title: Protection of hepatocytes from cytotoxic T cell mediated killing by interferon-alpha.
abstract: BACKGROUND
  Cellular immunity plays a key role in determining the outcome of hepatitis C virus (HCV) infection, although the majority of infections become persistent. The mechanisms behind persistence are still not clear; however, the primary site of infection, the liver, may be critical. We investigated the ability of CD8+ T-cells (CTL) to recognise and kill hepatocytes under cytokine stimulation.
  
  
  RESULTS
  Resting hepatocytes cell lines expressed low levels of MHC Class I, but remained susceptible to CTL cytotoxicity. IFN-alpha treatment, in vitro, markedly increased hepatocyte MHC Class I expression, however, reduced sensitivity to CTL cytotoxicity. IFN-alpha stimulated hepatocyte lines were still able to present antigen and induce IFN-gamma expression in interacting CTL. Resistance to killing was not due to the inhibition of the FASL/FAS- pathway, as stimulated hepatocytes were still susceptible to FAS-mediated apoptosis. In vitro stimulation with IFN-alpha, or the introduction of a subgenomic HCV replicon into the HepG2 line, upregulated the expression of the granzyme-B inhibitor-proteinase inhibitor 9 (PI-9). PI-9 expression was also observed in liver tissue biopsies from patients with chronic HCV infection.
  
  
  CONCLUSIONS
  IFN-alpha induces resistance in hepatocytes to perforin/granzyme mediate CTL killing pathways. One possible mechanism could be through the expression of the PI-9. Hindrance of CTL cytotoxicity could contribute to the chronicity of hepatic viral infections.
authors.affiliation: Nuffield Department of Medicine, Oxford University, Oxford, United Kingdom; Division of Experimental Medicine, University of California at San Francisco, San Francisco, California, United States of America.
authors.forename: Christian B
authors.initials: CB
authors.lastname: Willberg
authors.forename: Scott M
authors.initials: SM
authors.lastname: Ward
authors.forename: Reginald F
authors.initials: RF
authors.lastname: Clayton
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Naoumov
authors.forename: Christopher
authors.initials: C
authors.lastname: McCormick
authors.forename: Sandra
authors.initials: S
authors.lastname: Proto
authors.forename: Mark
authors.initials: M
authors.lastname: Harris
authors.forename: Arvind H
authors.initials: AH
authors.lastname: Patel
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D053804:Granzymes / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D016898:Interferon-alpha; D053804:Granzymes