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

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.