Abstract
BackgroundCellular 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.Methods/Principle FindingsResting hepatocytes cell lines expressed low levels of MHC Class I, but remained susceptible to CTL cytotoxicity. IFN-α treatment, in vitro, markedly increased hepatocyte MHC Class I expression, however, reduced sensitivity to CTL cytotoxicity. IFN-α stimulated hepatocyte lines were still able to present antigen and induce IFN-γ 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-α, 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.Conclusion/SignificanceIFN-α 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.
Highlights
The hepatitis C virus (HCV) is estimated to infect over 100 million people world wide, causing persistent infection in the majority [1]
Human hepatocyte expression of MHC Class I has been well documented as low to absent in vivo [9,10,11,12,13]
The ability of hepatocytes to act as good targets for CTLs is crucial for the clearance of heptotrophic viral infections
Summary
The hepatitis C virus (HCV) is estimated to infect over 100 million people world wide, causing persistent infection in the majority [1]. The cellular immune response is thought to play a major role in the clearance and control of the virus and failure of cellular responses to HCV is a major factor for chronic viral persistence [2,3,4]. The reasons behind this failure are still unclear. Resting hepatocytes cell lines expressed low levels of MHC Class I, but remained susceptible to CTL cytotoxicity. IFN-a stimulated hepatocyte lines were still able to present antigen and induce IFN-c expression in interacting CTL. Hindrance of CTL cytotoxicity could contribute to the chronicity of hepatic viral infections
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