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Publication : Auto-aggressive CXCR6<sup>+</sup> CD8 T cells cause liver immune pathology in NASH.

First Author  Dudek M Year  2021
Journal  Nature Volume  592
Issue  7854 Pages  444-449
PubMed ID  33762736 Mgi Jnum  J:310156
Mgi Id  MGI:6710192 Doi  10.1038/s41586-021-03233-8
Citation  Dudek M, et al. (2021) Auto-aggressive CXCR6(+) CD8 T cells cause liver immune pathology in NASH. Nature 592(7854):444-449
abstractText  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.
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