Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes

Monika Julia Wolf, Arlind Adili, Kira Piotrowitz, Zeinab Abdullah, Yannick Boege, Kerstin Stemmer, Marc Ringelhan, Nicole Simonavicius, Michèle Egger, Dirk Wohlleber, Anna Lorentzen, Claudia Einer, Sabine Schulz, Thomas Clavel, Ulrike Protzer, Christoph Thiele, Hans Zischka, Holger Moch, Matthias Tschöp, Alexei V. TumanovDirk Haller, Kristian Unger, Michael Karin, Manfred Kopf, Percy Knolle, Achim Weber, Mathias Heikenwalder

Research output: Contribution to journalArticlepeer-review

243 Scopus citations

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+ Tcells, NKT cells, and inflammatory cytokines, similar to NASH patients. CD8+ Tcells 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.

Original languageEnglish (US)
Pages (from-to)549-564
Number of pages16
JournalCancer Cell
Volume26
Issue number4
DOIs
StatePublished - Oct 13 2014

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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