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

Michael Dudek, Dominik Pfister, Sainitin Donakonda, Pamela Filpe, Annika Schneider, Melanie Laschinger, Daniel Hartmann, Norbert Hüser, Philippa Meiser, Felix Bayerl, Donato Inverso, Jennifer Wigger, Marcial Sebode, Rupert Öllinger, Roland Rad, Silke Hegenbarth, Martina Anton, Adrien Guillot, Andrew Bowman, Danijela Heide, Florian Müller, Pierluigi Ramadori, Valentina Leone, Cristina Garcia-Caceres, Tim Gruber, Gabriel Seifert, Agnieszka M. Kabat, Jan-Philipp Mallm, Simon Reider, Maria Effenberger, Susanne Roth, Adrian T. Billeter, Beat Müller-Stich, Edward J. Pearce, Friedrich Koch-Nolte, Rafael Käser, Herbert Tilg, Robert Thimme, Tobias Boettler, Frank Tacke, Jean-Francois Dufour, Dirk Haller, Peter J. Murray, Ron Heeren, Dietmar Zehn, Jan P. Böttcher, Mathias Heikenwälder and Percy A. Knolle ()
Additional contact information
Michael Dudek: Technical University of Munich (TUM)
Dominik Pfister: German Cancer Research Center
Sainitin Donakonda: Technical University of Munich (TUM)
Pamela Filpe: University Medical Centre Hamburg-Eppendorf
Annika Schneider: Technical University of Munich (TUM)
Melanie Laschinger: University Hospital München rechts der Isar, TUM
Daniel Hartmann: University Hospital München rechts der Isar, TUM
Norbert Hüser: University Hospital München rechts der Isar, TUM
Philippa Meiser: Technical University of Munich (TUM)
Felix Bayerl: Technical University of Munich (TUM)
Donato Inverso: German Cancer ResearchCenter Heidelberg (DKFZ-ZMBH Alliance)
Jennifer Wigger: University Medical Centre Hamburg-Eppendorf
Marcial Sebode: University Medical Centre Hamburg-Eppendorf
Rupert Öllinger: Institute of Molecular Oncology and Functional Genomics, TUM
Roland Rad: Institute of Molecular Oncology and Functional Genomics, TUM
Silke Hegenbarth: Technical University of Munich (TUM)
Martina Anton: Technical University of Munich (TUM)
Adrien Guillot: Charité Universitätsmedizin
Andrew Bowman: Maastricht University
Danijela Heide: German Cancer Research Center
Florian Müller: German Cancer Research Center
Pierluigi Ramadori: German Cancer Research Center
Valentina Leone: Technical University Munich and Helmholtz Zentrum Munich
Cristina Garcia-Caceres: Helmholtz Zentrum München
Tim Gruber: Helmholtz Zentrum München
Gabriel Seifert: University of Freiburg
Agnieszka M. Kabat: Max Planck Institute of Immunobiology and Epigenetics
Jan-Philipp Mallm: German Cancer Research Center
Simon Reider: Medical University Innsbruck
Maria Effenberger: Medical University Innsbruck
Susanne Roth: Heidelberg University
Adrian T. Billeter: Heidelberg University
Beat Müller-Stich: Heidelberg University
Edward J. Pearce: Max Planck Institute of Immunobiology and Epigenetics
Friedrich Koch-Nolte: University Medical Center Hamburg-Eppendorf
Rafael Käser: University of Freiburg
Herbert Tilg: Medical University Innsbruck
Robert Thimme: University of Freiburg
Tobias Boettler: University of Freiburg
Frank Tacke: Charité Universitätsmedizin
Jean-Francois Dufour: University of Bern
Dirk Haller: School of Life Sciences Weihenstephan, TUM
Peter J. Murray: Technical University of Munich (TUM)
Ron Heeren: Maastricht University
Dietmar Zehn: School of Life Sciences Weihenstephan, TUM
Jan P. Böttcher: Technical University of Munich (TUM)
Mathias Heikenwälder: German Cancer Research Center
Percy A. Knolle: Technical University of Munich (TUM)

Nature, 2021, vol. 592, issue 7854, 444-449

Abstract: Abstract 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (4)

Downloads: (external link)
https://www.nature.com/articles/s41586-021-03233-8 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:592:y:2021:i:7854:d:10.1038_s41586-021-03233-8

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-021-03233-8

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().