title: Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes.
abstract: Hepatocellular carcinoma (HCC), the fastest rising cancer in the United States and increasing in Europe, often occurs with nonalcoholic steatohepatitis (NASH). Mechanisms underlying NASH and NASH-induced HCC are largely unknown. We developed a mouse model recapitulating key features of human metabolic syndrome, NASH, and HCC by long-term feeding of a choline-deficient high-fat diet. This induced activated intrahepatic CD8(+) T cells, NKT cells, and inflammatory cytokines, similar to NASH patients. CD8(+) T cells and NKT cells but not myeloid cells promote NASH and HCC through interactions with hepatocytes. NKT cells primarily cause steatosis via secreted LIGHT, while CD8(+) and NKT cells cooperatively induce liver damage. Hepatocellular LTβR and canonical NF-κB signaling facilitate NASH-to-HCC transition, demonstrating that distinct molecular mechanisms determine NASH and HCC development.
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland.
authors.forename: Monika Julia
authors.initials: MJ
authors.lastname: Wolf
authors.affiliation: Institute of Virology, Technische Universität München and Helmholtz Zentrum München, Munich 81675, Germany.
authors.forename: Arlind
authors.initials: A
authors.lastname: Adili
authors.affiliation: LIMES Life and Medical Sciences Institute, University of Bonn, Bonn 53125, Germany.
authors.forename: Kira
authors.initials: K
authors.lastname: Piotrowitz
authors.affiliation: Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn 53105, Germany.
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Abdullah
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Boege
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München & Division of Metabolic Diseases, Technische Universität München, Munich 81657, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Stemmer
authors.affiliation: Institute of Virology, Technische Universität München and Helmholtz Zentrum München, Munich 81675, Germany; Second Medical Department, Klinikum Rechts der Isar, Technische Universität München, Munich 81657, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Ringelhan
authors.affiliation: Institute of Virology, Technische Universität München and Helmholtz Zentrum München, Munich 81675, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Simonavicius
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland.
authors.forename: Michèle
authors.initials: M
authors.lastname: Egger
authors.affiliation: Institute of Molecular Immunology, Technische Universität München, Munich 81675, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Wohlleber
authors.affiliation: Institute of Virology, Technische Universität München and Helmholtz Zentrum München, Munich 81675, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Lorentzen
authors.affiliation: Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg 85764, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Einer
authors.affiliation: Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg 85764, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schulz
authors.affiliation: Junior Group Intestinal Microbiome, Technische Universität München, Freising-Weihenstephan 85350, Germany; Chair of Nutrition and Immunology, ZIEL-Research Center for Nutrition and Food Sciences, Biofunctionality Unit, Technische Universität München, Freising-Weihenstephan 85350, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Clavel
authors.affiliation: Institute of Virology, Technische Universität München and Helmholtz Zentrum München, Munich 81675, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Protzer
authors.affiliation: LIMES Life and Medical Sciences Institute, University of Bonn, Bonn 53125, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiele
authors.affiliation: Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg 85764, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Zischka
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland.
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München & Division of Metabolic Diseases, Technische Universität München, Munich 81657, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Tschöp
authors.affiliation: Trudeau Institute, Saranac Lake, New York, NY 12983, USA.
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Tumanov
authors.affiliation: Chair of Nutrition and Immunology, ZIEL-Research Center for Nutrition and Food Sciences, Biofunctionality Unit, Technische Universität München, Freising-Weihenstephan 85350, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Haller
authors.affiliation: Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany.
authors.forename: Kristian
authors.initials: K
authors.lastname: Unger
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego, School of Medicine, San Diego, CA 92093, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: Molecular Biomedicine, Institute of Molecular Health Sciences, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kopf
authors.affiliation: Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn 53105, Germany; Institute of Molecular Immunology, Technische Universität München, Munich 81675, Germany.
authors.forename: Percy
authors.initials: P
authors.lastname: Knolle
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland. Electronic address: achim.weber@usz.ch.
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.affiliation: Institute of Virology, Technische Universität München and Helmholtz Zentrum München, Munich 81675, Germany. Electronic address: heikenwaelder@helmholtz-muenchen.de.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
mesh_terms: D065767:Activation, Metabolic; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005234:Fatty Liver / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008113:Liver Neoplasms / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL