Development of CD8 T cell responses

Infectious diseases invoke varying types of adaptive immune responses that are characterized by the clonal expansion of lymphocytes. CD8 T lymphocytes are important mediators of protection against intracellular pathogens and tumors. The factors that control how lymphocytes can develop into potent effectors to clear infection, and differentiate into memory to protect against re-infection have yet to be fully defined. Dissecting how CD8 T cell responses develop is the focus of this thesis. We investigated the mechanisms controlling the formation of CD8 T cell-mediated immunity using both in vitro and in vivo models. Initially, we proposed a novel role for the T-box containing protein Eomesodermin as a transcriptional regulator of CD8 T cell effector function. We discovered that this transcription factor is likely to complement the actions of T-bet and act as a critical regulatory gene in the development of cellular immunity. Although initial in vitro studies of CD8 T cell function were informative, we extended our analysis to an in vivo model to explore how CD8 T cells respond to infection. To begin to investigate CD8 T cell-mediated immunity in vivo, we functionally characterized an epitope specific MHC class II-restricted CD8 T cell response to infection in CD4-/- mice. We found that MHC class II-restricted T cells in CD4-/- mice do not share all phenotypic and functional characteristics with MHCI-restricted CD8 T cells or with MHCII-restricted CD4 T cells, but instead adopt attributes from each of these subsets. These results suggested that neither the thymic education nor the co-receptor specificity of a T cell singularly dictate the quality of its functional response. Thus, we began to investigate how other extrinsic factors like cytokines influence a CD8 T cell response. Unexpectedly, we uncovered a novel role for the pro-inflammatory cytokine IL-12 in regulating CD8 T cell memory formation. Collectively, the studies presented in this dissertation further our understanding of how cell-mediated immunity develops.