Apoptosis of activated CD4+ and CD8+ T cells is enhanced by co-culture with hepatocytes expressing hepatitis C virus (HCV) structural proteins through FasL induction

Virology. 2006 Mar 15;346(2):363-72. doi: 10.1016/j.virol.2005.11.017. Epub 2005 Dec 5.

Abstract

A central unresolved issue in hepatitis C virus (HCV) infection is how the virus establishes chronic infection. Recent studies suggest that the liver microenvironment leads to apoptosis of activated T cells, which may be involved in the tolerance to liver allograft. Here, We report that murine hepatocytes expressing a transgene encoding the HCV structural proteins core, envelope 1 (E1) and envelope 2 (E2) enhance apoptosis of activated T cells. Unlike normal liver, which appears to selectively remove only activated CD8+ T cells, enhanced apoptosis was seen for both CD4+ and CD8+ T cells. Enhanced apoptosis of activated T lymphocytes was associated with upregulation of FasL by HCV transgenic hepatocytes and was specifically inhibited by anti-FasL blocking antibody. Increased apoptosis of activated T cells induced by HCV structural proteins could amplify the ability of the liver to down-modulate T cell responses, leading to attenuation of anti-viral responses and facilitating viral persistence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Blotting, Western
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / physiology*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / physiology*
  • Caspase 3
  • Caspases / analysis
  • Cells, Cultured
  • Coculture Techniques
  • Fas Ligand Protein
  • Hepacivirus / pathogenicity*
  • Hepatitis C, Chronic / immunology
  • Hepatocytes / metabolism
  • Hepatocytes / virology*
  • Humans
  • Lymphocyte Activation
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / biosynthesis*
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Transgenic
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factors / biosynthesis*
  • Tumor Necrosis Factors / genetics
  • Up-Regulation
  • Viral Structural Proteins / physiology*

Substances

  • FASLG protein, human
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Membrane Glycoproteins
  • RNA, Messenger
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factors
  • Viral Structural Proteins
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases