This proposal investigates a unique function for CD8 T cells in the immune response against infectious agents. Our major focus is on the role that CD8 T cells play in the innate immune response during infection with Listeria monocytogenes (LM). We recently demonstrated that antigen non specific CD8 T memory cells participate in a cytokine driven innate response against LM by secreting interferon-gamma. Further transfer of """"""""innate"""""""" CD8 T cells into interferon-gamma deficient mice protects them from infection with LM. We propose that CD8 T cells play a major role in the INF-gamma mediated innate response. In the first Aim we investigate the relative potency of CD8 vs NK cells in providing this type of innate protection. We postulate that effector CD8 T memory cells (TEM) which have been shown to play a minor role in the adaptive immune response play an important role in the innate response and will test this hypothesis. In the second Aim we will examine the localization of CD8 central memory cells (TCM), TEM, and NK cells at sites of LM infection in spleen and liver. We will use mice deficient in CCR7 binding chemokines (CCL-19 and -21) to assess how this chemokine-receptor interaction affects CD8 T cells in the innate response. We will also utilize new BAC transgenic mice that express Thy-1.1 as a reporter for IFN-gamma secretion to examine IFN-gamma secreting CD8 and NK cells in situ. In the third Aim we will determine the role of CD8 T cells in polarizing naive CD4 T cells to the Th1 subset. In the fourth Aim we will examine by microarray analysis the gene display of CD8 T cells that are activated by IL-12/18 (innate) vs those that are activated through the TcR (adaptive). In summary, this proposal will add important new information on how CD8 T cells function in the innate immune response against intracellular pathogens.
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