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

Gennaro Prota1, Giuliano Berloffa1, Wael Awad2

  • 1Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel 4031, Switzerland.

Proceedings of the National Academy of Sciences of the United States of America
|May 12, 2025
PubMed

Insights

Mitochondria are crucial for MR1 antigen presentation, producing metabolites like 5-formyl-deoxyuridine (5-FdU) that activate T cells, suggesting a role in immune surveillance.

Area of Science:

  • Immunology
  • Mitochondrial Biology
  • Metabolic pathways

Background:

  • Mitochondria regulate metabolic pathways influencing immune responses.
  • The role of mitochondria in Major Histocompatibility Complex (MHC)-class-I-related molecule (MR1) antigen presentation is not well understood.
  • MR1 presents small molecules to MR1-restricted T-lymphocytes.

Purpose of the Study:

  • To investigate the impact of mitochondria on MR1-mediated antigen presentation.
  • To identify mitochondria-derived metabolites that bind to MR1.
  • To explore the role of these metabolites in T-cell activation and immune surveillance.

Main Methods:

  • Investigated the necessity of mitochondrial complex III and dihydroorotate dehydrogenase for MR1 cell-surface expression.
  • Identified uridine- and thymidine-related compounds produced by mitochondria.
  • Characterized the binding of 5-formyl-deoxyuridine (5-FdU) to MR1 using structural studies.
  • Assessed T-cell stimulation by 5-FdU and detected circulating T cells using MR1-tetramers.

Main Results:

  • Mitochondrial complex III and dihydroorotate dehydrogenase are essential for MR1 expression.
  • Mitochondria generate uridine- and thymidine-related compounds, including the immunogenic metabolite 5-formyl-deoxyuridine (5-FdU).
  • 5-FdU binds to MR1 and stimulates MR1-restricted T cells, with detected T cells exhibiting adaptive immune phenotypes.

Conclusions:

  • Mitochondria play a critical role in MR1 antigen presentation through the generation of specific metabolites.
  • 5-formyl-deoxyuridine (5-FdU) is a key mitochondria-derived metabolite that binds MR1 and activates T cells.
  • These findings highlight a potential role for mitochondria in MR1-mediated immune surveillance.
Keywords:
MR1T cellsantigen presentationformylated metabolitemitochondria

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