Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions

Leticia Soriano-Baguet, Melanie Grusdat, Henry Kurniawan, Mohaned Benzarti, Carole Binsfeld, Anouk Ewen, Joseph Longworth, Lynn Bonetti, Luana Guerra, Davide G. Franchina, Takumi Kobayashi, Veronika Horkova, Charlène Verschueren, Sergio Helgueta, Deborah Gérard, Tushar H. More, Antonia Henne, Catherine Dostert, Sophie Farinelle, Antoine LesurJean Jacques Gérardy, Christian Jäger, Michel Mittelbronn, Lasse Sinkkonen, Karsten Hiller, Johannes Meiser, Dirk Brenner*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

Pyruvate dehydrogenase (PDH) is the central enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle. The importance of PDH function in T helper 17 (Th17) cells still remains to be studied. Here, we show that PDH is essential for the generation of a glucose-derived citrate pool needed for Th17 cell proliferation, survival, and effector function. In vivo, mice harboring a T cell-specific deletion of PDH are less susceptible to developing experimental autoimmune encephalomyelitis. Mechanistically, the absence of PDH in Th17 cells increases glutaminolysis, glycolysis, and lipid uptake in a mammalian target of rapamycin (mTOR)-dependent manner. However, cellular citrate remains critically low in mutant Th17 cells, which interferes with oxidative phosphorylation (OXPHOS), lipid synthesis, and histone acetylation, crucial for transcription of Th17 signature genes. Increasing cellular citrate in PDH-deficient Th17 cells restores their metabolism and function, identifying a metabolic feedback loop within the central carbon metabolism that may offer possibilities for therapeutically targeting Th17 cell-driven autoimmunity.

Original languageEnglish
Article number112153
JournalCell Reports
Volume42
Issue number3
Early online date26 Feb 2023
DOIs
Publication statusPublished - 28 Mar 2023

Keywords

  • acetyl-CoA
  • citrate
  • CP: Immunology
  • CP: Metabolism
  • epigenetics
  • experimental autoimmune encephalomyelitis
  • glucose metabolism
  • histone acetylation
  • IL-17
  • pyruvate dehydrogenase
  • T cells
  • Th17 cells

Fingerprint

Dive into the research topics of 'Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions'. Together they form a unique fingerprint.

Cite this