During the initial funding period for this proposal, we made substantial progress in developing novel model systems to identify the specific aspects of T cell homeostasis that are influenced by IFN-gamma. Strikingly, these studies reveal that IFN-gamma produced after infection is able to regulate the initial expansion of antigen-specific CD8 T cells, the contraction phase and the rate at which T cells acquire memory characteristics. These data underlie and support our overall hypothesis for the current proposal, that that IFN-gamma is a major regulator of T cell homeostasis after infection. In this proposal, we will employ the model systems we developed in the preceding funding period to address the cellular and molecular basis for IFN-gamma regulation of T cell contraction. In addition, we will extend our studies to address the cross- talk between IFN-alpha-beta receptor and IFN-gamma receptor signaling in regulating the expansion of CDS T cells after infection. Our long-term goal is to understand how IFN-gamma and other signaling molecules regulate specific aspects of T cell homeostasis, such that this information can be used to enhance the T cell response to vaccination. Improvements in vaccination will allow the most cost effectiveand widespread defense against infectious disease. We will address our long-term goal through the following specific aims:
Specific Aim 1. Determine the timing, source, quantity and cellular targets of IFN-gamma required to regulate CDST cell contraction.
Specific Aim 2. Determine if IFN-gamma regulates T cell contraction through p53 and/or IL-18 signaling.
Specific Aim 3. Determine the requirements for IFN-alpha-beta and IFN-gamma signaling in regulating CDS T cell expansion.
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