Disruption of the immune-checkpoint VISTA gene imparts a proinflammatory phenotype with predisposition to the development of autoimmunity

Abstract

Significance The discovery of V domain-containing Ig suppressor of T-cell activation (VISTA) as a novel immune-checkpoint regulator comes at an exciting time, as the field of cancer immunotherapy has made significant progress owing to the clinical success of targeting immune-checkpoint proteins such as cytotoxic T lymphocyte-associated antigen 4 and programmed death 1 and ligand. Recent studies also show the promise of monoclonal antibody-mediated VISTA targeting for enhancing antitumor immunity in murine tumor models. The current study demonstrates the spectrum of immune alterations upon genetic disruption of VISTA in mice in the context of self-tolerance as well as immune response against neoantigen. These results enhance the understanding of the immune-regulatory role of VISTA and form the foundation for designing future clinical applications that target VISTA in treating human diseases.

Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses

“…To address this question, mice were immunized with soluble antigenic peptides together with poly (I:C) (TLR3 agonist) as adjuvant. 2W1S, an MHC class II-restricted peptide, and OVA 257-264 , an MHC class I-restricted peptide, were used (22). On day +7 postimmunization, splenic T cells were isolated and restimulated ex vivo with the respective peptides.…”

“…Genetic disruption of VISTA accelerated autoimmune disease on a susceptible background, as well as resulted in multiorgan chronic inflammation because of spontaneous T-cell activation (22). Aged PD-1 KO mice were reported to develop late-onset autoimmunity in the C57BL/6 background (10).…”

VISTA.COMP — an engineered checkpoint receptor agonist that potently suppresses T cell–mediated immune responses

“…Research is currently ongoing to characterize the cell-signaling mechanisms triggered by VISTA.COMP in both mouse and human T cells. Nonetheless, our data, combined with the observation of exacerbated autoimmune diseases upon genetic deletion of VISTA (15)(16)(17)(18), suggest a potential utility of targeting the VISTA-mediated immunosuppression pathway using a high-avidity VISTA-IgV containing scaffold to clinically suppress undesired immune responses.…”

“…increased levels of peripheral encephalitogenic T cells and develop an exacerbated form of experimental autoimmune encephalomyelitis (16). More recently, it was shown that VISTA-deficient mice exhibited worsened disease in a model of imiquimod-induced psoriasis, where enhanced TLR7 signaling in DCs led to augmented IL-23 production and increased expression of IL-17A in T cells (17).…”

“…More recently, it was shown that VISTA-deficient mice exhibited worsened disease in a model of imiquimod-induced psoriasis, where enhanced TLR7 signaling in DCs led to augmented IL-23 production and increased expression of IL-17A in T cells (17). The VISTA -/-mice bred on a wild-type C57BL/6 background display a mild proinflammatory phenotype, exemplified by an increase in DCs and a rise in T cell activation markers, but were not reported to develop inflammatory disorders (16). In slight contrast, another study described a more severe phenotype, where VISTA -/-C57BL/6 mice developed glomerulonephritis at 10 months of age (18).…”