Nature. 2021 Apr;592(7854):444-449. doi: 10.1038/s41586-021-03233-8. | PubMed

Michael Dudek¹, Dominik Pfister², Sainitin Donakonda^1,3, Pamela Filpe⁴, Annika Schneider¹, Melanie Laschinger⁵, Daniel Hartmann⁵, Norbert Hüser⁵, Philippa Meiser¹, Felix Bayerl¹, Donato Inverso^6,7, Jennifer Wigger⁴, Marcial Sebode⁴, Rupert Öllinger⁸, Roland Rad⁸, Silke Hegenbarth¹, Martina Anton¹, Adrien Guillot⁹, Andrew Bowman¹⁰, Danijela Heide², Florian Müller², Pierluigi Ramadori², Valentina Leone^11,12, Cristina Garcia-Caceres¹³, Tim Gruber¹³, Gabriel Seifert¹⁴, Agnieszka M Kabat¹⁵, Jan-Philipp Mallm¹⁶, Simon Reider^17,18, Maria Effenberger¹⁷, Susanne Roth¹⁹, Adrian T Billeter¹⁹, Beat Müller-Stich¹⁹, Edward J Pearce¹⁵, Friedrich Koch-Nolte²⁰, Rafael Käser²¹, Herbert Tilg¹⁷, Robert Thimme²¹, Tobias Boettler²¹, Frank Tacke⁹, Jean-Francois Dufour²², Dirk Haller²³, Peter J Murray^1,24, Ron Heeren¹⁰, Dietmar Zehn²⁵, Jan P Böttcher¹, Mathias Heikenwälder², Percy A Knolle^26,27,28

1. Institute of Molecular Immunology and Experimental Oncology, School of Medicine, Technical University of Munich (TUM), Munich, Germany.
2. Institute of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany.
3. German Center for Infection Research, Munich, Germany.
4. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
5. Department of Surgery, University Hospital München rechts der Isar, TUM, Munich, Germany.
6. Division of Vascular Oncology and Metastasis, German Cancer ResearchCenter Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.
7. European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
8. Institute of Molecular Oncology and Functional Genomics, TUM, Munich, Germany.
9. Department of Hepatology and Gastroenterology, Charité Universitätsmedizin, Berlin, Germany.
10. Maastricht MultiModal Molecular Imaging (M4I) Institute, Division of Imaging Mass Spectrometry, Maastricht University, Maastricht, the Netherlands.
11. Institute of Virology, Technical University Munich and Helmholtz Zentrum Munich, Munich, Germany.
12. Research Unit of Radiation Cytogenetics, Helmholtz Zentrum Munich, Neuherberg, Germany.
13. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.
14. Department of General and Visceral Surgery, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
15. Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
16. Division of Chromatin Networks, Single-cell Open Lab, German Cancer Research Center, Heidelberg, Germany.
17. Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria.
18. Christian Doppler Labor for Mucosal Immunology, Innsbruck, Austria.
19. Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany.
20. Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
21. Department of Medicine II, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
22. University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland.
23. Chair of Nutrition and Immunology, School of Life Sciences Weihenstephan, TUM, Freising, Germany.
24. Max Planck Institute for Biochemistry, Martinsried, Germany.
25. Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, TUM, Freising, Germany.
26. Institute of Molecular Immunology and Experimental Oncology, School of Medicine, Technical University of Munich (TUM), Munich, Germany. percy.knolle@tum.de.
27. German Center for Infection Research, Munich, Germany. percy.knolle@tum.de.
28. Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, TUM, Freising, Germany. percy.knolle@tum.de.

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.

Presented By Michael Dudek | ORCID iD