Targeting VISTA in lupus skin disease and photosensitivity

Dr. Skopelja-Gardner will use this Lupus Innovation Award to study the role of a protein called V-domain immunoglobulin suppressor of T cell activation (VISTA) – a well-established regulator that reduces immune cell activity – in controlling production of interferon (IFN-I), a marker of systemic lupus erythematosus.  Most people with lupus have high levels of IFN-I in their blood, skin, and kidneys. Moreover, most people with lupus are sensitive to sunlight ultraviolet (UV) rays. UV light is known to trigger local skin inflammation and systemic flares in lupus patients and is a potent stimulus of IFN-I production. Dr. Skopelja-Gardner’s team will test whether “turning on” the protein VISTA can “put the brakes on” the production of damaging IFN-I in the skin when the body is exposed to UV light.

What this study means for people with lupus

This study will help the scientific community better understand how IFN-I production is controlled and open new therapeutic pathways to address lupus skin disease and photosensitivity.

The majority of lupus patients (~75%) have a high type I interferon (IFN-I) signature in the blood, skin, and kidney. Our studies showed that ultraviolet light (UV), a known trigger of local skin disease and systemic flares is a potent stimulus of IFN-I in human and murine skin. The IFN-I response was not limited to the skin but was also found in the blood and the kidney. Why do skin cells in lupus patients fail to downregulate IFN-I production is unknown. Our preliminary data provide evidence that supports a role for the negative immune checkpoint VISTA in controlling IFN-I production in the skin by regulating DNA sensing: i) skin of VISTA-deficient mice has a ~50-fold higher IFN-I signature, exaggerated by UV, and accompanied by high expression of DNA sensors ZBPI-STING and AIM2, ii) VISTA-deficient keratinocytes express higher levels of IFNk, suppressed with a STING inhibitor; iii) keratinocytes upregulate VISTA in response to UV and activating VISTA inhibits their UV-triggered IFN-I; iv) skin exposure to UV stimulates systemic IFNß, exaggerated in VISTA-deficient mice. These data suggest a role for VISTA both locally and systemically and in different cell types. Therefore, the main objectives of this proposal are: i) to define the cell-specific role of VISTA in regulating local and systemic IFN-I, ii) to define the DNA sensing pathways involved in VISTA-mediated regulation of IFN-I, and iii) to assess the therapeutic potential of VISTA to control IFN-I production in lupus skin. We hypothesize that functional VISTA is required to suppress excessive local and systemic IFN-I response and that agonizing VISTA in keratinocytes and myeloid cells can downregulate IFN-I production in photosensitive lupus reactions. This hypothesis will be addressed with the following specific aims: Aim 1) Define cell-specific role of VISTA in regulating skin and systemic IFN-I response. Using conditional VISTA knockout mice, we will test how VISTA in keratinocytes, monocytes, neutrophils, and dendritic cells, impacts skin, blood, and kidney IFN-I response at baseline and in response to UV. The role of the DNA sensors will be tested in vivo, by examining if STING/AIM2/ZBP1 deficiency in VISTA knockout mice suppresses skin and systemic IFN-I. Aim 2) Test the hypothesis that VISTA can be targeted to suppress UV-triggered IFN-I response in lupus skin. If VISTA is aberrantly expressed or non-functional in lupus keratinocytes is unknown. Gene and protein levels of VISTA will be measured in lupus vs. healthy keratinocytes at baseline and in response to UV, in relation to the IFN-I signature. VISTA-activating antibodies will be used to test if enhancing VISTA function can suppress high IFN-I in lupus keratinocytes in vitro and in the skin of Trex1-/- mice (high baseline skin IFN-I) in vivo. These aims will allow us to understand the regulatory mechanisms of the IFN-I response and open new therapeutic pathways to address lupus skin disease and photosensitivity.