming.","evidence":"LRIG1 binding identification with conditional KO and TCR signaling; myeloid conditional KO with STAT3/polyamine/mitochondrial readouts; VISTA overexpression macrophage polarization, SIRPα, phagocytosis, and MHC-I assays","pmids":["38758807","38175754","38553748"],"confidence":"High","gaps":["Hierarchy among the multiple T cell receptors/ligands (LRIG1, VSIG-3, PSGL-1) not established","How VISTA physically downregulates SIRPα and MHC-I unresolved"]},{"year":2025,"claim":"Expanded the regulatory and signaling network through SP1-YAP/TEAD4 transcriptional control, intracellular galectin-9/TAK1 interaction, and FOXO1-dependent ILC2 metabolic control.","evidence":"SP1-YAP/TEAD4 Co-IP/ChIP/reporter with PKCζ phosphorylation in CRC; intracellular VISTA-galectin-9-TAK1 Co-IP and lysosomal protection; Vsir-/- ILC2 with FOXO1 modulation and metabolic profiling","pmids":["39875519","39983894","39745792"],"confidence":"Medium","gaps":["Intracellular galectin-9/TAK1 mechanism (Low confidence) lacks full characterization","How surface checkpoint signaling integrates with intracellular functions unresolved"]},{"year":null,"claim":"It remains unresolved which of the multiple identified ligands/receptors (PSGL-1, VSIG-3, VSIG-8, galectin-9, LRIG1, MMP-13) dominate in each cell context, and how VISTA's intracellular tail transduces both inhibitory and activating signals.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified signaling model linking ectodomain ligand engagement to cytoplasmic output","Cell-type-specific receptor usage not systematically mapped","Structural basis of pH-independent multi-partner binding unsolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,8,11]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2,16,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,30]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[14,30,31]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[14]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,5,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,11,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[24,23,32]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,14,26]}],"complexes":[],"partners":["PSGL-1","VSIG3","VSIG8","LRIG1","LGALS9","MMP13","TRAF6","TAK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H7M9","full_name":"V-type immunoglobulin domain-containing suppressor of T-cell activation","aliases":["Platelet receptor Gi24","Stress-induced secreted protein-1","Sisp-1","V-set domain-containing immunoregulatory receptor","V-set immunoregulatory receptor"],"length_aa":311,"mass_kda":33.9,"function":"Immunoregulatory receptor which inhibits the T-cell response (PubMed:24691993). May promote differentiation of embryonic stem cells, by inhibiting BMP4 signaling (By similarity). May stimulate MMP14-mediated MMP2 activation (PubMed:20666777)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9H7M9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VSIR","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VSIR","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"},{"mim_id":"608351","title":"IMMUNOGLOBULIN SUPERFAMILY, MEMBER 11; IGSF11","url":"https://www.omim.org/entry/608351"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":76.9},{"tissue":"lymphoid tissue","ntpm":87.9}],"url":"https://www.proteinatlas.org/search/VSIR"},"hgnc":{"alias_symbol":["SISP1","GI24","B7-H5","B7H5","VISTA","PD-1H","Dies1"],"prev_symbol":["C10orf54"]},"alphafold":{"accession":"Q9H7M9","domains":[{"cath_id":"2.60.40.10","chopping":"35-184","consensus_level":"high","plddt":89.5513,"start":35,"end":184},{"cath_id":"1.20.5","chopping":"186-230","consensus_level":"medium","plddt":76.7678,"start":186,"end":230}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H7M9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H7M9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H7M9-F1-predicted_aligned_error_v6.png","plddt_mean":73.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VSIR","jax_strain_url":"https://www.jax.org/strain/search?query=VSIR"},"sequence":{"accession":"Q9H7M9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H7M9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H7M9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H7M9"}},"corpus_meta":[{"pmid":"31645726","id":"PMC_31645726","title":"VISTA is an acidic pH-selective ligand for PSGL-1.","date":"2019","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/31645726","citation_count":317,"is_preprint":false},{"pmid":"25964334","id":"PMC_25964334","title":"Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25964334","citation_count":311,"is_preprint":false},{"pmid":"9247968","id":"PMC_9247968","title":"Metaplasticity: a new vista across the field of synaptic plasticity.","date":"1997","source":"Progress in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/9247968","citation_count":262,"is_preprint":false},{"pmid":"24743150","id":"PMC_24743150","title":"Coinhibitory receptor PD-1H preferentially suppresses CD4⁺ T cell-mediated immunity.","date":"2014","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24743150","citation_count":253,"is_preprint":false},{"pmid":"31949051","id":"PMC_31949051","title":"VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance.","date":"2020","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/31949051","citation_count":239,"is_preprint":false},{"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":"32600443","id":"PMC_32600443","title":"VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy.","date":"2020","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32600443","citation_count":187,"is_preprint":false},{"pmid":"33495077","id":"PMC_33495077","title":"VISTA: A Mediator of Quiescence and a Promising Target in Cancer Immunotherapy.","date":"2021","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33495077","citation_count":179,"is_preprint":false},{"pmid":"28258694","id":"PMC_28258694","title":"Immunoregulatory functions of VISTA.","date":"2017","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/28258694","citation_count":169,"is_preprint":false},{"pmid":"30382166","id":"PMC_30382166","title":"VISTA expressed in tumour cells regulates T cell function.","date":"2018","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30382166","citation_count":168,"is_preprint":false},{"pmid":"31340983","id":"PMC_31340983","title":"Immune-Checkpoint Protein VISTA Regulates Antitumor Immunity by Controlling Myeloid Cell-Mediated Inflammation and Immunosuppression.","date":"2019","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/31340983","citation_count":142,"is_preprint":false},{"pmid":"31604531","id":"PMC_31604531","title":"VISTA: a novel immunotherapy target for normalizing innate and adaptive immunity.","date":"2019","source":"Seminars in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31604531","citation_count":116,"is_preprint":false},{"pmid":"31826980","id":"PMC_31826980","title":"PD-1H (VISTA)-mediated suppression of autoimmunity in systemic and cutaneous lupus erythematosus.","date":"2019","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31826980","citation_count":115,"is_preprint":false},{"pmid":"31930484","id":"PMC_31930484","title":"VISTA: Coming of age as a multi-lineage immune checkpoint.","date":"2020","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31930484","citation_count":104,"is_preprint":false},{"pmid":"33329552","id":"PMC_33329552","title":"Ligand-Receptor Interactions of Galectin-9 and VISTA Suppress Human T Lymphocyte Cytotoxic Activity.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33329552","citation_count":92,"is_preprint":false},{"pmid":"28469254","id":"PMC_28469254","title":"Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28469254","citation_count":83,"is_preprint":false},{"pmid":"30306644","id":"PMC_30306644","title":"VISTA expression by microglia decreases during inflammation and is differentially regulated in CNS diseases.","date":"2018","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/30306644","citation_count":75,"is_preprint":false},{"pmid":"31940493","id":"PMC_31940493","title":"FOXD3 Regulates VISTA Expression in Melanoma.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31940493","citation_count":70,"is_preprint":false},{"pmid":"25917101","id":"PMC_25917101","title":"Mechanistic Assessment of PD-1H Coinhibitory Receptor-Induced T Cell Tolerance to Allogeneic Antigens.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25917101","citation_count":68,"is_preprint":false},{"pmid":"32205423","id":"PMC_32205423","title":"Galectin-9 and VISTA Expression Define Terminally Exhausted T Cells in HIV-1 Infection.","date":"2020","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/32205423","citation_count":64,"is_preprint":false},{"pmid":"32266446","id":"PMC_32266446","title":"Expression of the immune checkpoint VISTA in breast cancer.","date":"2020","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/32266446","citation_count":62,"is_preprint":false},{"pmid":"34093577","id":"PMC_34093577","title":"The Role of V-Domain Ig Suppressor of T Cell Activation (VISTA) in Cancer Therapy: Lessons Learned and the Road Ahead.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34093577","citation_count":60,"is_preprint":false},{"pmid":"31013360","id":"PMC_31013360","title":"PD-L1, B7-H3 and VISTA are highly expressed in gestational trophoblastic neoplasia.","date":"2019","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/31013360","citation_count":58,"is_preprint":false},{"pmid":"32117584","id":"PMC_32117584","title":"Expression of TIM3/VISTA checkpoints and the CD68 macrophage-associated marker correlates with anti-PD1/PDL1 resistance: implications of immunogram heterogeneity.","date":"2020","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/32117584","citation_count":57,"is_preprint":false},{"pmid":"32929361","id":"PMC_32929361","title":"Single-cell RNA-Seq reveals the transcriptional landscape and heterogeneity of skin macrophages in Vsir-/- murine psoriasis.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/32929361","citation_count":56,"is_preprint":false},{"pmid":"37567173","id":"PMC_37567173","title":"CD39 inhibition and VISTA blockade may overcome radiotherapy resistance by targeting exhausted CD8+ T cells and immunosuppressive myeloid cells.","date":"2023","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37567173","citation_count":54,"is_preprint":false},{"pmid":"33250890","id":"PMC_33250890","title":"The Expression Pattern and Clinical Significance of the Immune Checkpoint Regulator VISTA in Human Breast Cancer.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33250890","citation_count":53,"is_preprint":false},{"pmid":"39028818","id":"PMC_39028818","title":"Targeting conserved TIM3+VISTA+ tumor-associated macrophages overcomes resistance to cancer immunotherapy.","date":"2024","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/39028818","citation_count":50,"is_preprint":false},{"pmid":"38175754","id":"PMC_38175754","title":"VISTA promotes the metabolism and differentiation of myeloid-derived suppressor cells by STAT3 and polyamine-dependent mechanisms.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38175754","citation_count":45,"is_preprint":false},{"pmid":"37936192","id":"PMC_37936192","title":"VISTA and its ligands: the next generation of promising therapeutic targets in immunotherapy.","date":"2023","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/37936192","citation_count":45,"is_preprint":false},{"pmid":"34189130","id":"PMC_34189130","title":"VISTA: A Promising Target for Cancer Immunotherapy?","date":"2021","source":"ImmunoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34189130","citation_count":45,"is_preprint":false},{"pmid":"25070074","id":"PMC_25070074","title":"Effects of protein and carbohydrate on an insect herbivore: the vista from a fitness landscape.","date":"2014","source":"Integrative and comparative biology","url":"https://pubmed.ncbi.nlm.nih.gov/25070074","citation_count":45,"is_preprint":false},{"pmid":"31919279","id":"PMC_31919279","title":"Structural insight into T cell coinhibition by PD-1H (VISTA).","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31919279","citation_count":44,"is_preprint":false},{"pmid":"32554470","id":"PMC_32554470","title":"New emerging targets in cancer immunotherapy: the role of VISTA.","date":"2020","source":"ESMO open","url":"https://pubmed.ncbi.nlm.nih.gov/32554470","citation_count":44,"is_preprint":false},{"pmid":"32958683","id":"PMC_32958683","title":"Expression and clinical significance of PD-L1, B7-H3, B7-H4 and VISTA in craniopharyngioma.","date":"2020","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32958683","citation_count":43,"is_preprint":false},{"pmid":"33841409","id":"PMC_33841409","title":"Structural Basis of VSIG3: The Ligand for VISTA.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33841409","citation_count":43,"is_preprint":false},{"pmid":"38758807","id":"PMC_38758807","title":"LRIG1 engages ligand VISTA and impairs tumor-specific CD8+ T cell responses.","date":"2024","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38758807","citation_count":42,"is_preprint":false},{"pmid":"20666777","id":"PMC_20666777","title":"GI24 enhances tumor invasiveness by regulating cell surface membrane-type 1 matrix metalloproteinase.","date":"2010","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/20666777","citation_count":42,"is_preprint":false},{"pmid":"36891296","id":"PMC_36891296","title":"VISTA expression and patient selection for immune-based anticancer therapy.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36891296","citation_count":41,"is_preprint":false},{"pmid":"31803182","id":"PMC_31803182","title":"Defining the Signature of VISTA on Myeloid Cell Chemokine Responsiveness.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31803182","citation_count":40,"is_preprint":false},{"pmid":"36260656","id":"PMC_36260656","title":"VISTA Targeting of T-cell Quiescence and Myeloid Suppression Overcomes Adaptive Resistance.","date":"2023","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/36260656","citation_count":39,"is_preprint":false},{"pmid":"28479600","id":"PMC_28479600","title":"A crucial role of the PD-1H coinhibitory receptor in suppressing experimental asthma.","date":"2017","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28479600","citation_count":37,"is_preprint":false},{"pmid":"34106206","id":"PMC_34106206","title":"VISTA is an activating receptor in human monocytes.","date":"2021","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34106206","citation_count":34,"is_preprint":false},{"pmid":"33643285","id":"PMC_33643285","title":"VISTA: A Target to Manage the Innate Cytokine Storm.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33643285","citation_count":34,"is_preprint":false},{"pmid":"28931757","id":"PMC_28931757","title":"VISTA.COMP - an engineered checkpoint receptor agonist that potently suppresses T cell-mediated immune responses.","date":"2017","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/28931757","citation_count":34,"is_preprint":false},{"pmid":"36265568","id":"PMC_36265568","title":"VISTA immune regulatory effects in bypassing cancer immunotherapy: Updated.","date":"2022","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36265568","citation_count":32,"is_preprint":false},{"pmid":"36849939","id":"PMC_36849939","title":"Targeting STAT3-VISTA axis to suppress tumor aggression and burden in acute myeloid leukemia.","date":"2023","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36849939","citation_count":32,"is_preprint":false},{"pmid":"38088186","id":"PMC_38088186","title":"Aldehyde dehydrogenase 2-mediated aldehyde metabolism promotes tumor immune evasion by regulating the NOD/VISTA axis.","date":"2023","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38088186","citation_count":30,"is_preprint":false},{"pmid":"32856125","id":"PMC_32856125","title":"Exploring the VISTA of microglia: immune checkpoints in CNS inflammation.","date":"2020","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/32856125","citation_count":30,"is_preprint":false},{"pmid":"27721458","id":"PMC_27721458","title":"Dies1/VISTA expression loss is a recurrent event in gastric cancer due to epigenetic regulation.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27721458","citation_count":30,"is_preprint":false},{"pmid":"34752423","id":"PMC_34752423","title":"Kidney VISTA prevents IFN-γ/IL-9 axis-mediated tubulointerstitial fibrosis after acute glomerular injury.","date":"2022","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/34752423","citation_count":29,"is_preprint":false},{"pmid":"32057701","id":"PMC_32057701","title":"The expression and immunoregulation of immune checkpoint molecule VISTA in autoimmune diseases and cancers.","date":"2020","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/32057701","citation_count":28,"is_preprint":false},{"pmid":"39482534","id":"PMC_39482534","title":"VISTA-mediated immune evasion in cancer.","date":"2024","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39482534","citation_count":27,"is_preprint":false},{"pmid":"38503143","id":"PMC_38503143","title":"Viewing the immune checkpoint VISTA: landscape and outcomes across cancers.","date":"2024","source":"ESMO open","url":"https://pubmed.ncbi.nlm.nih.gov/38503143","citation_count":27,"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":"34778768","id":"PMC_34778768","title":"VISTA inhibitors in cancer immunotherapy: a short perspective on recent progresses.","date":"2021","source":"RSC medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34778768","citation_count":24,"is_preprint":false},{"pmid":"36368642","id":"PMC_36368642","title":"Expression and clinical significance of VISTA, B7-H3, and PD-L1 in glioma.","date":"2022","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/36368642","citation_count":23,"is_preprint":false},{"pmid":"37795437","id":"PMC_37795437","title":"Clinical and research updates on the VISTA immune checkpoint: immuno-oncology themes and highlights.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37795437","citation_count":23,"is_preprint":false},{"pmid":"31672704","id":"PMC_31672704","title":"Expression of the checkpoint receptors LAG-3, TIM-3 and VISTA in peripheral T cell lymphomas.","date":"2019","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31672704","citation_count":21,"is_preprint":false},{"pmid":"38042220","id":"PMC_38042220","title":"Dual silencing of tumor-intrinsic VISTA and CTLA-4 stimulates T-cell mediated immune responses and inhibits MCF7 breast cancer development.","date":"2023","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/38042220","citation_count":19,"is_preprint":false},{"pmid":"31883303","id":"PMC_31883303","title":"Overexpression of B7H5/CD28H is associated with worse survival in human gastric cancer.","date":"2019","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31883303","citation_count":18,"is_preprint":false},{"pmid":"35831836","id":"PMC_35831836","title":"IGSF11 and VISTA: a pair of promising immune checkpoints in tumor immunotherapy.","date":"2022","source":"Biomarker research","url":"https://pubmed.ncbi.nlm.nih.gov/35831836","citation_count":18,"is_preprint":false},{"pmid":"34072549","id":"PMC_34072549","title":"Expression of Immune Checkpoint Regulators IDO, VISTA, LAG3, and TIM3 in Resected Pancreatic Ductal Adenocarcinoma.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34072549","citation_count":17,"is_preprint":false},{"pmid":"38412237","id":"PMC_38412237","title":"Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors.","date":"2024","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38412237","citation_count":16,"is_preprint":false},{"pmid":"37152039","id":"PMC_37152039","title":"High VISTA expression is linked to a potent epithelial-mesenchymal transition and is positively correlated with PD1 in breast cancer.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37152039","citation_count":16,"is_preprint":false},{"pmid":"37460553","id":"PMC_37460553","title":"The checkpoint inhibitor PD-1H/VISTA controls osteoclast-mediated multiple myeloma bone disease.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37460553","citation_count":15,"is_preprint":false},{"pmid":"37695550","id":"PMC_37695550","title":"VISTA Expression on Cancer-Associated Endothelium Selectively Prevents T-cell Extravasation.","date":"2023","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/37695550","citation_count":15,"is_preprint":false},{"pmid":"34650712","id":"PMC_34650712","title":"Expression and clinicopathological significance of Foxp3 and VISTA in cervical cancer.","date":"2021","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/34650712","citation_count":15,"is_preprint":false},{"pmid":"34818120","id":"PMC_34818120","title":"Agonistic nanobodies and antibodies to human VISTA.","date":"2021","source":"mAbs","url":"https://pubmed.ncbi.nlm.nih.gov/34818120","citation_count":15,"is_preprint":false},{"pmid":"37847894","id":"PMC_37847894","title":"Effective Antitumor Immunity Can Be Triggered by Targeting VISTA in Combination with a TLR3-Specific Adjuvant.","date":"2023","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/37847894","citation_count":15,"is_preprint":false},{"pmid":"38060328","id":"PMC_38060328","title":"PD-1H/VISTA mediates immune evasion in acute myeloid leukemia.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/38060328","citation_count":14,"is_preprint":false},{"pmid":"38797321","id":"PMC_38797321","title":"VISTA: A Novel Checkpoint for Cancer Immunotherapy.","date":"2024","source":"Drug discovery today","url":"https://pubmed.ncbi.nlm.nih.gov/38797321","citation_count":14,"is_preprint":false},{"pmid":"36372318","id":"PMC_36372318","title":"Single-cell mapping reveals dysregulation of immune cell populations and VISTA+ monocytes in myasthenia gravis.","date":"2022","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/36372318","citation_count":14,"is_preprint":false},{"pmid":"39983894","id":"PMC_39983894","title":"Intracellular and extracellular activities of V-domain Ig-containing suppressor of T cell activation (VISTA) modulated by immunosuppressive factors of tumour microenvironment.","date":"2025","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/39983894","citation_count":14,"is_preprint":false},{"pmid":"34006329","id":"PMC_34006329","title":"VISTA regulates microglia homeostasis and myelin phagocytosis, and is associated with MS lesion pathology.","date":"2021","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/34006329","citation_count":14,"is_preprint":false},{"pmid":"37804401","id":"PMC_37804401","title":"Imatinib and M351-0056 enhance the function of VISTA and ameliorate the development of SLE via IFN-I and noncanonical NF-κB pathway.","date":"2023","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/37804401","citation_count":14,"is_preprint":false},{"pmid":"38553748","id":"PMC_38553748","title":"VISTA drives macrophages towards a pro-tumoral phenotype that promotes cancer cell phagocytosis yet down-regulates T cell responses.","date":"2024","source":"Experimental hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38553748","citation_count":13,"is_preprint":false},{"pmid":"36898416","id":"PMC_36898416","title":"Chemotherapy induces immune checkpoint VISTA expression in tumor cells via HIF-2alpha.","date":"2023","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36898416","citation_count":13,"is_preprint":false},{"pmid":"35183994","id":"PMC_35183994","title":"The expression pattern of VISTA in the PBMCs of relapsing-remitting multiple sclerosis patients: A single-cell RNA sequencing-based study.","date":"2022","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/35183994","citation_count":13,"is_preprint":false},{"pmid":"37969728","id":"PMC_37969728","title":"Identification and optimization of peptide inhibitors to block VISTA/PSGL-1 interaction for cancer immunotherapy.","date":"2023","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/37969728","citation_count":13,"is_preprint":false},{"pmid":"31790558","id":"PMC_31790558","title":"VISTA Is Crucial for Corneal Allograft Survival and Maintenance of Immune Privilege.","date":"2019","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/31790558","citation_count":13,"is_preprint":false},{"pmid":"37594853","id":"PMC_37594853","title":"Novel Benzimidazoles as Potent Small-Molecule Inhibitors and Degraders of V-Domain Ig Suppressor of T-Cell Activation (VISTA).","date":"2023","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37594853","citation_count":13,"is_preprint":false},{"pmid":"38889269","id":"PMC_38889269","title":"Gut Dysbiosis Drives Inflammatory Bowel Disease Through the CCL4L2-VSIR Axis in Glycogen Storage Disease.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38889269","citation_count":12,"is_preprint":false},{"pmid":"37190254","id":"PMC_37190254","title":"VISTA Ligation Reduces Antitumor T-Cell Activity in Pancreatic Cancer.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37190254","citation_count":12,"is_preprint":false},{"pmid":"39810191","id":"PMC_39810191","title":"Metabolically activated and highly polyfunctional intratumoral VISTA+ regulatory B cells are associated with tumor recurrence in early-stage NSCLC.","date":"2025","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39810191","citation_count":12,"is_preprint":false},{"pmid":"37810458","id":"PMC_37810458","title":"VISTA: visualizing the spatial transcriptome of the C.elegans nervous system.","date":"2023","source":"Bioinformatics advances","url":"https://pubmed.ncbi.nlm.nih.gov/37810458","citation_count":12,"is_preprint":false},{"pmid":"35113284","id":"PMC_35113284","title":"Investigation of the effects of the toll-like receptor 4 pathway on immune checkpoint vista in pancreatic cancer.","date":"2022","source":"Investigational new drugs","url":"https://pubmed.ncbi.nlm.nih.gov/35113284","citation_count":12,"is_preprint":false},{"pmid":"32726937","id":"PMC_32726937","title":"The Conformational Plasticity Vista of PDZ Domains.","date":"2020","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32726937","citation_count":12,"is_preprint":false},{"pmid":"39653551","id":"PMC_39653551","title":"METTL3-VISTA axis-based combination immunotherapy for APC truncation colorectal cancer.","date":"2024","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39653551","citation_count":11,"is_preprint":false},{"pmid":"34905507","id":"PMC_34905507","title":"Ablation of T cell-associated PD-1H enhances functionality and promotes adoptive immunotherapy.","date":"2022","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/34905507","citation_count":11,"is_preprint":false},{"pmid":"39209454","id":"PMC_39209454","title":"Nanoparticles targeting immune checkpoint protein VISTA induce potent antitumor immunity.","date":"2024","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39209454","citation_count":11,"is_preprint":false},{"pmid":"37907049","id":"PMC_37907049","title":"VISTA blockade alleviates immunosuppression of MDSCs in oral squamous cell carcinoma.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37907049","citation_count":11,"is_preprint":false},{"pmid":"29527580","id":"PMC_29527580","title":"Gene array analysis of PD-1H overexpressing monocytes reveals a pro-inflammatory profile.","date":"2018","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/29527580","citation_count":11,"is_preprint":false},{"pmid":"35933919","id":"PMC_35933919","title":"VISTA as a ligand downregulates LPS-mediated inflammation in macrophages and neutrophils.","date":"2022","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35933919","citation_count":11,"is_preprint":false},{"pmid":"39875519","id":"PMC_39875519","title":"YAP/TEAD4/SP1-induced VISTA expression as a tumor cell-intrinsic mechanism of immunosuppression in colorectal cancer.","date":"2025","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/39875519","citation_count":10,"is_preprint":false},{"pmid":"24743142","id":"PMC_24743142","title":"A VISTA on PD-1H.","date":"2014","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24743142","citation_count":10,"is_preprint":false},{"pmid":"38428824","id":"PMC_38428824","title":"Expression and function of VISTA on myeloid cells.","date":"2024","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38428824","citation_count":10,"is_preprint":false},{"pmid":"37435070","id":"PMC_37435070","title":"Immune-checkpoint protein VISTA in allergic, autoimmune disease and transplant rejection.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37435070","citation_count":10,"is_preprint":false},{"pmid":"39617949","id":"PMC_39617949","title":"A pair of promising immune checkpoints PSGL-1 and VISTA from immunotolerance to immunotherapy.","date":"2024","source":"Biomarker research","url":"https://pubmed.ncbi.nlm.nih.gov/39617949","citation_count":9,"is_preprint":false},{"pmid":"39745792","id":"PMC_39745792","title":"FOXO1 pathway activation by VISTA immune checkpoint restrains pulmonary ILC2 functions.","date":"2025","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/39745792","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46963,"output_tokens":8738,"usd":0.13598,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19023,"output_tokens":4925,"usd":0.10912,"stage2_stop_reason":"end_turn"},"total_usd":0.2451,"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\": 2019,\n      \"finding\": \"VISTA binds to PSGL-1 selectively at acidic pH (as found in tumor microenvironments), mediated by multiple histidine residues along the rim of the VISTA extracellular domain. Antibodies engineered to block this interaction specifically at acidic pH reversed VISTA-mediated immune suppression in vivo.\",\n      \"method\": \"Binding assays, mutagenesis of histidine residues, pH-selective antibody engineering, in vivo tumor models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of active-site residues combined with in vivo functional validation; replicated structurally in subsequent structural paper (PMID:31919279)\",\n      \"pmids\": [\"31645726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of human PD-1H (VISTA) extracellular domain at 1.9 Å resolution reveals an elongated CC' loop, a striking concentration of surface-exposed histidine clusters in the CDR-like proximal region, a noncanonical IgV-like topology with an extra 'H' β-strand and a 'clamping' disulfide absent in known IgV-like structures. Surface-exposed histidine clusters are essential for robust inhibition of T cell activation, as shown by mutagenesis.\",\n      \"method\": \"X-ray crystallography (1.9 Å), site-directed mutagenesis, T cell activation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus functional mutagenesis in one rigorous study\",\n      \"pmids\": [\"31919279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"VSIG-3/IGSF11 is a binding ligand for VISTA; VSIG-3 binds VISTA (but not other B7 family members) and inhibits human T cell proliferation and cytokine production (IFN-γ, IL-2, IL-17, CCL5, CCL3, CXCL11). Anti-VISTA neutralizing antibodies block the VSIG-3/VISTA interaction and reverse VSIG-3-induced T cell inhibition.\",\n      \"method\": \"Functional ELISA binding screening, T cell proliferation assays, cytokine production assays, neutralizing antibody blockade\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays in single lab; binding confirmed by ELISA with specificity controls\",\n      \"pmids\": [\"30220083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structure of the VSIG3 extracellular domain at 2.64 Å resolution determined; VISTA–VSIG3 protein–protein interaction confirmed by Co-IP. Protein–protein docking identified the binding interface, enabling identification of a small-molecule inhibitor K284-3046 of VSIG3.\",\n      \"method\": \"X-ray crystallography (2.64 Å), co-immunoprecipitation, protein-protein docking, small-molecule inhibitor assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus reciprocal Co-IP in single lab with functional inhibitor validation\",\n      \"pmids\": [\"33841409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PD-1H (VISTA) functions as a coinhibitory receptor on CD4+ T cells (in addition to its known ligand role on APCs). PD-1H-deficient CD4+ T cells show dramatically increased responses to antigen stimulation; agonist mAb delivery directly inhibits CD4+ T cell activation in vitro and in vivo. In a glioma model, PD-1H-deficient animals were highly resistant to tumor induction and this effect was reversed by CD4+ T cell depletion but not CD8+ T cell depletion.\",\n      \"method\": \"Genetic knockout mice, agonistic mAb treatment, in vitro T cell activation assays, in vivo tumor model, CD4/CD8 T cell depletion\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse phenotype plus agonist mAb rescue plus specific cell-depletion experiments; replicated by other labs\",\n      \"pmids\": [\"24743150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"VISTA and PD-1 are nonredundant immune checkpoint proteins: VISTA-KO and PD-1-KO mice both show spontaneous T cell activation and chronic inflammation, but double-KO mice show synergistically higher phenotypes. VISTA/PD-1 double KO mice on 2D2 TCR transgenic background show markedly higher CNS autoimmune disease penetrance. Combinatorial blockade with anti-VISTA and anti-PD-L1 mAbs achieves optimal tumor-clearing efficacy.\",\n      \"method\": \"Single and double genetic knockout mice, 2D2 TCR transgenic crosses, T cell response assays, combination antibody treatment in tumor models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double KO mice plus orthogonal combination antibody therapy experiments\",\n      \"pmids\": [\"25964334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PD-1H (VISTA) acts as a coinhibitory receptor on alloreactive T cells via two distinct mechanisms: (1) signaling via PD-1H potently arrests alloreactive donor T cells from activation and expansion in the initiation phase; (2) donor regulatory T cells are subsequently expanded to maintain long-term tolerance and GVHD suppression.\",\n      \"method\": \"PD-1H agonistic mAb treatment in murine GVHD model, flow cytometric analysis of T cell activation and Treg expansion\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined two-phase mechanism by in vivo model with agonist mAb; single lab\",\n      \"pmids\": [\"25917101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VISTA modulates TLR signaling in myeloid cells by regulating the polyubiquitination and protein expression of TRAF6, consequently dampening TLR-mediated activation of MAPK/AP-1 and IKK/NF-κB signaling cascades. VISTA deficiency augments myeloid-derived suppressor cell and tolerogenic DC effector functions, and VISTA blockade promotes proinflammatory mediator production while diminishing T cell-suppressive functions of these myeloid cells.\",\n      \"method\": \"VISTA KO myeloid cells, TRAF6 polyubiquitination assay, MAPK/NF-κB signaling assays, MDSC/DC functional assays, in vivo tumor model\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical pathway analysis with KO cells plus in vivo model; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31340983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VISTA is expressed on naïve T cells and maintains a major quiescent naïve T cell subset. Loss of VISTA disrupts naïve T cell quiescence and enhances self-reactivity. Agonistic VISTA engagement increases T cell tolerance by promoting antigen-induced peripheral T cell deletion. VISTA's ability to restrain naïve T cell responses is lost under inflammatory conditions.\",\n      \"method\": \"Vsir-/- mouse model, naïve T cell subset characterization by flow cytometry, agonistic VISTA engagement, peripheral tolerance assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO phenotype plus agonistic engagement experiment; high-quality journal with multiple orthogonal methods\",\n      \"pmids\": [\"31949051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GI24 (VSIR) promotes tumor invasiveness by regulating cell-surface levels of MT1-MMP. Co-expression of GI24 with MT1-MMP increases cell-surface MT1-MMP concomitant with cleavage of GI24 at the juxtamembrane site to shed the extracellular domain. MT1-MMP-mediated cleavage of GI24 was blocked by MMP inhibitor BB94 or MT1-MMP siRNA. GI24 knockdown in HSC-4 oral squamous carcinoma cells reduced MT1-MMP expression and invasive growth in collagen matrix.\",\n      \"method\": \"Overexpression in HEK293T cells, MMP inhibitor treatment, MT1-MMP siRNA, GI24 siRNA knockdown, collagen invasion assay\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (overexpression, siRNA, inhibitor, invasion assay); single lab\",\n      \"pmids\": [\"20666777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"VISTA deficiency in dendritic cells leads to hyper-activation of Erk1/2 and Jnk1/2 upon TLR7 stimulation and augmented production of IL-23, which promotes IL-17A expression in both TCRγδ+ T cells and CD4+ Th17 cells. VISTA also regulates peripheral homeostasis of CD27- γδ T cells and their activation upon TCR or cytokine stimulation.\",\n      \"method\": \"Vsir-/- mice, IMQ-induced psoriasis model, signaling pathway analysis (Erk1/2, Jnk1/2), IL-23/IL-17 cytokine assays, γδ T cell flow cytometry\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with defined signaling pathway analysis; single lab with multiple orthogonal measurements\",\n      \"pmids\": [\"28469254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LRIG1 (leucine-rich repeats and immunoglobulin-like domains 1) is a VISTA binding partner that acts as an inhibitory receptor on T cells by engaging VISTA and suppressing TCR signaling pathways. T cell-specific LRIG1 deletion in mice led to expansion of tumor-specific CTLs with increased effector function and superior antitumor responses.\",\n      \"method\": \"Co-immunoprecipitation/binding partner identification, T cell-specific conditional KO mice, tumor models, TCR signaling assays, flow cytometry of CTL subsets\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding partner identification plus conditional KO with defined downstream signaling and tumor phenotype; single lab multiple orthogonal methods\",\n      \"pmids\": [\"38758807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VISTA promotes MDSC differentiation and expansion through STAT3 activation and STAT3-dependent polyamine biosynthesis, which supports mitochondrial respiration. VISTA deficiency reduced STAT3 activation and polyamine production, impairing MDSC expansion. In mixed bone marrow chimera and myeloid-specific VISTA conditional KO mice, VISTA deficiency reduced tumor-associated MDSCs and expanded monocyte-derived DCs.\",\n      \"method\": \"Myeloid-specific conditional KO mice, bone marrow chimera assays, STAT3 activation assays, polyamine biosynthesis measurements, mitochondrial respiration assays, flow cytometry\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO plus multiple orthogonal mechanistic readouts (STAT3, polyamine, mitochondria); single lab but rigorous\",\n      \"pmids\": [\"38175754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PD-1H (VISTA) is the bona fide receptor for MMP-13 on osteoclasts. Silencing PD-1H or using Pd-1h-/- bone marrow cells abrogates MMP-13-enhanced osteoclast fusion and bone-resorptive activity. PD-1H interacts with the actin cytoskeleton and plays a necessary role in supporting c-Src activation and sealing zone formation in osteoclasts.\",\n      \"method\": \"PD-1H siRNA silencing, Pd-1h-/- bone marrow cells, Pd-1h-/-/Rag2-/- myeloma bone disease mouse model, osteoclast fusion assay, c-Src activation assay, sealing zone formation analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor identification confirmed by KO model plus multiple downstream mechanistic readouts (actin cytoskeleton, c-Src, sealing zone) in in vivo bone disease model\",\n      \"pmids\": [\"37460553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VISTA expression on endothelial cells in tumors selectively prevents T cell transmigration over endothelial layers under physiologic flow conditions, without affecting migration of other immune cell types. Endothelial VISTA is present on the plasma membrane and in recycling endosomes, and its expression is upregulated by cancer cell-secreted factors in a VEGF-A-dependent manner.\",\n      \"method\": \"Ex vivo human vasculature model, T cell transmigration assay under physiologic flow, immunofluorescence/confocal localization, VEGF-A blockade experiments, flow cytometry\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ex vivo functional model with specific cell-type selectivity and upstream VEGF-A mechanism; single lab\",\n      \"pmids\": [\"37695550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VISTA functions as an activating receptor in human monocytes. Novel VISTA antibodies agonized VISTA in an Fc-functional manner to elicit transcriptional and functional changes in monocytes consistent with activation. Pentameric VISTA identified Syndecan-2 and heparan sulfate proteoglycan synthesis genes as novel regulators of VISTA interactions with monocytic cells, providing evidence of bidirectional signaling.\",\n      \"method\": \"Novel VISTA antibody development, scRNA/CITE-seq of human PBMCs, pentameric VISTA pulldown/binding assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq plus novel antibody functional assay plus pentameric VISTA binding; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34106206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A stable pentameric VISTA construct (VISTA.COMP), but not dimeric VISTA-Fc, functions as a checkpoint receptor agonist in vivo without requiring surface immobilization, suppressing T cell-mediated immune responses. VISTA.COMP prolonged skin allograft survival and rescued mice from acute concanavalin-A-induced hepatitis, demonstrating engagement of a putative VISTA receptor.\",\n      \"method\": \"Pentameric VISTA.COMP construct design, in vitro T cell proliferation assay, murine skin allograft model, ConA-induced hepatitis model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — engineered agonist with multiple in vivo models; single lab\",\n      \"pmids\": [\"28931757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VISTA deficiency dramatically impacts macrophage cytokine and chemokine production (CCL2, CCL3, CCL4, CCL5 strikingly elevated in VISTA KO macrophages) and alters chemokine receptor recycling, profoundly disrupting myeloid chemotaxis. VISTA-deficient macrophages and MDSCs show reduced ability to migrate to the tumor microenvironment in vivo.\",\n      \"method\": \"VISTA KO macrophages, cytokine/chemokine measurement in culture supernatants, chemokine receptor recycling assay, in vivo tumor migration assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model with multiple functional readouts (cytokines, receptor recycling, chemotaxis) in single lab\",\n      \"pmids\": [\"31803182\"],\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 (measured by MST). When relevant VISTA amino acid binding sites were mutated to alanine, the interaction disappeared. VSIG-8 protein induced decreased IL-2 in VISTA-overexpressing cells but increased IL-2 in VISTA-/- cells, demonstrating VISTA-dependent inhibitory signaling through the VSIG-8/VISTA interaction.\",\n      \"method\": \"ELISA binding assay, Microscale Thermophoresis (MST), Co-IP, VISTA alanine mutagenesis, IL-2 cytokine assay in VISTA-KO vs. overexpressing cells\",\n      \"journal\": \"Investigational new drugs\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — MST affinity measurement plus mutagenesis of binding site plus functional readout; single lab\",\n      \"pmids\": [\"35404016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VISTA interacts with galectin-9 as a ligand. Galectin-9 secreted by AML cells is recognized by VISTA expressed on T cells. Soluble VISTA released by AML cells enhances galectin-9 effects, likely forming multiprotein complexes on T cell surfaces, causing plasma membrane potential changes, activating granzyme B inside cytotoxic T cells, and inducing apoptosis.\",\n      \"method\": \"Binding assays, soluble VISTA experiments, membrane potential measurements, granzyme B activation assay, T cell apoptosis assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, binding assay plus downstream functional readout without full mechanistic characterization of the interaction\",\n      \"pmids\": [\"33329552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VISTA deletion in Cx3Cr1-expressing microglia induces a more amoeboid morphology and increased expression of cell cycle and immune-activation genes. VISTA KO in microglia in vitro decreased myelin phagocytic uptake, demonstrating a role for VISTA in microglial function and myelin phagocytosis.\",\n      \"method\": \"Cx3Cr1-Cre VISTA conditional KO mice, microglia morphology analysis, transcriptional profiling, myelin phagocytosis assay in vitro\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with morphological, transcriptional, and functional phagocytosis readouts; single lab\",\n      \"pmids\": [\"34006329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VISTA deficiency in kidney macrophages leads to increased contact frequency of macrophages with infiltrated T cells, altered T cell immunometabolism (elevated oxidative phosphorylation and fatty acid metabolism), and overproduction of IFN-γ. This altered milieu causes increased IL-9 production by parenchymal cells, augmenting tubulointerstitial fibrosis. Blocking antibodies against IFN-γ and IL-9 protected against this pathological process in VISTA-depleted conditions.\",\n      \"method\": \"Vsir-/- mouse nephrotoxic serum model, macrophage-T cell contact frequency analysis, T cell metabolic profiling, IFN-γ/IL-9 measurements, blocking antibody treatment\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model plus cytokine blocking rescue plus metabolic profiling; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34752423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Dies1/VISTA expression loss in gastric cancer is caused by promoter methylation and/or miR-125a-5p overexpression. VISTA also regulates BMP-pathway downstream effectors, though this relationship is cell-context-dependent. VISTA expression is controlled by epigenetic mechanisms including promoter methylation in a TGFβ1-induced EMT model and cancer cell lines.\",\n      \"method\": \"Promoter methylation analysis, miR-125a-5p overexpression, TGFβ1-induced EMT model, cancer cell line analysis, primary gastric cancer sample analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter methylation and miRNA regulation demonstrated by multiple methods in cell lines and primary samples; single lab\",\n      \"pmids\": [\"27721458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FOXD3 transcription factor regulates VISTA transcript levels in melanoma. BRAF inhibition upregulates FOXD3 expression, which in turn reduces VISTA expression. Tumor cell-specific VISTA expression promotes tumor onset in vivo, associated with increased intratumoral T regulatory cells and enhanced PDL-1 expression on tumor-infiltrating macrophages.\",\n      \"method\": \"FOXD3 modulation experiments, BRAF inhibitor treatment, in vivo syngeneic tumor model, flow cytometry of TILs\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FOXD3 transcriptional regulation plus in vivo tumor model with defined immune phenotype; single lab\",\n      \"pmids\": [\"31940493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STAT3 functions as a transcriptional regulator of VISTA expression by directly binding to a DNA response element in the VISTA gene. High VISTA expression is positively associated with hyperactive STAT3 in AML. A STAT3 inhibitor down-regulates VISTA expression and enhances the efficacy of anti-VISTA mAb.\",\n      \"method\": \"ChIP/STAT3 binding to VISTA promoter, STAT3 inhibitor treatment, co-treatment with anti-VISTA mAb in AML models in vitro and in vivo\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct STAT3-VISTA promoter binding plus functional rescue; single lab\",\n      \"pmids\": [\"36849939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALDH2-mediated aldehyde metabolism drives VISTA expression via the NOD/NF-κB signaling pathway. Inhibiting ALDH2 downregulates VISTA expression through inactivation of NOD/NF-κB signaling, revitalizing CD8+ T cell cytotoxic function. Mechanism confirmed by RNA sequencing, flow cytometry, Western blot, ChIP assay, and luciferase reporter assays.\",\n      \"method\": \"CRISPR KO of ALDH2, RNA sequencing, flow cytometry, Western blot, ChIP assay, luciferase reporter, immunocompetent tumor models\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal mechanistic methods establishing NOD/NF-κB/VISTA axis; single lab\",\n      \"pmids\": [\"38088186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Chemotherapy promotes VISTA expression in tumor cells via HIF-2α. VISTA overexpression on melanoma cells promotes immune evasion, and this is reversible by VISTA-blocking antibody in combination with carboplatin.\",\n      \"method\": \"HIF-2α pathway analysis, VISTA expression after chemotherapy treatment, VISTA-blocking antibody in combination with carboplatin in melanoma model\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, HIF-2α link shown but mechanistic detail on the HIF-2α–VISTA transcriptional axis is limited in the abstract\",\n      \"pmids\": [\"36898416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VISTA interacts intracellularly with galectin-9, facilitating its interaction with TGF-β-activated kinase 1 (TAK1), a process required for lysosomal protection. VISTA expression is differentially regulated by TGF-β (via TGF-β–Smad3 pathway), hypoxic signaling, TAK1/ASK1-induced activation of ATF-2, and other TME factors. Five critical functions of VISTA were determined through these regulatory networks.\",\n      \"method\": \"Co-IP of intracellular VISTA with galectin-9 and TAK1, TGF-β and hypoxia treatment, pathway inhibitor experiments, lysosomal protection assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — intracellular interaction shown by Co-IP; full mechanistic characterization limited in abstract; single lab\",\n      \"pmids\": [\"39983894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VISTA stimulation in ILC2s activates FOXO1, leading to modulation of ILC2 proliferation and function. VISTA-deficient ILC2s show enhanced fatty acid oxidation and oxidative phosphorylation and increased type 2 cytokine production, exacerbating airway hyperreactivity. VISTA agonist treatment reduces ILC2 function ex vivo and in vivo, alleviating ILC2-driven airway hyperreactivity.\",\n      \"method\": \"Vsir-/- mice and VISTA-deficient ILC2 transfer, FOXO1 inhibitors/activators, metabolic profiling (FAO and OXPHOS), ILC2 cytokine assays, AHR model, humanized mouse model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model plus pharmacological FOXO1 manipulation plus metabolic profiling plus in vivo therapeutic model; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39745792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PD-1H (VISTA) on both T cells and myeloid cells (including neutrophils and plasmacytoid dendritic cells) transmits inhibitory signals, resulting in reduced activation and function. Agonistic mAb in MRL/lpr lupus mice reduces cutaneous disease, autoantibodies, inflammatory cytokines, and immune cell expansion.\",\n      \"method\": \"PD-1H KO mice on BALB/c background (spontaneous lupus model), mass cytometry, agonistic mAb treatment in MRL/lpr mice, cell-type-specific inhibitory signaling assays\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple KO mouse models plus mass cytometry plus agonist mAb therapeutic experiments; single lab\",\n      \"pmids\": [\"31826980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VISTA expression in macrophages drives M2-like differentiation, strongly downregulates SIRPα (a 'don't eat me' signal), augments phagocytic activity against cancer cells, and reduces IL-1β while elevating IL-10 secretion. VISTA interacts with MHC-I and downregulates its surface expression, leading to diminished T cell activation. Expression of VISTA's extracellular domain alone was sufficient to trigger phagocytosis in ~50% of cell lines.\",\n      \"method\": \"VISTA overexpression in THP-1 and primary monocytes, macrophage polarization assays (qRT-PCR, flow cytometry, ELISA), phagocytosis assay with Rituximab-opsonized target cells, SIRPα expression analysis, MHC-I surface expression analysis, T cell co-culture\",\n      \"journal\": \"Experimental hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression in cell line and primary cells plus multiple functional readouts; single lab\",\n      \"pmids\": [\"38553748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VISTA agonist (VISTA.COMP) treatment of LPS-stimulated macrophages and neutrophils ex vivo downregulates pro-inflammatory cytokines and increases expression of immunoregulatory genes. In vivo administration of VISTA.COMP attenuated circulating TNFα, IL-6, and IL-12p40 in LPS-treated mice. A VISTA receptor is rapidly expressed on the surface of macrophages and neutrophils upon LPS exposure.\",\n      \"method\": \"Ex vivo LPS stimulation of macrophages/neutrophils, VISTA.COMP agonist treatment, cytokine measurement, in vivo LPS model with VISTA.COMP\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional agonist experiments in ex vivo and in vivo models; single lab\",\n      \"pmids\": [\"35933919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The transcription factor SP1 physically interacts with and stabilizes the YAP/TEAD4 complex at VISTA regulatory genomic loci in colorectal cancer. PKCζ phosphorylates SP1, enhancing its interaction with TEAD4 and coregulating VISTA expression. VISTA was identified as a direct transcriptional target of the SP1-YAP/TEAD4 complex. YAP-induced VISTA upregulation in CRC cells strongly suppresses CD8+ T cell antitumor function.\",\n      \"method\": \"SP1-YAP/TEAD4 Co-IP, ChIP assay, PKCζ phosphorylation assay, VISTA promoter reporter assay, VISTA KD/OE in CRC cells, CD8+ T cell co-culture functional assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, reporter) establishing transcriptional regulation plus functional T cell suppression assay; single lab\",\n      \"pmids\": [\"39875519\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VISTA (VSIR/PD-1H) is a dual-function immune checkpoint protein that acts as both a ligand on myeloid cells and a coinhibitory receptor on T cells and other immune cells; its extracellular IgV domain contains a distinctive histidine-rich region and noncanonical topology (established by crystal structure) that mediates pH-dependent binding to PSGL-1 and pH-independent interactions with VSIG-3, VSIG-8, galectin-9, and LRIG1, suppressing T cell activation through multiple downstream pathways including FOXO1 and TCR signaling; on myeloid cells, VISTA controls TLR/TRAF6/NF-κB and MAPK signaling, STAT3-dependent polyamine biosynthesis supporting MDSC differentiation, chemokine production and receptor recycling, macrophage polarization towards M2-like states with SIRPα downregulation and augmented phagocytosis, and MHC-I surface levels; VISTA transcription is directly regulated by STAT3, FOXD3, the SP1-YAP/TEAD4 complex, HIF-2α, and epigenetic promoter methylation; in osteoclasts, PD-1H serves as the MMP-13 receptor and supports c-Src activation and sealing zone formation; and in endothelial cells, VISTA selectively blocks T cell transmigration in a VEGF-A-dependent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VSIR (VISTA/PD-1H) is a dual-function immune checkpoint protein that operates both as an inhibitory ligand on myeloid cells and as a coinhibitory receptor on T cells, enforcing immune quiescence and peripheral tolerance [#4, #8]. Its extracellular IgV-like domain has a noncanonical topology—an elongated CC' loop, an extra 'H' β-strand, a clamping disulfide, and surface-exposed histidine clusters that are essential for T cell inhibition [#1]; these histidine residues confer selective binding to PSGL-1 at the acidic pH of the tumor microenvironment, and pH-selective antibodies blocking this interaction reverse VISTA-mediated suppression [#0]. VISTA additionally engages a panel of binding partners—VSIG-3/IGSF11, VSIG-8, and LRIG1—that suppress TCR signaling and T cell proliferation and cytokine production [#2, #18, #11]. Genetically, VISTA acts nonredundantly with PD-1, with double-knockout mice showing synergistic autoimmunity and combination blockade achieving optimal tumor clearance [#5]. As a receptor on naive and regulatory T cells, agonistic engagement arrests T cell activation and promotes tolerance, in part through FOXO1-dependent control of innate lymphoid cell metabolism and function [#8, #28]. On myeloid cells, VISTA restrains TLR signaling by regulating TRAF6 polyubiquitination to dampen MAPK/AP-1 and NF-κB cascades [#7], drives MDSC differentiation through STAT3-dependent polyamine biosynthesis [#12], controls chemokine production and receptor recycling to enable myeloid chemotaxis [#17], and promotes M2-like macrophage polarization with SIRPα downregulation, augmented phagocytosis, and reduced surface MHC-I [#30]. VISTA transcription is directly controlled by STAT3, FOXD3, and an SP1-stabilized YAP/TEAD4 complex, and is modulated by promoter methylation and aldehyde/NOD/NF-κB signaling [#24, #23, #32, #22, #25]. Beyond immune regulation, PD-1H serves as the osteoclast receptor for MMP-13, supporting c-Src activation and sealing zone formation [#13], and on tumor endothelium selectively blocks T cell transmigration in a VEGF-A-dependent manner [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established an early, non-immune cellular function for VSIR (GI24) in tumor invasion, before its checkpoint role was recognized.\",\n      \"evidence\": \"Overexpression, siRNA knockdown, MMP inhibitor treatment, and collagen invasion assay in oral squamous carcinoma cells\",\n      \"pmids\": [\"20666777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not connect this MT1-MMP cell-surface regulation to immune checkpoint signaling\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved whether VISTA acts only as a ligand by showing it also functions as a coinhibitory receptor on CD4+ T cells, broadening its mechanistic identity.\",\n      \"evidence\": \"Genetic knockout mice, agonistic mAb, in vitro T cell assays, glioma model with CD4/CD8 depletion\",\n      \"pmids\": [\"24743150\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The receptor counter-ligand on T cells was not identified\", \"Downstream signaling pathway undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Determined that VISTA operates nonredundantly with PD-1, establishing it as a distinct checkpoint axis amenable to combination blockade.\",\n      \"evidence\": \"Single and double knockout mice, 2D2 TCR transgenic crosses, combination antibody tumor therapy\",\n      \"pmids\": [\"25964334\", \"25917101\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of nonredundancy with PD-1 not resolved\", \"Whether the two phases of T cell suppression use the same receptor unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified transcriptional/epigenetic control of VISTA, addressing how its expression is silenced or induced in cancer.\",\n      \"evidence\": \"Promoter methylation analysis, miR-125a-5p overexpression, TGFβ1-EMT model in gastric cancer\",\n      \"pmids\": [\"27721458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BMP-pathway relationship described as cell-context dependent\", \"Direct transcription factors not identified here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed multimeric VISTA acts as a soluble agonist of a T cell receptor, and that VISTA controls Th17/γδ T cell responses via myeloid signaling.\",\n      \"evidence\": \"Pentameric VISTA.COMP construct in allograft and hepatitis models; Vsir-/- mice in psoriasis model with Erk/Jnk and IL-23/IL-17 readouts\",\n      \"pmids\": [\"28931757\", \"28469254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The putative T cell receptor engaged by VISTA.COMP was not molecularly identified\", \"Avidity requirements not fully defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified VSIG-3/IGSF11 as the first defined VISTA ligand mediating T cell suppression.\",\n      \"evidence\": \"Functional ELISA binding screen, T cell proliferation/cytokine assays, neutralizing antibody blockade\",\n      \"pmids\": [\"30220083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural definition of the interface in this study\", \"Downstream T cell signaling not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the structural and pH-dependent basis of VISTA binding and established myeloid-intrinsic mechanisms of suppression.\",\n      \"evidence\": \"Histidine mutagenesis with pH-selective antibodies and tumor models (PSGL-1); TRAF6 polyubiquitination and NF-κB/MAPK assays in myeloid cells; chemokine/receptor-recycling assays; mass cytometry in lupus models\",\n      \"pmids\": [\"31645726\", \"31340983\", \"31803182\", \"31826980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How acidic-pH PSGL-1 binding integrates with pH-independent ligands unresolved\", \"Mechanism linking VISTA to TRAF6 ubiquitination machinery not detailed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided atomic structure of the VISTA ectodomain and established its role in maintaining naive T cell quiescence and in galectin-9 engagement.\",\n      \"evidence\": \"1.9 Å crystal structure with functional mutagenesis; Vsir-/- naive T cell quiescence and tolerance assays; FOXD3/BRAF inhibitor transcriptional studies; galectin-9 binding and granzyme B/apoptosis assays\",\n      \"pmids\": [\"31919279\", \"31949051\", \"31940493\", \"33329552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Galectin-9 interaction (Low confidence) lacks full mechanistic characterization\", \"Structural basis of pH-independent partner binding not solved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Solved the VSIG3 ectodomain structure to enable small-molecule inhibition and revealed VISTA can function as an activating receptor on monocytes.\",\n      \"evidence\": \"2.64 Å VSIG3 crystal structure, Co-IP, docking, and inhibitor assay; scRNA/CITE-seq with Fc-functional agonist antibodies and pentameric VISTA pulldowns identifying Syndecan-2\",\n      \"pmids\": [\"33841409\", \"34106206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How VISTA toggles between inhibitory and activating signaling on monocytes unresolved\", \"Syndecan-2/heparan sulfate role not functionally dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended VISTA mechanism into tissue-specific macrophage/microglia biology and quantified the VSIG-8 interaction.\",\n      \"evidence\": \"Cx3Cr1-Cre conditional KO microglia phagocytosis; Vsir-/- kidney macrophage T cell contact and immunometabolism with IFN-γ/IL-9 blockade; MST-measured VSIG-8 affinity with alanine mutagenesis and IL-2 readout; VISTA.COMP in LPS sepsis models\",\n      \"pmids\": [\"34006329\", \"34752423\", \"35404016\", \"35933919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific receptors mediating these effects not all identified\", \"Whether VSIG-8 is a physiologically dominant ligand unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified VISTA as the osteoclast MMP-13 receptor, the tumor endothelial gatekeeper of T cell transmigration, and a direct STAT3 transcriptional target.\",\n      \"evidence\": \"Pd-1h-/- osteoclast fusion/c-Src/sealing zone assays; ex vivo vasculature transmigration under flow with VEGF-A blockade; ChIP/STAT3 promoter binding with inhibitor rescue; HIF-2α chemotherapy-induced expression\",\n      \"pmids\": [\"37460553\", \"37695550\", \"36849939\", \"36898416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single ectodomain serves both immune-ligand and MMP-13-receptor roles unresolved\", \"HIF-2α transcriptional axis (Low confidence) mechanistically thin\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined LRIG1 as a VISTA-engaging T cell inhibitory receptor and established the STAT3-polyamine axis for MDSC differentiation plus VISTA-driven macrophage reprogramming.\",\n      \"evidence\": \"LRIG1 binding identification with conditional KO and TCR signaling; myeloid conditional KO with STAT3/polyamine/mitochondrial readouts; VISTA overexpression macrophage polarization, SIRPα, phagocytosis, and MHC-I assays\",\n      \"pmids\": [\"38758807\", \"38175754\", \"38553748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among the multiple T cell receptors/ligands (LRIG1, VSIG-3, PSGL-1) not established\", \"How VISTA physically downregulates SIRPα and MHC-I unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the regulatory and signaling network through SP1-YAP/TEAD4 transcriptional control, intracellular galectin-9/TAK1 interaction, and FOXO1-dependent ILC2 metabolic control.\",\n      \"evidence\": \"SP1-YAP/TEAD4 Co-IP/ChIP/reporter with PKCζ phosphorylation in CRC; intracellular VISTA-galectin-9-TAK1 Co-IP and lysosomal protection; Vsir-/- ILC2 with FOXO1 modulation and metabolic profiling\",\n      \"pmids\": [\"39875519\", \"39983894\", \"39745792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular galectin-9/TAK1 mechanism (Low confidence) lacks full characterization\", \"How surface checkpoint signaling integrates with intracellular functions unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which of the multiple identified ligands/receptors (PSGL-1, VSIG-3, VSIG-8, galectin-9, LRIG1, MMP-13) dominate in each cell context, and how VISTA's intracellular tail transduces both inhibitory and activating signals.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified signaling model linking ectodomain ligand engagement to cytoplasmic output\", \"Cell-type-specific receptor usage not systematically mapped\", \"Structural basis of pH-independent multi-partner binding unsolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 8, 11]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 16, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 30]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [14, 30, 31]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 11, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [24, 23, 32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 14, 26]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PSGL-1\", \"VSIG3\", \"VSIG8\", \"LRIG1\", \"LGALS9\", \"MMP13\", \"TRAF6\", \"TAK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}