Vaccinia Inhibition of gd T cells is a Immune Evasion Mechanism

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DESCRIPTION (provided by applicant): Gammadelta T cells use an alternative receptor for MHCunrestricted recognition and are found in all lymphoid compartments of the human body. The gammadelta (gd) cells recognize cells infected by virus or intracellular bacteria, tumor cells and small molecule antigens. A major question is: Are gd T cells are required for protection against human viral diseases? Previous studies including our own work on HIV disease, provided correlative data for a gd T cell role in viral disease but there are no compelling studies in human or nonhuman primate systems and mechanisms of action have not been defined. Using the model of vaccinia infection, we will determine whether gd T cells are required and define their contributions to protective immunity. Vaccinia is a naturally attenuated vaccine against smallpox in man. The gd T cells are essential for vaccinia immunity in the mouse, where they provide T cell help in the absence of CD4+ cells and promote IgM to IgG isotype switching with the development of neutralizing antibodies although similar functions for g T cells have not been studied in primate species. Our own work revealed a potent, vaccinia-mediated inhibition of human gd T cells. Immune evasion mechanisms generally indicate that the target cells (here gd T cells) are part of the protective response. Studies in this proposal seek to define the mechanism for vaccinia-mediated inhibition of human gd T cells, to test cytokines and TLR agonists for the ability to reverse inhibition, and to perform pilot studies in nonhuman primates for testing the role of gd T cells in the development of vaccinia immunity. Work in this proposal, representing efforts of the Pauza group, the Hoft laboratory in St. Louis University, Bernie Moss at the NIH/NIAID and Yiming Shao from the China CDC, are highly significant for advancing our understanding of gd T cells, for evaluating novel therapeutic approaches to viral disease, for improving vaccine efficacy by stimulating gd T cells, and for efforts to generate safer and more immunogenic vaccinia as smallpox vaccines or as viral vectors. The major human gd T cell subset can be activated in vivo with existing clinical drugs, a direction being tested in novel therapies for cancer, and similar approaches may be useful for viral diseases and vaccination. A subset of human lymphocytes called gammadelta (gd) T cells, are postulated to be important for protective immunity against viral diseases but existing studies provide correlations with disease and have not proven the requirement or defined a mechanism of action for their contribution. Recently, we showed that vaccinia virus (the naturally occurring vaccine against smallpox) potently inhibits gd T cells, suggesting they are part of the mechanism that controls vaccinia infection in man. Our goals are to test the hypothesis that gd T cells are necessary for viral immunity and to pursue the development of new therapies and improved vaccination approaches that incorporate direct stimulation of gd T cells.