[en] 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.
Disciplines :
Immunology & infectious disease
Author, co-author :
Bonetti, Lynn; Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Horkova, Veronika; Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Longworth, Joseph; Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Guerra, Luana; Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Kurniawan, Henry; Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Franchina, Davide G; Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Soriano-Baguet, Leticia; Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Grusdat, Melanie; Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Spath, Sabine; Institute of Experimental Immunology, Inflammation Research, University of Zurich, 8057 Zurich, Switzerland ; Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA 98101, USA
Koncina, Eric; Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg
Ewen, Anouk; Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Binsfeld, Carole; Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Verschueren, Charlène; Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Gérardy, Jean-Jacques; National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg ; Luxembourg Center of Neuropathology (LCNP), Dudelange, L-3555, Luxembourg
Kobayashi, Takumi; Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Dostert, Catherine; Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Farinelle, Sophie; Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Härm, Janika; Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Chen, Ying; Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, USA
Harris, Isaac S; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
Lang, Philipp A; Department of Molecular Medicine II, Medical Faculty Heinrich Heine University Düsseldorf, Germany
Vasiliou, Vasilis; Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, USA
Waisman, Ari; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
LETELLIER, Elisabeth ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Becher, Burkhard; Institute of Experimental Immunology, Inflammation Research, University of Zurich, 8057 Zurich, Switzerland
Mittelbronn, Michel; National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg ; Luxembourg Center of Neuropathology (LCNP), Dudelange, L-3555, Luxembourg ; Department of Life Sciences and Medicine (DLSM), University of Luxembourg, Esch-sur-Alzette, Luxembourg ; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, L-4362, Luxembourg ; Faculty of Science, Technology and Medicine (FSTM), University of Luxembourg, Esch-sur-Alzette, Luxembourg ; Department of Cancer Research (DoCR), Luxembourg Institute of Health (LIH), Luxembourg, L-1526, Luxembourg
BRENNER, Dirk ; University of Luxembourg ; Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Odense Research Center for Anaphylaxis (ORCA), Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark