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

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Abstract

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 response 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 a ~10-fold increase in basal skin IFN-I scores and a heightened UV-induced skin injury score, both of which are dependent on IFN-I signaling. VISTA-targeting monoclonal antibodies suppress the UV-induced IFN-I response in human keratinocytes and in mice expressing human VISTA in vivo, thereby reducing UV-induced skin injury scores. Together, these findings identify VISTA as a keratinocyte-intrinsic checkpoint that restrains STING-associated IFN-I response in the skin and suggest VISTA agonism as a therapeutic strategy to limit photosensitivity in CLE.

Authors

Zachary T. Peters, Lindsay K. Mendyka, J'Voughnn A. Blake, Himanshu B. Goswami, Angelique N. Cortez, Grace E. Crossland, Sicong Shan, Elizabeth C. Nowak, Myana Keusch, Mrinal K. Sarkar, Johann E. Gudjonsson, Christopher M. Burns, Dorothea T. Barton, Bruce R. Blazar, Tyler J. Curiel, Rodwell Mabaera, Victoria P. Werth, Andrea Kalus, Keith B. Elkon, Randolph J. Noelle, Sladjana Skopelja-Gardner