The regulation of immune responses is critically dependent on the development of T-cell subsets which produce particular cytokine profiles and not others, e.g., Th1 versus Th2 cytokines, in response to antigenic stimuli. In addition, the outcome of infection with a variety of pathogens is determined by the cytokines produced by antigen specific CD4+ T-cells, and inappropriate production of Th2 cytokines can result in the dissemination of infection or in allergic disease, while inappropriate production of Th1 cytokines can result in autoimmune pathology. The long term objective of this project is to elucidate the mechanisms that govern the development, activation and function of CD4+ T-cells with restricted cytokine profiles in antigen specific responses. In the previous project period, it was demonstrated that the antigen presenting cell (APC) type, cytokines such as IL-12 and IL-10 produced by APC, and genetic factors expressed at the level of the APC play a major role in governing the cytokine profile which develops in the CD4+ T-cell. The goal of this application is to further elucidate how these key elements allow APC to direct the developing cytokine profile in CD4+ T-cells. Specifically, these studies will: 1. Examine how macrophages from distinct strains of mice differentially regulate IL-4 and IFN-gamma during antigen specific immune responses; 2. Determine how differences in B-cells from distinct strains of mice control the quantity of IL-4 and IFN-gamma produced in CD4+ T-cells; 3. Examine the molecular mechanisms by which B-cells induce IL-4 synthesis in CD4+ T-cells. Insights gained from the proposed studies regarding the precise mechanism(s) that regulate cytokine synthesis should highlight potential therapeutic approaches likely to optimize the development of the appropriate T-cell subset.
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