Low perforin expression of early differentiated HCV-specific CD8+ T cells limits their hepatotoxic potential

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• 作者：Juandy Jo¹ ; ² ; ³ ; ^&dagger ; ; Bertram Bengsch¹ ; ² ; ³ ; ^&dagger ; ; Bianca Seigel¹ ; ² ; ³ ; ^&dagger ; ; Sibylle J. Rau¹ ; ² ; ^&dagger ; ; Julia Schmidt¹ ; ² ; ⁴ ; Emmanuel Bisse⁵ ; Peter Aichele⁶ ; Ulrike Aichele¹ ; Lars Joeckel² ; ³ ; ⁷ ; ⁸ ; Cathy Royer⁹ ; Karine S&aacute ; Ferreira² ; ⁷ ; ⁸ ; Christoph Borner² ; ³ ; Thomas F. Baumert⁹ ; Hubert E. Blum¹ ; Volker Lohmann¹⁰ ; Richard Fischer¹ ; Robert Thimme¹ ; ^{robert.thimme@uniklinik-freiburg.de}
• 关键词：HCV ; CD8+ T cells ; Antiviral efficacy ; Cytotoxicity ; Perforin ; T cell dysfunction
• 刊名：Journal of Hepatology
• 出版年：2012
• 期刊代码：162_01688278
• 类别：med
• 出版时间：July, 2012
• 卷：57
• 期：1
• 页码：9-16
• 文件大小：1025 K

摘要

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Background & Aims

Perforin plays a central role in the immunopathogenesis of different viral infections. However, its role in hepatitis C virus (HCV) infection has not been fully understood. Here, we analyzed two closely related questions: first, is CD8+ T cell-mediated killing of HCV-replicating human hepatoma cells mediated by perforin? Second, if so, do HCV-specific CD8+ T cells obtained from chronically HCV infected patients express and upregulate perforin?

Methods

Susceptibility of HCV-replicating human hepatoma cells to the cytotoxic pathway was tested m>in vitrom> by addition of perforin substitute streptolysin O and granzyme B and by co-culture experiments with a perforin-expressing HCV-specific CD8+ T cell clone in the presence of perforin or caspase inhibitors. HCV-specific CD8+ T cells were obtained and analyzed for perforin expression and differentiation markers m>ex vivom> from 12 chronically infected patients and 12 patients with resolved HCV infection.

Results

HCV-replicating human hepatoma cells were susceptible to cytotoxic killing m>in vitrom> and a dominant role of perforin in HCV-specific CD8+ T cell-mediated cytolysis was observed. However, HCV-specific CD8+ T cells obtained m>ex vivom> from chronically HCV infected patients expressed only low levels of perforin and showed an impaired ability to upregulate perforin. This was tightly linked to the distinct differentiation stage of HCV-specific CD8+ T cell differentiation m>ex vivom> since early and intermediate differentiated HCV-specific CD8+ T cells only showed weak perforin expression in contrast to late differentiated CD8+ T cells that displayed strong perforin expression.

Conclusions

Our results suggest that perforin plays a dominant role in CD8+ T cell-mediated lysis of HCV-replicating human hepatoma cells but that lysis may be limited in human chronic viral infection by the low perforin expression of early/intermediate differentiated HCV-specific CD8+ T cells.