In response to infection, CD8+ T cells are selected by interaction with APC to undergo significant expansion and differentiation into effector cells. These effector cells participate in clearance of the infection and then undergo a rapid death phase where the majority (80-95 percent) of the effector population is lost. The remaining cells represent the memory pool and are maintained at relatively constant levels for life. Additionally, CD8+ T-cell responses to different epitopes from the same pathogen exhibit reproducible immunodominance hierarchies. Together, the expansion, death, memory and immunodominance relationships define homeostasis of Ag-specific CD8+ T cell in response to infection. Surprisingly, little is known regarding the regulation of these facets of Ag-specific CD8+ T cell homeostasis. In particular, essentially no information has been obtained regarding the regulation of the death phase of Ag-specific CD8+ T cells. Homeostasis of Ag-specific CD8+ T cells in response to infection of mice with Listeria monocytogenes (LM) or Lymphocytic Choriomeningitis Virus (LCMV) has been well documented. Our preliminary results demonstrate that all facets of Ag-specific CD8+ I cell homeostasis-expansion, death, memory and immunodominance are aberrant in perforin/IFN-y double deficient mice after LM infection. Examination of Ag-specific CD8+ T cell homeostasis in the parental perforin- and IFN-y-deficient mice reveals that perforin regulates the expansion phase after LM infection while IFN-y regulates immunodominance hierarchies after LM infection and the death phase and after LM or LCMV infection. The overall goal of this application is to further our understanding the role of IFN-y in regulation of immunodominance and the death phase of CD8+ T cell homeostasis and to determine if IFN-y also regulates the death phase of CD4+ T cells. The following Specific Aims address the overall hypothesis that IFN-y regulates immunodominance and the death phase of Ag-specific T cells independently of its role as an effector molecule in resistance to infection. SA-1. Determine the role of IFN-y in regulation of immunodominance. SA-2. Analyze the role of IFN-y regulation of the death phase of CD8+ T cells. SA-3. Determine the impact of IFN-y on regulation of Ag-specific CD4 T cell homeostasis. Since memory levels of Ag-specific T cells result from the magnitude of expansion minus the death phase understanding the regulation of the death phase has important implications, not only to increase our fundamental understanding of the immune system, but also to enhance the process of rational vaccine design.
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