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

Cancer Cell. 2014 Oct 13;26(4):549-64. doi: 10.1016/j.ccell.2014.09.003.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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