Protection of hepatocytes from cytotoxic T cell mediated killing by interferon-alpha

Willberg, C.B., Ward, S.M., Clayton, R.F., Naoumov, N.V., McCormick, C., Proto, S., Harris, M., Patel, A.H. and Klenerman, P. (2007) Protection of hepatocytes from cytotoxic T cell mediated killing by interferon-alpha. PLoS ONE, 2(8), e791. (doi:10.1371/journal.pone.0000791) (PMID:17726521) (PMCID:PMC1949144)

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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.

Methods/Principle Findings: Resting 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/Significance: IFN-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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Patel, Professor Arvind
Authors: Willberg, C.B., Ward, S.M., Clayton, R.F., Naoumov, N.V., McCormick, C., Proto, S., Harris, M., Patel, A.H., and Klenerman, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN:1932-6203
ISSN (Online):1932-6203
Published Online:29 August 2007
Copyright Holders:Copyright © 2007 The Authors
First Published:First published in PloS ONE 2(8):e791
Publisher Policy:Reproduced under a Creative Commons License

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