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  ORCID: https://orcid.org/0000-0002-2020-7522 and De Libero, Gennaro
2025.
Mitochondria regulate MR1 protein expression and produce self-metabolites that activate MR1-restricted T cells.
Proceedings of the National Academy of Sciences
122
(20)
, e2418525122.
10.1073/pnas.2418525122
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Abstract
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.
| Item Type: | Article |
|---|---|
| Date Type: | Published Online |
| Status: | Published |
| Schools: | Schools > Medicine |
| Publisher: | National Academy of Sciences |
| ISSN: | 0027-8424 |
| Date of First Compliant Deposit: | 20 May 2025 |
| Date of Acceptance: | 11 March 2025 |
| Last Modified: | 21 May 2025 10:30 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/178385 |
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