Liver damage by infiltrating CD8+ T cells is Fas dependent.
Ag stimulation of CD8+ lymphocytes in vivo results in their migration to various tissues as well as the activation of a cytolytic program involving perforin, TNF-alpha, and Fas ligand. The liver is one of the main sites for infiltration by activated CD8+ T cells, and this is followed by the death of hepatocytes. The contribution of the various cytolytic components to this process is unclear. Hepatocyte damage by CD8+ T cells was studied using the MHC class I-restricted OVA-specific TCR transgenic mouse (OT-1) to examine the contribution of Fas to hepatocyte death. Activated CD8+ T cells from both OT-1 and Fas-deficient OT-1lpr mice migrated to the liver in similar numbers after OVA administration, but only in OT-1 mice was there evidence of significant hepatocyte damage histologically and by elevation of serum aspartate transaminase. These differences were not the result of inefficient induction of cytolytic activity in OT-1lpr liver T cells, since they were as cytolytic in vitro as OT-1 liver T cells. This was supported by findings of similar high levels of message for perforin, TNF-alpha, and Fas ligand in liver lymphocytes from both mice. These findings demonstrate that following Ag activation, infiltrating liver CD8+ T lymphocytes induce hepatocyte damage in a Fas-dependent manner.
Kennedy
N J
NJ
Immunobiology Program, Department of Medicine, University of Vermont College of Medicine, Burlington, VT 05405, USA.
Russell
J Q
JQ
Michail
N
N
Budd
R C
RC
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D016923:Cell Death / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004527:Egg Proteins / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology; D016130:Immunophenotyping; D007274:Injections, Intraperitoneal; D008099:Liver / Q000276:immunology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D013045:Species Specificity; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology* / Q000633:toxicity
D004527:Egg Proteins; C110366:OVA-8; D010446:Peptide Fragments; D019014:fas Receptor; D010047:Ovalbumin