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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 &gt;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\n                  <jats:italic>in vivo<\/jats:italic>\n                  , 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.\n                <\/jats:p>","DOI":"10.64898\/2025.12.04.692370","type":"posted-content","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T19:25:35Z","timestamp":1765308335000},"source":"Crossref","is-referenced-by-count":1,"title":["Keratinocyte VISTA attenuates UV light-induced skin injury by suppressing cutaneous type I interferon (IFN-I) response"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2447-0691","authenticated-orcid":false,"given":"Zachary T.","family":"Peters","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay K.","family":"Mendyka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u2019Voughnn","family":"Blake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Himanshu B.","family":"Goswami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelique N.","family":"Cortez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace E.","family":"Crossland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sicong","family":"Shan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth C.","family":"Nowak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarkar","family":"Mrinal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. Gudjodsson","family":"Johann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Burns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothea T.","family":"Barton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce R.","family":"Blazar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler J.","family":"Curiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodwell","family":"Mabaera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria P.","family":"Werth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Kalus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Elkon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randolph J.","family":"Noelle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sladjana","family":"Skopelja-Gardner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025121102250812000_2025.12.04.692370v1.1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029161"},{"key":"2025121102250812000_2025.12.04.692370v1.2","doi-asserted-by":"crossref","first-page":"1429817","DOI":"10.3389\/fimmu.2024.1429817","article-title":"Identification and validation of interferon-stimulated gene 15 as a biomarker for dermatomyositis by integrated bioinformatics analysis and machine learning","volume":"15","year":"2024","journal-title":"Front Immunol"},{"key":"2025121102250812000_2025.12.04.692370v1.3","doi-asserted-by":"crossref","first-page":"905960","DOI":"10.3389\/fimmu.2022.905960","article-title":"Assessment of type I interferon signatures in undifferentiated inflammatory diseases: A Japanese multicenter experience","volume":"13","year":"2022","journal-title":"Front Immunol"},{"key":"2025121102250812000_2025.12.04.692370v1.4","doi-asserted-by":"crossref","unstructured":"A. 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