Year: 2013
Type: article
Abstract: Infection with the hepatitis C virus still remains a global health problem. The antiviral immune response against HCV by CD8+ T cells plays a central role in viral containment, however, it has been highlighted in numerous studies that the CD8+ T cell responses during HCV infection are relatively weak and dysfunctional. Activation of virus-specific CD8+ T cells is a multi-step process, in which the sequence of the presented antigen, as well as the site of antigen presentation has important consequences for the quality of the CD8+ T cell response. Hence, in the present thesis, determinants of HCV-specific CD8+ T cell expansion were analyzed. HCV is characterized by high levels of genetic variation between genotypes and subtypes but also between isolates of the same subtype. This high sequence variation in immunodominant epitopes precludes protective immunity and represents a major obstacle to vaccine design. In this study, we analyzed the global sequence diversity of the immunodominant HLA-A*02-restricted CD8+ T cell epitope NS31406-1415 in circulating genotype 1a and 1b isolates and its impact on CD8+ T cell priming and induction of cross-reactive T cell responses. Circulating sequence variants of the NS31406-1415 epitope showed distinct priming potential and cross-reactivity patterns. Importantly, the highest degree of cross-reactivity was induced by a sequence that is rarely observed in the European population. Upon vaccination, the elicited CD8+ T cells should be polyfunctional and target multiple epitope variants. This study highlights the relevance of antigen sequence variation for subsequent CD8+ T cell responses and provides a rational for the selection of the optimal epitope sequence for a vaccine against HCV, associated with the induction of a broad cross-reactive and polyfunctional CD8+ T cell response. A hallmark of chronic infections with hepatotropic viruses such as HCV is the notoriously weak antiviral immune response by CD8+ T cells. Primary antigen encounter in HCV infections happens in the liver. It is believed that the liver-specific environment can induce tolerance either by induction of dysfunctional CD8+ T cells or by premature death of activated CD8+ T cells. Recent reports from mouse models indicate that hepatocytes can act as antigen-presenting. Direct antigen presentation by virally infected hepatocytes thus might inhibit the CD8+ T cell response. This study showed that the frequency of virus-specific CD8+ T cells after 10 days expansion was dramatically reduced in the presence of hepatocytes. This suppressive effect was independent of the cell-type that was used for antigen-presentation (hepatocyte or PBMC) and of antigen-specific contact. Expansion of CD8+ T cells in the presence of hepatocytes was almost completely restored in transwell experiments indicating that the suppressive effect is cell-contact dependent. Analysis of the cytokine profile from culture supernatants revealed increased concentrations of TGF-β in the presence of hepatocytes compared to their absence. This study gives important hints for the establishment of chronic infections by hepatotropic viruses.
Author: Susanne Ziegler
Language: English
Topic: Hepatitis C virus research
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1549305586