Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH

• Published in: Nature (London) Vol. 592; no. 7854; pp. 444 - 449
• Main Authors: Dudek, Michael, Pfister, Dominik, Donakonda, Sainitin, Filpe, Pamela, Schneider, Annika, Laschinger, Melanie, Hartmann, Daniel, Hüser, Norbert, Meiser, Philippa, Bayerl, Felix, Inverso, Donato, Wigger, Jennifer, Sebode, Marcial, Öllinger, Rupert, Rad, Roland, Hegenbarth, Silke, Anton, Martina, Guillot, Adrien, Bowman, Andrew, Heide, Danijela, Müller, Florian, Ramadori, Pierluigi, Leone, Valentina, Garcia-Caceres, Cristina, Gruber, Tim, Seifert, Gabriel, Kabat, Agnieszka M., Mallm, Jan-Philipp, Reider, Simon, Effenberger, Maria, Roth, Susanne, Billeter, Adrian T., Müller-Stich, Beat, Pearce, Edward J., Koch-Nolte, Friedrich, Käser, Rafael, Tilg, Herbert, Thimme, Robert, Boettler, Tobias, Tacke, Frank, Dufour, Jean-Francois, Haller, Dirk, Murray, Peter J., Heeren, Ron, Zehn, Dietmar, Böttcher, Jan P., Heikenwälder, Mathias, Knolle, Percy A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.04.2021; Nature Publishing Group
• Subjects: 13/106; 13/31; 13/51; 14/19; 38; 38/91; 39; 42/44; 631/250/2152/1566/1618; 631/250/256/2515; 64/110; 64/60; Accumulation; Acetates - pharmacology; Acetic acid; Animals; Antigens; Apoptosis; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell Death - drug effects; Cell Death - immunology; Cellular stress response; Diet, High-Fat - adverse effects; Disease Models, Animal; FOXO1 protein; Genes; Hepatocytes; Humanities and Social Sciences; Humans; Interleukin 15; Interleukin-15 - immunology; Interleukin-15 - pharmacology; Liver; Liver - drug effects; Liver - immunology; Liver - pathology; Liver cancer; Liver diseases; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Male; Metabolic disorders; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; multidisciplinary; Non-alcoholic Fatty Liver Disease - immunology; Non-alcoholic Fatty Liver Disease - pathology; Obesity; Pathology; PD-1 protein; Phenotypes; Purine receptors; Receptors, CXCR6 - immunology; Science; Science (multidisciplinary); T cell receptors; Transcription factors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-03233-8

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer 1 , 2 . The accumulation of metabolites leads to cell stress and inflammation in the liver 3 , but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6 + CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6 + CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6 + CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity. Liver resident CD8 T cells have an essential role in immunopathology in a mouse model of nonalcoholic steatohepatitis, by becoming auto-aggressive following sequential transcriptional and metabolic activation steps .