| 2019 |
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. |
Binding assays, mutagenesis of histidine residues, pH-selective antibody engineering, in vivo tumor models |
Nature |
High |
31645726
|
| 2020 |
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. |
X-ray crystallography (1.9 Å), site-directed mutagenesis, T cell activation assays |
Proceedings of the National Academy of Sciences of the United States of America |
High |
31919279
|
| 2018 |
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. |
Functional ELISA binding screening, T cell proliferation assays, cytokine production assays, neutralizing antibody blockade |
Immunology |
Medium |
30220083
|
| 2021 |
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. |
X-ray crystallography (2.64 Å), co-immunoprecipitation, protein-protein docking, small-molecule inhibitor assay |
Frontiers in immunology |
High |
33841409
|
| 2014 |
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. |
Genetic knockout mice, agonistic mAb treatment, in vitro T cell activation assays, in vivo tumor model, CD4/CD8 T cell depletion |
The Journal of clinical investigation |
High |
24743150
|
| 2015 |
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. |
Single and double genetic knockout mice, 2D2 TCR transgenic crosses, T cell response assays, combination antibody treatment in tumor models |
Proceedings of the National Academy of Sciences of the United States of America |
High |
25964334
|
| 2015 |
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. |
PD-1H agonistic mAb treatment in murine GVHD model, flow cytometric analysis of T cell activation and Treg expansion |
Journal of immunology |
Medium |
25917101
|
| 2019 |
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. |
VISTA KO myeloid cells, TRAF6 polyubiquitination assay, MAPK/NF-κB signaling assays, MDSC/DC functional assays, in vivo tumor model |
Cancer immunology research |
Medium |
31340983
|
| 2020 |
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. |
Vsir-/- mouse model, naïve T cell subset characterization by flow cytometry, agonistic VISTA engagement, peripheral tolerance assays |
Science |
High |
31949051
|
| 2010 |
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. |
Overexpression in HEK293T cells, MMP inhibitor treatment, MT1-MMP siRNA, GI24 siRNA knockdown, collagen invasion assay |
Cancer science |
Medium |
20666777
|
| 2017 |
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. |
Vsir-/- mice, IMQ-induced psoriasis model, signaling pathway analysis (Erk1/2, Jnk1/2), IL-23/IL-17 cytokine assays, γδ T cell flow cytometry |
Scientific reports |
Medium |
28469254
|
| 2024 |
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. |
Co-immunoprecipitation/binding partner identification, T cell-specific conditional KO mice, tumor models, TCR signaling assays, flow cytometry of CTL subsets |
Science immunology |
High |
38758807
|
| 2024 |
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. |
Myeloid-specific conditional KO mice, bone marrow chimera assays, STAT3 activation assays, polyamine biosynthesis measurements, mitochondrial respiration assays, flow cytometry |
Cell reports |
High |
38175754
|
| 2023 |
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. |
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 |
Nature communications |
High |
37460553
|
| 2023 |
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. |
Ex vivo human vasculature model, T cell transmigration assay under physiologic flow, immunofluorescence/confocal localization, VEGF-A blockade experiments, flow cytometry |
Cancer immunology research |
Medium |
37695550
|
| 2021 |
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. |
Novel VISTA antibody development, scRNA/CITE-seq of human PBMCs, pentameric VISTA pulldown/binding assays |
The Journal of experimental medicine |
Medium |
34106206
|
| 2017 |
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. |
Pentameric VISTA.COMP construct design, in vitro T cell proliferation assay, murine skin allograft model, ConA-induced hepatitis model |
JCI insight |
Medium |
28931757
|
| 2019 |
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. |
VISTA KO macrophages, cytokine/chemokine measurement in culture supernatants, chemokine receptor recycling assay, in vivo tumor migration assay |
Frontiers in immunology |
Medium |
31803182
|
| 2022 |
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. |
ELISA binding assay, Microscale Thermophoresis (MST), Co-IP, VISTA alanine mutagenesis, IL-2 cytokine assay in VISTA-KO vs. overexpressing cells |
Investigational new drugs |
Medium |
35404016
|
| 2020 |
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. |
Binding assays, soluble VISTA experiments, membrane potential measurements, granzyme B activation assay, T cell apoptosis assay |
Frontiers in immunology |
Low |
33329552
|
| 2022 |
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. |
Cx3Cr1-Cre VISTA conditional KO mice, microglia morphology analysis, transcriptional profiling, myelin phagocytosis assay in vitro |
Acta neuropathologica communications |
Medium |
34006329
|
| 2022 |
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. |
Vsir-/- mouse nephrotoxic serum model, macrophage-T cell contact frequency analysis, T cell metabolic profiling, IFN-γ/IL-9 measurements, blocking antibody treatment |
The Journal of clinical investigation |
Medium |
34752423
|
| 2016 |
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. |
Promoter methylation analysis, miR-125a-5p overexpression, TGFβ1-induced EMT model, cancer cell line analysis, primary gastric cancer sample analysis |
Scientific reports |
Medium |
27721458
|
| 2020 |
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. |
FOXD3 modulation experiments, BRAF inhibitor treatment, in vivo syngeneic tumor model, flow cytometry of TILs |
Cell reports |
Medium |
31940493
|
| 2023 |
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. |
ChIP/STAT3 binding to VISTA promoter, STAT3 inhibitor treatment, co-treatment with anti-VISTA mAb in AML models in vitro and in vivo |
Journal of hematology & oncology |
Medium |
36849939
|
| 2023 |
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. |
CRISPR KO of ALDH2, RNA sequencing, flow cytometry, Western blot, ChIP assay, luciferase reporter, immunocompetent tumor models |
Journal for immunotherapy of cancer |
Medium |
38088186
|
| 2023 |
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. |
HIF-2α pathway analysis, VISTA expression after chemotherapy treatment, VISTA-blocking antibody in combination with carboplatin in melanoma model |
Biochemical pharmacology |
Low |
36898416
|
| 2025 |
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. |
Co-IP of intracellular VISTA with galectin-9 and TAK1, TGF-β and hypoxia treatment, pathway inhibitor experiments, lysosomal protection assay |
Cancer letters |
Low |
39983894
|
| 2025 |
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. |
Vsir-/- mice and VISTA-deficient ILC2 transfer, FOXO1 inhibitors/activators, metabolic profiling (FAO and OXPHOS), ILC2 cytokine assays, AHR model, humanized mouse model |
The Journal of clinical investigation |
Medium |
39745792
|
| 2019 |
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. |
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 |
Science translational medicine |
Medium |
31826980
|
| 2024 |
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. |
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 |
Experimental hematology & oncology |
Medium |
38553748
|
| 2022 |
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. |
Ex vivo LPS stimulation of macrophages/neutrophils, VISTA.COMP agonist treatment, cytokine measurement, in vivo LPS model with VISTA.COMP |
Cellular immunology |
Medium |
35933919
|
| 2025 |
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. |
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 |
Cell death and differentiation |
Medium |
39875519
|