The long term, goal of this study is to understand how various aspects of bacteria antigens influence the nature and magnitude of host defense, and how the resulting immune response modifies the course of infection. The Gram- positive bacterium, Listeria monocytogenes (LM), offers an excellent model to address these questions since both the pathogen and the murine host are amenable to experimental manipulation. The investigators have developed a genetic system for constructing recombinant LM (rLM) expressing foreign antigens, molecular tools for manipulating bacterial antigens and the pathogenic process, and a murine model for characterizing immune responses induced by the rLM strains. By manipulating antigen secretion, they have shown that both secreted and non-secreted bacterial proteins efficiently prime CD8 T cells. However, only secreted bacterial proteins serve as protective antigens for CTL- mediated immunity. Thus, antigen compartmentalization results in a striking dichotomy between CTL priming and protective immunity. The objective of this proposal is to understand the mechanism(s) that is responsible for this dichotomy. Specifically, they will: 1) examine the kinetics of activating naive and memory CD8 T cells by secreted vs. non-secreted bacterial antigens. These studies will directly test a long standing hypothesis that secreted proteins are recognized by the immune system before non-secreted ones, and thus are more relevant vaccine targets. 2) test a Quantitative Difference model which stipulates that CTL responses to non-secreted bacterial antigens are too weak and/or too late to prevent the progression of LM infection. 3) test a Cell Tropism model which stipulates that non-secreted antigens are presented only by a subset of infected cells. As a result, CTL specific to the non-secreted antigen are unable to recognize all infected cells and thus, cannot control infection. The results of these studies should unveil the mechanism(s) responsible for the dichotomy between CTL priming and protective immunity as a result of antigen compartmentalization. Elucidation of the underlying mechanisms will have important implications in our understanding of immune surveillance of intracellular bacteria, for designing effective vaccines that will induce a potent response, and for selecting candidate antigens that can serve as protective targets.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Special Emphasis Panel (ZRG1-BM-1 (04))
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University of Pennsylvania
Schools of Medicine
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Dispirito, Joanna R; Shen, Hao (2010) Histone acetylation at the single-cell level: a marker of memory CD8+ T cell differentiation and functionality. J Immunol 184:4631-6
Northrop, John K; Wells, Andrew D; Shen, Hao (2008) Cutting edge: chromatin remodeling as a molecular basis for the enhanced functionality of memory CD8 T cells. J Immunol 181:865-8
Zenewicz, Lauren A; Shen, Hao (2007) Innate and adaptive immune responses to Listeria monocytogenes: a short overview. Microbes Infect 9:1208-15
Pearce, Erika L; Shen, Hao (2007) Generation of CD8 T cell memory is regulated by IL-12. J Immunol 179:2074-81
Ekkens, Melinda J; Shedlock, Devon J; Jung, Euihye et al. (2007) Th1 and Th2 cells help CD8 T-cell responses. Infect Immun 75:2291-6
Krawczyk, Connie M; Shen, Hao; Pearce, Edward J (2007) Functional plasticity in memory T helper cell responses. J Immunol 178:4080-8
Krawczyk, Connie M; Shen, Hao; Pearce, Edward J (2007) Memory CD4 T cells enhance primary CD8 T-cell responses. Infect Immun 75:3556-60
Foulds, Kathryn E; Shen, Hao (2006) Clonal competition inhibits the proliferation and differentiation of adoptively transferred TCR transgenic CD4 T cells in response to infection. J Immunol 176:3037-43
Northrop, John K; Thomas, Rajan M; Wells, Andrew D et al. (2006) Epigenetic remodeling of the IL-2 and IFN-gamma loci in memory CD8 T cells is influenced by CD4 T cells. J Immunol 177:1062-9
Lau, Lisa L; Jiang, Jiu; Shen, Hao (2005) In vivo modulation of T cell responses and protective immunity by TCR antagonism during infection. J Immunol 174:7970-6

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