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 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.

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Publication Details

Journal
JCI Insight
Published
2026-10-06
DOI
https://doi.org/10.1172/jci.insight.200540
Primary Topic
Systemic Lupus Erythematosus Research
Type
article
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article

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

Keith B. Elkon, Rodwell Mabaera, Angelique N. Cortez, Andrea Kalus et al.
JCI Insight
Systemic Lupus Erythematosus Research
article

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

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

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.

JCI Insight
Dartmouth College (US), Dartmouth–Hitchcock Medical Center (US), University of Washington (US), University of Michigan (US), Philadelphia VA Medical Center (US), University of Minnesota Medical Center (US)
Openalex Percentile: Top 11%
Systemic Lupus Erythematosus Research
DOIOpen Access PDFOpenAlex
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