{Reference Type}: Journal Article
{Title}: A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.
{Author}: Bonetti L;Horkova V;Grusdat M;Longworth J;Guerra L;Kurniawan H;Franchina DG;Soriano-Baguet L;Binsfeld C;Verschueren C;Spath S;Ewen A;Koncina E;Gérardy JJ;Kobayashi T;Dostert C;Farinelle S;Härm J;Fan YT;Chen Y;Harris IS;Lang PA;Vasiliou V;Waisman A;Letellier E;Becher B;Mittelbronn M;Brenner D;
{Journal}: Cell Metab
{Volume}: 36
{Issue}: 8
{Year}: 2024 Aug 6
{Factor}: 31.373
{DOI}: 10.1016/j.cmet.2024.06.010
{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.