Independent Cycling and Differentiation in CD4+ T cells

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DESCRIPTION (provided by applicant): Activated T cells undergo both proliferation, which results in clonal expansion, and differentiation, resulting in effector function. These phenomena occur together in many immune responses, but how are they linked? Some published data show that the number of divisions undergone by a CD4+ T cell is tightly correlated with differentiation and the synthesis of effector cytokines, suggesting that a molecular mechanism couples differentiation to cell division cycles. Other published data, including our own, suggest that cell division and differentiation are uncoupled. Our new preliminary data, developed in an adoptive transfer model in which the dye CFSE was used to count cell division cycles, also favor the independence of proliferation and differentiation in CD4+ T cells. To accommodate all of the data, we view the entry into S phase of the cell cycle, and the activation of the genes that encode effector cytokines, as distinct, unlinked probabilistic events. To explore this idea, we will use a model in which the synthesis of effector cytokines (IFN-gamma, IL-4 and IL-5)in CD4+ T cells occurs independent of proliferation. In Specific Aim 1, we will determine the conditions of T cell activation that result in non-cycling but functional effector T cells. In Specific Aim 2, we will define the state of cell cycle regulation in these cells, and test the hypothesis that they are arrested in the G 1 phase of the cycle, due to the action of one or more cyclin-dependent kinase inhibitors. In Specific Aim 3, we will determine whether these non-cycling but functional effector CD4+ T cells are undergoing lineage commitment to the Th1 and Th2 pathways. These studies will clarify the relationships between activation, cell division, differentiation, and lineage commitment in CD4+ T cells.