Lopes, A.R.; (2008) CD8+ T cell attrition in chronic hepatitis B virus infection. Doctoral thesis , University of London.

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Abstract

Hepatitis B virus (HBV)-specific CD8+ T cells are critical for a successful immune response to HBV infection. These cells are markedly diminished in patients that are unable to contain the virus and the mechanisms contributing to their depletion are not well-understood. The aim of this work was to further dissect this response in individuals with chronic infection. Studies of the HBV-specific CD8+ T cell immunodominance hierarchy demonstrated that persistent infection was associated with a hyporesponsiveness that was exacerbated with increasing antigenic load. The immunodominant core 18-27-specific response appeared to be particularly prone to deletion whereas a population of envelope 183-191-specific CD8+ T cells managed to persist despite excessively high viral loads but with an inability to exert effective antiviral function. cDNA microarrays were used to compare these responses in resolved and chronic infection and helped identify a group of functionally-related genes that were selectively up-regulated in HBV-peptide stimulated CD8+ T cells from individuals with chronic infection. The most striking of these was the pro-apoptotic mediator of cross-tolerance induction, Bim, whose expression was confirmed to be upregulated at the protein level. Inhibition of Bim-mediated apoptosis resulted in enhanced detection of HBV-specific CD8+ T cells both in culture and directly ex vivo. In accordance to Bim-mediated deletion of CD127low CD8+ T cells, the HBV-specific CD8+ T cells surviving in chronic HBV infection were found to be CD127hlgh. These populations had elevated levels of the anti-apoptotic protein Mcl-1, suggesting they had been subject to IL-7 mediated rescue from apoptosis. This study indicates that Bim-mediated attrition of HBV-specific CD8+ T cells contributes to the inability of these populations to persist and control viral replication.

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