Research output per year
Research output per year
Michael Dudek, Dominik Pfister, Sainitin Donakonda, Pamela Filpe, Annika Schneider, Melanie Laschinger, Daniel Hartmann, Norbert Hueser, Philippa Meiser, Felix Bayerl, Donato Inverso, Jennifer Wigger, Marcial Sebode, Rupert Oellinger, Roland Rad, Silke Hegenbarth, Martina Anton, Adrien Guillot, Andrew Bowman, Danijela Heide
Research output: Contribution to journal › Article › Academic › peer-review
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.
Original language | English |
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Pages (from-to) | 444-449 |
Number of pages | 31 |
Journal | Nature |
Volume | 592 |
Issue number | 7854 |
DOIs | |
Publication status | Published - 15 Apr 2021 |
Research output: Contribution to journal › Erratum / corrigendum / retractions › Academic