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Metabolic Activation of Intrahepatic CD8+ T Cells and NKT Cells Causes Nonalcoholic Steatohepatitis and Liver Cancer via Cross-Talk with Hepatocytes

Cancer cell, 2014-10, Vol.26 (4), p.549-564 [Peer Reviewed Journal]

2014 Elsevier Inc. ;Copyright © 2014 Elsevier Inc. All rights reserved. ;ISSN: 1535-6108 ;EISSN: 1878-3686 ;DOI: 10.1016/j.ccell.2014.09.003 ;PMID: 25314080

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Title:
Metabolic Activation of Intrahepatic CD8+ T Cells and NKT Cells Causes Nonalcoholic Steatohepatitis and Liver Cancer via Cross-Talk with Hepatocytes
Author: Wolf, Monika Julia ; Adili, Arlind ; Piotrowitz, Kira ; Abdullah, Zeinab ; Boege, Yannick ; Stemmer, Kerstin ; Ringelhan, Marc ; Simonavicius, Nicole ; Egger, Michèle ; Wohlleber, Dirk ; Lorentzen, Anna ; Einer, Claudia ; Schulz, Sabine ; Clavel, Thomas ; Protzer, Ulrike ; Thiele, Christoph ; Zischka, Hans ; Moch, Holger ; Tschöp, Matthias ; Tumanov, Alexei V. ; Haller, Dirk ; Unger, Kristian ; Karin, Michael ; Kopf, Manfred ; Knolle, Percy ; Weber, Achim ; Heikenwalder, Mathias
Subjects: Activation, Metabolic ; Animals ; CD8-Positive T-Lymphocytes - immunology ; Fatty Liver - immunology ; Hepatocytes - immunology ; Humans ; Killer Cells, Natural - immunology ; Liver Neoplasms - immunology ; Mice ; Mice, Inbred C57BL
Is Part Of: Cancer cell, 2014-10, Vol.26 (4), p.549-564
Description: 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. [Display omitted] •CD-HFD recapitulates metabolic syndrome, NASH, and NASH-induced HCC in humans•NKT cells mediate lipid uptake via LTβR activation on hepatocytes•CD8+ and NKT cells promote liver damage, NASH, and HCC development•NASH-to-HCC transition is facilitated by hepatic LTβR and canonical NF-κB signaling Wolf et al. examine a mouse model of human metabolic syndrome that predispose patients to hepatocellular carcinoma (HCC) and find that activated CD8+ T cells and NKT cells in the liver are important in promoting nonalcoholic steatohepatitis that leads to HCC.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 1535-6108
EISSN: 1878-3686
DOI: 10.1016/j.ccell.2014.09.003
PMID: 25314080
Source: Cell Press Free Archives
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Metabolic Activation of Intrahepatic CD8+ T Cells and NKT Cells Causes Nonalcoholic Steatohepatitis and Liver Cancer via Cross-Talk with Hepatocytes

2014 Elsevier Inc. ;Copyright © 2014 Elsevier Inc. All rights reserved. ;ISSN: 1535-6108 ;EISSN: 1878-3686 ;DOI: 10.1016/j.ccell.2014.09.003 ;PMID: 25314080

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