Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Nature (London), 2021-04, Vol.592 (7854), p.444-449

Ort / Verlag

London: Nature Publishing Group UK

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 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 .