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Autor(en) / Beteiligte

Titel

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

Ist Teil von

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer . The accumulation of metabolites leads to cell stress and inflammation in the liver , 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.

Sprache: Englisch
Identifikatoren: ISSN: 0028-0836
eISSN: 1476-4687
DOI: 10.1038/s41586-021-03233-8
Titel-ID: cdi_proquest_miscellaneous_2505358202

Format: –
Schlagworte: 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, 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, Non-alcoholic Fatty Liver Disease - immunology, Non-alcoholic Fatty Liver Disease - pathology, Obesity, Pathology, PD-1 protein, Phenotypes, Purine receptors, Receptors, CXCR6 - immunology, T cell receptors, Transcription factors

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