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

• Published in: PloS one Vol. 2; no. 8; p. e791
• Main Authors: Willberg, Christian B, Ward, Scott M, Clayton, Reginald F, Naoumov, Nikolai V, McCormick, Christopher, Proto, Sandra, Harris, Mark, Patel, Arvind H, Klenerman, Paul
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.08.2007; Public Library of Science (PLoS)
• Subjects: Apoptosis; CD8 antigen; CD95 antigen; Cell Line; Cell lines; Cell-mediated immunity; Chronic infection; Cytotoxicity; Cytotoxicity, Immunologic; Fas antigen; FasL protein; Granzymes - metabolism; Health aspects; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatocytes; Hepatocytes - cytology; Hepatocytes - immunology; Humans; Immunity; Immunologic factors; Immunology/Immune Response; Immunology/Immunity to Infections; Infection; Inhibitors; Interferon; Interferon-alpha - metabolism; Liver; Liver cancer; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Medical research; Perforin; Proteinase; Proteinase inhibitor 9; Rodents; Stimulation; T cells; T-Lymphocytes, Cytotoxic - immunology; Toxicity; Viral infections; Virus diseases; Viruses; α-Interferon; γ-Interferon; United States > US; San Francisco California; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0000791

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. 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. 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.