Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis

Abstract

V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an inhibitory immune-checkpoint molecule that suppresses CD4+ and CD8+ T cell activation when expressed on antigen-presenting cells. Vsir−/− mice developed loss of peripheral tolerance and multi-organ chronic inflammatory phenotypes. Vsir−/− CD4+ and CD8+ T cells were hyper-responsive towards self- and foreign antigens. Whether or not VISTA regulates innate immunity is unknown. Using a murine model of psoriasis induced by TLR7 agonist imiquimod (IMQ), we show that VISTA deficiency exacerbated psoriasiform inflammation. Enhanced TLR7 signaling in Vsir−/− dendritic cells (DCs) led to the hyper-activation of Erk1/2 and Jnk1/2, and augmented the production of IL-23. IL-23, in turn, promoted the expression of IL-17A in both TCRγδ+ T cells and CD4+ Th17 cells. Furthermore, VISTA regulates the peripheral homeostasis of CD27− γδ T cells and their activation upon TCR-mediated or cytokine-mediated stimulation. IL-17A-producing CD27− γδ T cells were expanded in the Vsir−/− mice and amplified the inflammatory cascade. In conclusion, this study has demonstrated that VISTA critically regulates the inflammatory responses mediated by DCs and IL-17-producing TCRγδ+ and CD4+ Th17 T cells following TLR7 stimulation. Our finding provides a rationale for therapeutically enhancing VISTA-mediated pathways to benefit the treatment of autoimmune and inflammatory disorders.

Lifting the innate immune barriers to antitumor immunity

“…While this can function in suppressing T cell activation in an autologous manner, a study using imiquimod-induced murine psoriasis demonstrated that VISTA inhibits the activation of DCs and the production of IL-23 following TLR 7 activation. 110 The same study also demonstrated that VISTA negatively regulates the activation of IL-17producting γδ T cells and Th17 cells. 110 Therefore, it is conceivable that at least some aspects of VISTA blockade in boosting antitumor immunity involve releasing the brakes on innate immunity.…”

“…110 The same study also demonstrated that VISTA negatively regulates the activation of IL-17producting γδ T cells and Th17 cells. 110 Therefore, it is conceivable that at least some aspects of VISTA blockade in boosting antitumor immunity involve releasing the brakes on innate immunity.…”

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.…”

“…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).…”

Immunological Targets for Immunotherapy: Inhibitory T Cell Receptors

“…Combination VISTA/PD-L1 blockade produced greater antitumor effects than either agent alone, suggesting that VISTA and PD-1/PD-L1 signaling have overlapping but nonredundant inhibitory effects on CD8 T cells [178]. The effects of VISTA blockade appears to be mediated by IL-23/IL-17 axis, although how IL-17 regulates TA-specific adaptive immunity remains to be clarified [179].…”