%0 Journal Article
%T A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.
%A Bonetti L
%A Horkova V
%A Grusdat M
%A Longworth J
%A Guerra L
%A Kurniawan H
%A Franchina DG
%A Soriano-Baguet L
%A Binsfeld C
%A Verschueren C
%A Spath S
%A Ewen A
%A Koncina E
%A Gérardy JJ
%A Kobayashi T
%A Dostert C
%A Farinelle S
%A Härm J
%A Fan YT
%A Chen Y
%A Harris IS
%A Lang PA
%A Vasiliou V
%A Waisman A
%A Letellier E
%A Becher B
%A Mittelbronn M
%A Brenner D
%J Cell Metab
%V 36
%N 8
%D 2024 Aug 6
%M 38986617
%F 31.373
%R 10.1016/j.cmet.2024.06.010
%X 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.