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

Peters, Z. T.; Mendyka, L. K.; Blake, J.; Goswami, H. B.; Cortez, A. N.; Crossland, G. E.; Shan, S.; Nowak, E.; Sarkar, M.; Gudjonsson, J. T.; Burns, C. M.; Barton, D. T.; Blazar, B. R.; Curiel, T. J.; Mabaera, R.; Werth, V. P.; Kalus, A.; Elkon, K.; Noelle, R. J.; Skopelja-Gardner, S.

doi:10.64898/2025.12.04.692370

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bioRxiv · 10.64898/2025.12.04.692370

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 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 in vivo, 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.

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Peters, Z. T., Mendyka, L. K., Blake, J., Goswami, H. B., Cortez, A. N., Crossland, G. E., Shan, S., Nowak, E., Sarkar, M., Gudjonsson, J. T., Burns, C. M., Barton, D. T., Blazar, B. R., Curiel, T. J., Mabaera, R., Werth, V. P., Kalus, A., Elkon, K., Noelle, R. J., Skopelja-Gardner, S.. 2025-12-09. Keratinocyte VISTA attenuates UV light-induced skin injury by suppressing cutaneous type I interferon (IFN-I) response. https://doi.org/10.64898/2025.12.04.692370

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