Immune checkpoint VISTA protects the skin from injury by ultraviolet light by regulating the STING-mediated (IFN-I) response 2793

Abstract Description Exposure to ultraviolet (UV) light induces type I interferons (IFN-Is) that are essential to repair skin injury but if excessive can result in pathogenic skin sensitivity in autoimmune diseases like lupus. In previous studies, we showed that VISTA deficient (Vsir-/- ) mice and mice with conditional deletion of VISTA in their keratinocytes (KRT14creVsirfl/fl) have elevated baseline and UV-induced skin IFN-I responses. To test whether Vsir-/- mice exhibit skin sensitivity to UV light, we exposed WT B6, Vsir-/-, KRT14creVsirfl/fl, and cre-Vsirfl/fl female mice (3 mo) to an acute dose of UVB and quantified their cutaneous lupus activity and severity index (CLASI) 48 hr post exposure. Vsir-/- and KRT14creVsirfl/fl mice had elevated CLASI scores, increased Ly6CHI monocytes and higher CD8:Treg ratios in the skin post UVB. Treatment of Vsir-/- and KRT14creVsirfl/fl mice with anti-interferon receptor antibody (IFNAR, i.p. 3hr after UV) to suppress IFN-I signaling or genetic deletion of the cytosolic DNA sensor STING (Vsir.Sting-/- mice) to suppress IFN-I production reduced UV-induced CLASI scores and suppressed monocytic and T cell infiltration and activation. Vsir-/- keratinocytes had elevated UV-induced IFN-I ex vivo, which was abrogated in the absence of STING. Finally, antibody-mediated VISTA activation on human keratinocytes reduced UV-induced IFN-I response, highlighting its potential as a therapeutic target to mitigate UV-driven skin inflammation in lupus. Funding Sources 5R01AI148430-05- VISTA is a negative checkpoint regulator of innate immunity Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)