The Role of CD4+ T cells in the CD8+ T cell Response to Vaccinia Viral Infection

Abstract

<p>The role of CD4 T cell help in primary and secondary CD8 T cell responses to infectious pathogens remains incompletely defined. The primary CD8 T response to infections was initially thought to be largely independent of CD4 T cells, but it is not clear why some primary, pathogen-specific CD8 T cell responses are CD4 T cell-dependent. Furthermore, although the generation of functional memory CD8 T cells is CD4 T cell help-dependent, it remains controversial when the "help" is needed. The goal of this thesis project is to determine requirement and mechanisms of CD4 help during the CD8 response to vaccinia viral (VV) infection.</p><p>The first aim of this project was to determine when CD4 T cell help is required during the CD8 response to VV infection. Using both CD4-deficient mice and mice with transient depletion of CD4 T cells, we demonstrated that CD4 T cell help was not needed for the activation and effector differentiation of CD8 T cells during the primary response to VV infection. However, the activated CD8 T cells showed poor survival without CD4 T cell help, leading to a reduction in clonal expansion and a diminished, but stable CD8 memory pool. In addition, we observed that CD4 T cell help provided during both the primary and secondary responses was required for the survival of memory CD8 T cells during recall expansion. Our study indicates that CD4 T cells play a crucial role in multiple stages of CD8 T cell response to VV infection and may help to design effective vaccine strategies. </p><p>Given that CD4 T cell help is critical for the survival of activated CD8 T cells during both the primary and memory recall responses, it is still unclear how CD4 T cell help promotes CD8 T cell survival. The second aim of this project was to determine the mechanism of CD4 help for the survival of activated CD8 cells. We first showed that CD4 help in vitro was mediated by IL-21, a cytokine produced predominantly by activated CD4 T cells. We then demonstrated direct action of IL-21 on CD8 T cells was critical for the VV-specific CD8 T cell response in vivo. This intrinsic IL-21 signaling was essential for the survival of activated CD8 T cells and the generation of long-lived memory cells. We further revealed that IL-21 promoted CD8 T cell survival in a mechanism dependent on activation of the STAT1 and STAT3 pathways and subsequent upregulation of the pro-survival molecules Bcl-2 and Bcl-xL. Collectively, these results identify a critical role for CD4-derived IL-21 signaling in CD8 T cell responses to acute VV infection in vivo and may help design effective vaccine strategies in situations where CD4 cells are not fully functional.</p>