Keratinocyte VISTA attenuates UV light-induced skin injury by suppressing cutaneous type I interferon (IFN-I) response

Persistent production of type I interferons (IFN-Is) is a hallmark of cutaneous lupus erythematosus (CLE). Ultraviolet (UV) light stimulates IFN-I response in the skin and exacerbates CLE. Here, we identify V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) as a negative regulator of both basal and UV-induced IFN-I responses in the skin and show that VISTA limits skin photosensitivity in an IFN-I- dependent manner, in part through Stimulator of Interferon Genes (STING). Furthermore, we demonstrate a novel role for VISTA in keratinocytes both at steady state and in response to UV light. Conditional deletion of VISTA in epidermal keratinocytes results in >10-fold increase in the basal skin IFN-I score and a heightened UV-induced skin injury score, which is dependent on IFN-I signaling. VISTA-targeting monoclonal antibodies suppress UV-induced IFN-I response in human keratinocytes and in mice expressing human VISTA <i>in vivo</i> , which also reduces UV-induced skin injury score. Our findings highlight VISTA as a potential therapeutic target for suppressing IFN-I responses in cutaneous lupus patients who suffer from UV-induced skin inflammation.