Gamma Delta T Cell Recognition in Tularemia

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Francisella tularensis infects at local sites before being disseminated throughout the body via bacteremia and/or infected macrophages. The first few days of infection are often critical in determining whether or not the host will survive. Positioned at the interface between innate and adaptive immunity, NK cells and y5 T cells are present in large numbers and respond rapidly to infection by a variety of viruses, bacteria, and parasites. These "rapid response" lymphocytes kill infected cells and.secrete large amounts of IFN-y and TNF-a that stimulate infected macrophages to kill intracellular bacteria. Human V72V52 T cells expand rapidly during tularemia infections to very high levels (22-50% of circulating T cells) supporting their important role in the immune response to Francisella tularensis. We have shown that identical expansions of monkey V?2Vd2 T cells have characteristics of memory T cell responses and that these expansions coincide with the resolution of mycobacterial infections. We find that V?2Vd2 T cells use their TCRs to recognize bacterial and protozoal infections by responding to a common microbial metabolic intermediate, (E)-4- hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). In support of memory responses by y8 T cells, we find that adult V?2Vd2 T cells are almost exclusively memory cells that are divided into 3 subsets, central memory, effector memory, and effector CD45RA+ memory. We hypothesize that the response of human memory V?2Vd2 T cells to phosphoantigens on the surface of F. tularensis infected cells provides vital bridge immunity" in tularemia before a¿ T cell and B cell responses. Despite the importance of V?2Vd2 T cells in human tularemia there are no vaccines that stimulate this T cell subset. Priming or boosting V?2Vd2 T cell memory should help provide early, partial immunity and will also have an adjuvant effects on pathogen-specific ap T cells for tularemia and for other infections with pathogens that produce HMBPP including anthrax and plague. Here we propose to (1) test V?2Vd2 T cell ¿ecognition of F. tularensis infected cells, (2) determine the contribution of V?2Vd2 T cell to the survival of human PBMC-SCID-beige mice infected with F. tularensis, (3) derive live bacterial vaccines for V?2Vd2 T ells that overproduce HMBPP from attenuated Salmonella, and (4) test HMBPP/adjuvant vaccines and live bacterial vaccines for their ability to stimulate V?2Vd2 T cell immunity in monkeys. These studies will lucidate the critical role of V?2Vd2 T cells in tularemia and will develop vaccines that target V?2Vd2 T cells.