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

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; ... (2021). Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. Nature, 592(7854), pp. 444-449. Springer Nature 10.1038/s41586-021-03233-8

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Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver3, 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie

UniBE Contributor:

Dufour, Jean-François

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1476-4687

Publisher:

Springer Nature

Language:

English

Submitter:

Rahel Fuhrer

Date Deposited:

12 May 2021 14:54

Last Modified:

12 May 2021 14:54

Publisher DOI:

10.1038/s41586-021-03233-8

PubMed ID:

33762736

BORIS DOI:

10.48350/155778

URI:

https://boris.unibe.ch/id/eprint/155778

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