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

• 成果类型: Article
• 署名作者: Prota, Gennaro; Berloffa, Giuliano; Awad, Wael; Vacchini, Alessandro; Chancellor, Andrew; Schaefer, Verena; Constantin, Daniel; Littler, Dene R.; Colombo, Rodrigo; Nosi, Vladimir; Mori, Lucia; Rossjohn, Jamie; De Libero, Gennaro
• 署名单位: University of Basel; Monash University; Monash University; Cardiff University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11023
• DOI: 10.1073/pnas.2418525122
• 发表日期: 2025-05-20
• 关键词: electron-transport; down-regulation; dna-adducts; molecules; antigens; complex; hyperglycemia; inflammation; mechanism; PATHWAY

摘要

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 ofMR1 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 na & iuml;ve, memory, and effector cells, indicating prior in vivo stimulation. These findings suggest that mitochondria may play a role in MR1-mediated immune surveillance.