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

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

*Corresponding author for this work

Research output: Working paperPreprint


Although the intestinal tract is a major site of reactive oxygen species (ROS) generation, the mechanisms by which antioxidant defense in gut T cells contribute to intestinal homeostasis are currently unknown. Here we show, using T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that the ensuing loss of glutathione (GSH) impairs the production of gut-protective IL-22 by Th17 cells within the lamina propria. Although Gclc ablation does not affect T cell cytokine secretion in the gut of mice at steady-state, infection with C. rodentium increases ROS, inhibits mitochondrial gene expression and mitochondrial function in Gclc-deficient Th17 cells. These mitochondrial deficits affect the PI3K/AKT/mTOR pathway, leading to reduced phosphorylation of the translation repressor 4E-BP1. As a consequence, the initiation of translation is restricted, resulting in decreased protein synthesis of IL-22. Loss of IL-22 results in poor bacterial clearance, enhanced intestinal damage, and high mortality. ROS-scavenging, reconstitution of IL-22 expression or IL-22 supplementation in vivo prevent the appearance of these pathologies. Our results demonstrate the existence of a previously unappreciated role for Th17 cell-intrinsic GSH coupling to promote mitochondrial function, IL-22 translation and signaling. These data reveal an axis that is essential for maintaining the integrity of the intestinal barrier and protecting it from damage caused by gastrointestinal infection.

Original languageEnglish
Publication statusPublished - 7 Jul 2023

Publication series

PublisherCold Spring Harbor Laboratory Press


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