A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation

Lynn Bonetti, Veronika Horkova, Melanie Grusdat, Joseph Longworth, Luana Guerra, Henry Kurniawan, Davide G. Franchina, Leticia Soriano-Baguet, Carole Binsfeld, Charlène Verschueren, Sabine Spath, Anouk Ewen, Eric Koncina, Jean Jacques Gérardy, Takumi Kobayashi, Catherine Dostert, Sophie Farinelle, Janika Härm, Yu Tong Fan, Ying ChenIsaac S. Harris, Philipp A. Lang, Vasilis Vasiliou, Ari Waisman, Elisabeth Letellier, Burkhard Becher, Michel Mittelbronn, Dirk Brenner*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

Abstract

The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C. rodentium infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections.

Original languageEnglish
Pages (from-to)1726-1744.e10
JournalCell Metabolism
Volume36
Issue number8
Early online date3 Jul 2024
DOIs
Publication statusPublished - 6 Aug 2024

Keywords

  • C. rodentium
  • colitis
  • gastrointestinal infection
  • Gclc
  • glutathione
  • IL-22
  • intestinal barrier
  • mitochondrial function
  • ROS
  • T cells
  • Th17 cells

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