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Dudek, M.* ; Pfister, D.* ; Donakonda, S.* ; Filpe, P.* ; Schneider, A.* ; Laschinger, M.* ; Hartmann, D.* ; Hüser, N.* ; Meiser, P.* ; Bayerl, F.* ; Inverso, D.* ; Wigger, J.* ; Sebode, M.* ; Öllinger, R.* ; Rad, R.* ; Hegenbarth, S.* ; Anton, M.* ; Guillot, A.* ; Bowman, A.* ; Heide, D.* ; Müller, F.* ; Ramadori, P.* ; Leone, V. ; García-Cáceres, C. ; Gruber, T. ; Seifert, G.* ; Kabat, A.M.* ; Malm, J.P.* ; Reider, S.* ; Effenberger, M.* ; Roth, S.* ; Billeter, A.T.* ; Müller-Stich, B.* ; Pearce, E.J.* ; Koch-Nolte, F.* ; Käser, R.* ; Tilg, H.* ; Thimme, R.* ; Böttler, T.* ; Tacke, F.* ; Dufour, J.F.* ; Haller, D.* ; Murray, P.J.* ; Heeren, R.* ; Zehn, D.* ; Böttcher, J.P.* ; Heikenwälder, M.* ; Knolle, P.A.*

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

Nature 592, 444-449 (2021)
Postprint DOI PMC
Open Access Green
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.
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Publication type Article: Journal article
Document type Scientific Article
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Journal Nature
Quellenangaben Volume: 592, Issue: 7854, Pages: 444-449 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Translational Metabolic Oncology (IDC-TMO)
Institute of Diabetes and Obesity (IDO)
POF-Topic(s) 30203 - Molecular Targets and Therapies
90000 - German Center for Diabetes Research
30201 - Metabolic Health
Research field(s) Radiation Sciences
Helmholtz Diabetes Center
PSP Element(s) G-501000-001
G-501900-224
G-502200-001
Grants DZIF Munich site
SFB
CIBSS EXC-2189
DFG
DOI 10.1038/s41586-021-03233-8
WOS ID WOS:000632345400002
Scopus ID 85103012811
PubMed ID 33762736
Erfassungsdatum 2021-05-21
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