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 effective and 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 CDS T 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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|Martin, Matthew D; Condotta, Stephanie A; Harty, John T et al. (2012) Population dynamics of naive and memory CD8 T cell responses after antigen stimulations in vivo. J Immunol 188:1255-65|
|Nolz, Jeffrey C; Rai, Deepa; Badovinac, Vladimir P et al. (2012) Division-linked generation of death-intermediates regulates the numerical stability of memory CD8 T cells. Proc Natl Acad Sci U S A 109:6199-204|
|Kashiwada, Masaki; Pham, Nhat-Long L; Pewe, Lecia L et al. (2011) NFIL3/E4BP4 is a key transcription factor for CD8?? dendritic cell development. Blood 117:6193-7|
|Nolz, Jeffrey C; Harty, John T (2011) Protective capacity of memory CD8+ T cells is dictated by antigen exposure history and nature of the infection. Immunity 34:781-93|
|Butler, Noah S; Nolz, Jeffrey C; Harty, John T (2011) Immunologic considerations for generating memory CD8 T cells through vaccination. Cell Microbiol 13:925-33|
|Wirth, Thomas C; Martin, Matthew D; Starbeck-Miller, Gabriel et al. (2011) Secondary CD8+ T-cell responses are controlled by systemic inflammation. Eur J Immunol 41:1321-33|
|Nolz, Jeffrey C; Starbeck-Miller, Gabriel R; Harty, John T (2011) Naive, effector and memory CD8 T-cell trafficking: parallels and distinctions. Immunotherapy 3:1223-33|
|Wirth, Thomas C; Harty, John T; Badovinac, Vladimir P (2010) Modulating numbers and phenotype of CD8+ T cells in secondary immune responses. Eur J Immunol 40:1916-26|
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