Skin Gamma Delta T Cell Gene Expression Highlights Stress Response in Alopecia Areata 2258104

Abstract Introduction Alopecia areata is an autoimmune skin disease characterized by nonscarring, patchy hair loss, and affects roughly 2% of the global population. The onset of alopecia areata involves both genetic and environmental factors, leading to the loss of immune privilege. γδ T cells help regulate skin homeostasis and are elevated during alopecia areata; however, their role in disease progression remains unclear. Methods By reanalyzing publicly available single-cell RNA sequencing data from mouse and human skin, we identified genes upregulated in γδ T cells during alopecia areata. In humans, V•1 T cells respond to stress in alopecia areata by upregulating heat shock response genes (HSP70, HSP90AA1, HSPA1A, HSPA1B, DNAJB1). We validated HSP70 upregulation by skin γδ T cells in the C3H/HeJ mouse model of alopecia areata using immunofluorescent microscopy. Results Further, murine skin gd T cells also up-regulate chaperones, including CD74 and receptors that regulate T cell activation, such as Ly6A/E, in alopecia areata. We quantified CD74 and Ly6A/E expression in the skin of mice with alopecia areata and found upregulation at the hair follicle, upper dermis, and epidermis. To identify which cells are regulating gd T cell stress and activation, we further examined single-cell RNA sequencing data and have identified the genes expressed by helper CD4+ T cells to regulate gd T cell stress and activation responses during alopecia areata. Conclusion Our findings show that T cells are undergoing a prominent stress response in response to alopecia areata, which leads to their activation, making them interesting targets for therapeutics. Funding Source National Institute of Health Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)