CONTROL OF NK & T CELLS BY TGF DURING VIRAL INFECTION

这个项目的目标是描述“关闭”急性的途径

The goal of this project is to characterize pathways that "turn off" acute natural killer (NK) cell and T lymphocyte responses in vivo. Both NK cells and T lymphocytes are activated and undergo proliferation during acute viral infections. The kinetics of the two responses are different, however, NK cells respond early whereas T cells respond late. The tight regulation of these two responses suggest that it is not only important to "turn off" but also to "turn off" NK cell and T cell proliferation at appropriate times. The studies proposed in the application are based on interesting new data suggesting that TGF-betas are induced during viral infections and that NK cell proliferation is extremely sensitive to inhibition mediated by these factors. The experiments proposed in this application will use experimental infections of mice with lymphocytic choriomeningitis virus (LCMV) to characterize the mechanisms regulating acute lymphocyte proliferation during viral infections and to evaluate the consequences of activating such pathways on resistance to subsequent viral infection. The following will be evaluated: (1) the sensitivity of in vivo elicited NK cell and T lymphocyte proliferation to inhibition mediated by different forms of TGF-beta, (2) the mechanism for differential sensitivities of the NK and T cell subsets to TGF-beta-mediated inhibition, (3) the production of various forms of TGF-beta during infection, (4) the phenotype of cell populations make these factors in vivo, (5) the role of endogenously produced TGF-betas in regulating NK cell and/or T lymphocyte proliferation in vivo, and (6) the consequences of inducing TGF-betas, during LCMV infections, on subsequent infections with murine cytomegalovirus (MCMV). A multi-faceted approach will be used to carry out this project. Biochemical studies will characterize the mechanisms for differential sensitivities to TGF-betas. The expression of various forms of TGF-betas during infection will be examined by molecular studies. In situ hybridizations and immunohistochemical studies will be performed to examine the expression of the TGF-betas within different splenic leukocyte subsets post-infection. The physiological role of TGF-betas in regulating acute lymphocyte proliferative responses and in contributing to increased susceptibility to infections will be evaluated in whole animals. The information obtained from these studies will result in a better understanding of the naturally occurring regulatory processes controlling acute lymphocyte proliferation in vivo. Furthermore, they will provide insights as to possible immunosuppressive consequences of an acute response to viral infection and possible points of intervention to either enhance or inhibit the immune response.