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Inflammation and T cell immunity to Listeria

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The murine immune response to Listeria monocytogenes infection is rapid, robust and highly effective at providing long term protective immunity. We have characterized the expansion of L. monocytogenes specific CD8 T cells during in vivo infection and find that the duration of T cell proliferation is not influenced by the duration or severity of infection. The experiments described in this grant application will test the hypothesis that CD8 T cells and the immune environment are programmed during the first 24 to 48 hours of infection by the innate inflammatory response, and that subsequent expansion and memory formation occurs independently of in vivo antigen presentation or infection induced inflammation. Our first aim is to test this hypothesis by transferring antigen specific T cells from infected mice into recipients that are uninfected, infected with antigen deficient strains of L. monocytogenes or infected for different durations with wild type bacteria. These studies will characterize the in vivo impact of inflammation and antigen presentation on antigen specific T lymphocytes expansion and memory formation. Our second aim is to characterize the CD8 T cell response to immunization with heat killed L. monocytogenes (HKLM). Our preliminary studies demonstrate that immunization with HKLM induces antigen specific CD8 T cell proliferation, but the duration and extent of proliferation is attenuated compared to that induced by live infection. We have designed experiments to determine the role of CD40 and IL-12 in the programming of CD8 T cell expansion. The third aim is to determine the role of innate inflammation induced by TLR signaling and by inflammatory chemokines on CD8 T cell expansion and memory formation. We will use mice deficient in TLR-2, TLR-4, MyD88, MIP-1a, CCR2 and CCR5 for these studies. Understanding the mechanisms that drive in vivo T cell expansion and memory information is important, since potent vaccines should be designed to elicit robust, long lasting T cell responses. Our studies will shed light on the important interactions between innate immunity and adaptive T cell responses.

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