MOLECULAR MECHANISMS OF TH1/TH2 DEVELOPMENT

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This Multi-Project Program investigates the regulation of Th1 and Th2 cells at two specific levels, control by gammadelta T cells and by transcription. The first two projects study the model the gammadelta T cells promote a Th1 environment by selectively killing Th2 cells. This model evolved from work in two laboratories. Dr. Sally Huber showed that susceptibility to murine Coxsackievirus (CVB3)-induced autoimmune myocarditis correlated with a Th1 response and resulted from gammadelta T cell-mediated death of Th2 cells. Dr. Ralph Budd showed that gammadelta T cells selectively kill differentiated Th2 cells, but spare Th1 cells during the pathogenesis of Borrelia Burgdorferi- induced Lyme arthritis. In the Coxsackievirus system, depletion of gammadelta T cells alleviated the myocarditis and left a Th2 response whereas adoptive transfer of gammadelta T cells enhanced disease and a Th1 response. Drs. Karen Newell and Huber have extended these results showing that expression of MHC class II IE in resistant C57BL/6 mice renders them susceptible to CVB3 myocarditis. This susceptibility is alleviated by the removal of gammadelta T cells which results in a Th2 response. Project 1 uses in vivo murine systems in Drs. Newell and Huber s laboratories, and in vitro murine systems with Dr. Susan Swain s group, to establish a link between expression of MHC class II IE molecules and the activation of gammadelta T cells that kill Th2 cells during the course of Coxsackieviral infection. Project 2 uses human synovial Vdelta1 T cell clones to determine if gammadelta T cells bias the Cd4+ immune response in vitro by selectively lysing Th2 cells in a Fas (CD95)-dependent manner. These two projects are complementary and will provide a basis for comparison between Coxsackievirus and Borrelia Burgdorferi- induced autoimmune diseases. Surviving antigen-specific T cells provide long lived specific memory. Little is known of the regulatory mechanisms that control the balance between naive, effector Th1 and Th2, and ultimately memory T cell responses to antigens. Dr. Mercedes Rincon s group has shown that Th2 effector cells manifest considerably more NFAT and AP-1 transcriptional activity than Th1 cells. In Project 3 Dr. Rincon will extend these findings to determine a) mechanisms that regulate NFAT transcriptional activity in naive, effector Th1 and Th2, and memory CD4+ T cells, and b) the role of specific NFAT family members in the activation, differentiation, and survival of these CD4+ T cell populations. These studies will provide information about the cellular regulation of effector Th1 and Th2 cells (Projects 1 and 2) as well as the molecular regulation of cytokine differentiation during the transition from naive to become memory T cells (Project 3).