Role of VISTA in discoid lupus erythematosus

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PROJECT SUMMARY Discoid lupus erythematosus (DLE) is a chronic inflammatory skin disease that severely impairs quality of life and is characterized by disfiguring scarring, hair loss, itching, and pain. It is estimated that DLE affects nearly 225,000 US persons and disproportionally affects woman of color. There are no FDA-approved treatments and current off-label therapies are often ineffective for many patients. Emerging targeted therapies for DLE are in early clinical development, but we lack understanding of the full spectrum of pathogenic immune cells and cytokines that could be therapeutically targeted. Evidence suggests that plasmacytoid dendritic cells (pDCs) are a key driver of DLE and trials are starting to target pDCs for DLE therapy. Our previous work demonstrated that immune inhibitory receptor V-domainIg suppressor of T cell activation (VISTA)inhibits DLE development in the murine MRL/lpr lupus model. VISTA is a unique immune inhibitory receptor as it is expressed on T cells and myeloid cell subsets. We showed that mice lacking VISTA spontaneously develop DLE-like disease and that stimulation of VISTA reduces production of type I interferons by pDCs in MRL/lpr lupus mice. We also found that skin biopsies from human DLE express high levels of VISTA when compared to other autoimmune skin diseases. However, not much else is known about the role of VISTA in DLE or the function of VISTA on pDCs. The goal of this proposal is to determine if pDCs are critical for DLE development in VISTA knockout mice, the human DLE express VISTA, the transcriptional profile of VISTA+ pDCs in human DLE and. In Aim 1, we will identify which immune cells subsets within human DLE express VISTA, their cellular connections, VISTA receptor-ligand pairing and determine the transcriptional profile of VISTA+ cells by performing highly multiplexed single cell imaging and spatial transcriptomics. In Aim 2, we will determine the critical cells involved in DLE development in conditional VISTA knockout mice and the mechanism of pDC inhibition by VISTA using an agonist VISTA antibody. The Principal Investigator, Matthew Vesely MD, PhD, is a dermatologist and immunologist at Yale School of Medicine. His goal is to lead an independent academic research lab studying the immunopathogenesis of autoimmune skin diseases such as DLE. He will pursue this goal by 1) developing expertise in the generation and analysis of spatial proteomics and in situ transcriptomic data; 2) becoming an expert in immune cell inhibition by VISTA; 3) establishing a community of mentors and collaborators in DLE and single cell imaging technologies; 4) completing coursework to expand his computational and statistical background. These mentors and his career development plan will help him acquire the skills and expertise needed to develop his own distinct niche in immune inhibition of autoimmune skin diseases, become an expert in single-cell imaging, and potentially develop new therapies for these diseases.