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.
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.
Iken
Khadija
K
Division of Infectious Disease, Beth Israel Deaconess Hospital, HIM 223a, 330 Brookline Ave., Boston, MA 02115, USA.
Huang
Lin
L
Bekele
Hewan
H
Schmidt
Emmett V
EV
Koziel
Margaret James
MJ
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D002478:Cells, Cultured; D018920:Coculture Techniques; D053222:Fas Ligand Protein; D016174:Hepacivirus / Q000472:pathogenicity*; D019698:Hepatitis C, Chronic / Q000276:immunology; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology*; D006801:Humans; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation; D015678:Viral Structural Proteins / Q000502:physiology*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; D015678:Viral Structural Proteins; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases