Analysis of Successful Virus-Specific CD8+ T Cell Responses in acute HBV infection

Depletion studies in acutely HBV-infected chimpanzees have demonstrated that CD8+ T cells are the main effector cells responsible for viral clearance and liver disease pathogenesis during acute HBV infection. In a successful immune response, an antigen-specific memory CD8+ T cell pool is established. However, there is only limited information available to date about the functional and phenotypical characteristics of HBV-specific CD8+ T cells and their association with clinical parameters in acute HBV infection. Thus, in order to elucidate these important issues, we have studied prospectively the frequency, function and phenotype of HBV-specific CD8+ T cells in six individuals with acute resolving HBV infection using HLA-A2 HBV-specific multimers. Our results can be summarized as follows: First, high frequencies of multispecific (e.g. targeting several HBV proteins) HBV-specific CD8+ T cells are detectable at the peak of liver disease, decline thereafter and are associated with viral elimination. Second, at the peak of liver disease, HBV-specific CD8+ T cells are activated but impaired in their ability to proliferate and to secrete antiviral cytokines such as IFN-γ. Third, in the course of infection, HBV specific CD8+ T cells regain their ability to proliferate but not to secrete antiviral cytokines, indicating that these two antiviral effector functions are differentially regulated. Fourth, the switch in antiviral functions (e.g. the ability to proliferate) was associated with a switch in the phenotype of HBV-specific CD8+ T cells since they lost the activation marker CD38, down-regulated the inhibitory receptor PD–1 and started to express the IL–7 receptor alpha chain (CD127) and the lymph-node homing factor CCR7. In sum, our results provide several new insights into the functional and phenotypic characteristics of the virus-specific CD8+ T cell response during acute HBV infection. Specifically, we describe the emergence of CD127 expressing HBV-specific CD8+ memory T cells in the course of acute resolving HBV infection that are characterized by specific antiviral functions. These results will facilitate the design of T cell based vaccines.