Protection of hepatocytes from cytotoxic T cell mediated killing by interferon-alpha.
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.
Willberg
Christian B
CB
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.
Ward
Scott M
SM
Clayton
Reginald F
RF
Naoumov
Nikolai V
NV
McCormick
Christopher
C
Proto
Sandra
S
Harris
Mark
M
Patel
Arvind H
AH
Klenerman
Paul
P
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*
D016898:Interferon-alpha; D053804:Granzymes