CD8+ T cells, which recognize pathogen derived peptides bound to MHC class I molecules, are important mediators of immunity to viral, protozoan and bacterial pathogens of humans. Infection of mice with Listeria monocytogenes (LM), a gram positive, enteric bacterial pathogen, provides an outstanding model to analyze the in vivo CD8+ T cell response to bacterial infection. Recently, we used recombinant Listeria (rLM), expressing a model antigen as a secreted or non-secreted molecule, to demonstrate that both secreted and non-secreted LM antigens primed CD8+ T cell responses under vaccine conditions but only the secreted antigen was a target for protective CD8+ T cells in previously immunized mice. We hypothesize that this dichotomy between CD8+ T cell priming and protective immunity, based on antigen location, results from previously unappreciated differences in the roles of endogenous and exogenous MHC class I antigen presentation pathways. These differences were only revealed by using precisely characterized rLM, expressing the same antigen in different bacterial locations, and the in vivo analysis of CD8+ T cell priming and protective immunity after LM infection. Thus, our goal is to use these rLM strains to increase our fundamental understanding of the in vivo role of endogenous and exogenous MHC class I presentation pathways in response to infection. We will use the rLM strains expressing defined CD8+ T cell epitopes in different bacterial locations to probe the function of endogenous and exogenous MHC class I antigen presentation pathways and address following Specific Aims:
Specific Aim 1. Determine the relationship between in vivo epitope levels, CD8+ T cell priming and CD8+ T cell protective immunity against LM.
Specific Aim 2. Identify the cell types that present the non-secreted antigens in vivo.
Specific Aim 3. Determine the capacity of dendritic cells (DCs) to present secreted and non-secreted LM antigens to CD8+ T cells after infection or through cross-presentation.
Specific Aim 4. Determine the requirement for CD4O and neutrophils for in vivo presentation of non-secreted bacterial antigens to CD8+ T cells. Results of these studies will provide important fundamental information regarding the in vivo roles of endogenous and exogenous MHC class I presentation pathways in CD8+ T cell responses to infection. Such basic information will impact evolving strategies for rational vaccine design, addressing the utility of the various antigen presentation pathways for vaccine delivery and for providing targets for protective immunity.
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