Project Summary / Abstract Systemic lupus erythematosus (SLE, lupus) is a multi-organ autoimmune disease with 5-10% mortality in 10 years. Skin is severely affected by this disease and sensitivity to ultraviolet (UV) sunlight rays affects up to 80% of patients. The immunologic mechanisms involved in cutaneous lupus (CLE) remain poorly understood. In particular, the role of different types of T cells, highly prevalent lymphocytes in CLE skin, is unknown. The overall objectives in this proposal are: (i) to profile and determine the function of MAIT cells in CLE in relation to the skin microbiome and (ii) to define the role of MAIT cells in lupus skin disease and photosensitive responses in vivo. The central hypothesis is that activation of MAIT cells, influenced by preferential expansion of riboflavin-producing bacteria, mediates skin pathogenesis in CLE. The rationale for this project stems from the gap in the knowledge of how the altered microbiome in lupus skin impacts immune activation, and specifically MAIT cells, and leads to tissue damage. The central hypothesis will be tested by pursuing two specific aims: 1 Define how skin microbiome shapes MAIT cell function in CLE patients and 2) Establish how lupus-specific interactions between skin microbiota and MAIT cells mediate cutaneous lupus in vivo. Under the first aim, MAIT cells from lupus skin (lesional and unaffected) will be evaluated for quantity, heterogeneity, transcriptomic signatures, and TCR usage (relative to healthy skin) and these findings analyzed in relation to the abundance of microbial communities and riboflavin gene expression. For the second aim, the role of MAIT cells in the development of lupus skin disease will be evaluated in Mrl-lpr mice deficient in MAIT cells (Mrl.lprMR1-/-). This new murine strain will be used to investigate how dermal association with riboflavin or Staphylococcus bacteria influences MAIT cell function in spontaneous and UV light- accelerated CLE in vivo. The research proposed in this application is innovative because it will generate a novel mechanism of lupus skin disease and interrogate a T cell population reported to have inflammatory properties in other skin disease but has not yet been studied in CLE. The proposed research is significant because it is expected to provide a strong scientific rationale to address the imbalance in lupus skin microbiome and/or modulate MAIT cells for therapeutic purposes in lupus skin disease.