Protection of hepatocytes from cytotoxic T cell mediated killing by interferon-alpha.
<h4>Background</h4>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 c...
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Public Library of Science (PLoS)
2007-08-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0000791&type=printable |
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| author | Christian B Willberg Scott M Ward Reginald F Clayton Nikolai V Naoumov Christopher McCormick Sandra Proto Mark Harris Arvind H Patel Paul Klenerman |
| author_facet | Christian B Willberg Scott M Ward Reginald F Clayton Nikolai V Naoumov Christopher McCormick Sandra Proto Mark Harris Arvind H Patel Paul Klenerman |
| author_sort | Christian B Willberg |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methods/principle findings</h4>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.<h4>Conclusion/significance</h4>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. |
| format | Article |
| id | doaj-art-6b4bad83d4664a9bae615eac97fdfdc1 |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2007-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-6b4bad83d4664a9bae615eac97fdfdc12025-08-20T03:55:22ZengPublic Library of Science (PLoS)PLoS ONE1932-62032007-08-0128e79110.1371/journal.pone.0000791Protection of hepatocytes from cytotoxic T cell mediated killing by interferon-alpha.Christian B WillbergScott M WardReginald F ClaytonNikolai V NaoumovChristopher McCormickSandra ProtoMark HarrisArvind H PatelPaul Klenerman<h4>Background</h4>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.<h4>Methods/principle findings</h4>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.<h4>Conclusion/significance</h4>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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0000791&type=printable |
| spellingShingle | Christian B Willberg Scott M Ward Reginald F Clayton Nikolai V Naoumov Christopher McCormick Sandra Proto Mark Harris Arvind H Patel Paul Klenerman Protection of hepatocytes from cytotoxic T cell mediated killing by interferon-alpha. PLoS ONE |
| title | Protection of hepatocytes from cytotoxic T cell mediated killing by interferon-alpha. |
| title_full | Protection of hepatocytes from cytotoxic T cell mediated killing by interferon-alpha. |
| title_fullStr | Protection of hepatocytes from cytotoxic T cell mediated killing by interferon-alpha. |
| title_full_unstemmed | Protection of hepatocytes from cytotoxic T cell mediated killing by interferon-alpha. |
| title_short | Protection of hepatocytes from cytotoxic T cell mediated killing by interferon-alpha. |
| title_sort | protection of hepatocytes from cytotoxic t cell mediated killing by interferon alpha |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0000791&type=printable |
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