Pathogenic T cells in discoid lupus erythematosus - PROJECT SUMMARY Discoid lupus erythematosus (DLE) is a disfiguring autoimmune skin disease with a predilection for affecting the head and neck that causes permanent scarring, hypopigmentation, and alopecia. DLE disproportionately affects African American women, and it severely impairs quality of life. DLE may occur alone or in the setting of systemic lupus erythematosus (SLE), and treatments for DLE are currently unsatisfactory. The DLE inflammatory infiltrate is predominantly composed of T cells, which appear to promote tissue inflammation and damage, but how they adapt to the skin environment and subsequently promote tissue injury is unknown. We recently identified an inflammatory gene program induced by the transcription factor hypoxia inducible factor (HIF) that is necessary for the survival and effector ability of pathogenic T cells in lupus-prone mice, with a similar program upregulated in human SLE. Yet, how HIF1 promotes damage and what other tissue adaptation and effector pathways are activated in skin-infiltrating T cells in DLE are not known. Based on my preliminary studies, I hypothesize that HIF1 regulates pathogenic T cell survival and effector function in DLE skin, causing inflammation and damage that may be mediated in part by enhanced cytotoxicity. This HIF1-regulated effector program also suggests a paradigm of pathogenic adaptation in tissue-infiltrating T cells with the potential to drive tissue damage. To test my hypothesis, I will determine the mechanism of HIF1 blockade in alleviating skin disease in a murine lupus model. I will also study human DLE skin and blood samples using single cell RNA sequencing to probe the developmental trajectory, phenotypic, and functional profile of T cells in human DLE. Finally, I will use imaging techniques to examine the role of cytotoxicity in tissue damage in human DLE, with parallel studies in mouse tissue. My studies will not only elucidate the role of HIF1 and cytotoxicity in DLE, but will also yield the first detailed characterization of infiltrating and circulating T cells in human DLE, paving the way for future studies to develop and evaluate novel therapeutics for this devastating disease. My proposal will also support a period of career development during which I will receive additional training in basic and translational immunology in the laboratory of Dr. Joseph Craft, a leader in the fields of lupus research and T cell biology. Dr. Craft's laboratory in the Yale Department of Immunobiology provides a highly collaborative and supportive research environment. To further support my training, I have assembled an advisory committee with experts in transcriptomic analyses, translational dermatology, cutaneous T cell biology, and autoimmune skin disease. My research studies and directed additional career development activities focused on computational approaches, human translational research, and biostatistics in clinical investigation will allow me to successfully achieve research independence as a physician scientist and open my own laboratory so that I can use basic and translational immunologic approaches to study cutaneous autoimmune diseases including DLE.
