JMJD3 promotes MAIT cell thymic egress and differentiation into MAIT17 cells

Mucosal Associated Invariant T (MAIT) cells are a subset of innate, invariant, T cells that recognize microbial antigens presented by MHC class I-related molecules. They are involved in a broad spectrum of diseases. A Th17-like subset of MAIT cells, MAIT17 cells, have been implicated to promote cancer and autoimmunity in several studies. However, the mechanisms governing MAIT cell differentiation into MAIT17 cells is poorly understood, impeding the development of MAIT cell-based therapies. Here, we investigate the role of Jumanji domain-containing protein-3 (JMJD3), a histone demethylase which regulates trimethylation of histone H3 lysine 27, in MAIT cell development, differentiation into MAIT17 cells, and function. Utilizing multiparameter flow cytometry analysis of MAIT cells in CD4cre+JMJD3^fl/fl mice (JMJD3KO), we observed repression of thymic egress which altered MAIT cell abundance in specific organs. Furthermore, we found a halt in differentiation of MAIT cells into MAIT17 cells despite normal thymic MAIT cell maturation. A combined GO term and GSEA analysis of RNA sequencing data from thymic MAIT cells in JMJD3KO mice suggests that JMJD3 promotes MAIT cell microtubule dynamics which promotes thymic egress. Furthermore, this data also suggests that JMJD3 regulates MAIT cell cellular metabolism which may halt differentiation of MAIT cells into MAIT17 cells. Overall, our work suggests that JMJD3 may serve as a therapeutic target for diseases promoted by MAIT17 cells.