Date of Award

Spring 4-27-2026

Document Type

Thesis (Ph.D.)

Department or Program

Microbiology and Immunology

First Advisor

Sladjana Skopelja-Gardner

Abstract

Type I interferons (IFN-I) are central mediators of innate immune activation and are pathologically elevated in the tissues of patients with autoimmune diseases, including cutaneous lupus erythematosus (CLE). Paradoxically, in cancer, chronic IFN-I signaling fosters an immunosuppressive microenvironment, driven in part by the upregulation of immune checkpoint molecules. VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint that has also been identified on non-immune, non-malignant cells, yet its function in these contexts remains poorly understood. This dissertation defines a keratinocyte-intrinsic role for VISTA in suppressing STING-mediated IFN-I responses to ultraviolet (UV) light, with implications for both lupus sensitivity to ultraviolet light and cutaneous T cell lymphoma (CTCL). We first demonstrate that VISTA-deficient mice exhibit an elevated baseline interferon gene signature and increased IFN-I expression in the skin at steady state. Given the established role of IFN-I in driving UV photosensitivity in lupus, we exposed mice to an acute UV dose and found that VISTA deficiency predisposes mice to enhanced UV-induced skin injury. To define the relevant cellular compartment, we showed that keratinocyte-specific VISTA deletion recapitulates this phenotype, with mice exhibiting impaired skin barrier integrity, elevated IFN-I, and increased inflammatory monocyte recruitment. We then establish STING as the key driver of this injury. Blockade of the IFN-I receptor (IFNAR) or genetic loss of STING, globally or restricted to keratinocytes, reduced UV-induced injury and IFN-I, placing keratinocyte-intrinsic STING downstream of VISTA in this pathway. We also demonstrate that systemic anti-VISTA antibody treatment reduces UV-induced injury in humanized VISTA knock-in mice and suppresses IFN-I responses in keratinocytes in vitro. Finally, we implicate VISTA as a potential therapeutic target in CTCL, where UVB exposure is used to eliminate malignant T cells in the skin, by demonstrating that cutaneous VISTA expression correlates with poor clinical responses to UV therapy and that topical suppression of VISTA levels enhance IFN-I responses to UV exposure. Together, these findings establish VISTA as a keratinocyte-intrinsic brake on STING-driven IFN-I responses to UV, expanding the concept of immune checkpoints to include cell-autonomous innate immune regulation in barrier tissues.

Original Citation

Peters, Z. T. et al. Keratinocyte VISTA attenuates UV light-induced skin injury by suppressing cutaneous type I interferon (IFN-I) response. Preprint at https://doi.org/10.64898/2025.12.04.692370 (2025).

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Available for download on Monday, May 17, 2027

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