Mitochondria regulate MR1 protein expression and produce self-metabolites that activate MR1-restricted T cells

Mitochondria coordinate several metabolic pathways, producing metabolites that influence the immune response in various ways. It remains unclear whether mitochondria impact antigen presentation by the MHC-class-I-related antigen-presenting molecule, MR1, which presents small molecules to MR1-restricted T-lymphocytes. Here, we demonstrate that mitochondrial complex III and the enzyme dihydroorotate dehydrogenase are essential for the cell-surface expression of MR1 and for generating uridine- and thymidine-related compounds that bind to MR1 and are produced upon oxidation by reactive oxygen species. One mitochondria-derived immunogenic formylated metabolite we identified is 5-formyl-deoxyuridine (5-FdU). Structural studies indicate that 5-FdU binds in the A'-antigen-binding pocket of MR1, positioning the deoxyribose toward the surface of MR1 for TCR interaction. 5-FdU stimulates specific T cells and detects circulating T cells when loaded onto MR1-tetramers. 5-FdU-reactive cells resemble adaptive T cells and express the phenotypes of naïve, memory, and effector cells, indicating prior in vivo stimulation. These findings suggest that mitochondria may play a role in MR1-mediated immune surveillance.