DIFFERENTIAL ACTIVATION OF CD4+ T CELL SUBSETS

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The generation of distinct cytokine-producing CD4 T cell subsets is influenced by the strength of T cell receptor mediated signaling. The signal strength model for Thl/Th2 cells differentiation predicts that high avidity interactions between a TcR and its ligand will induce Thl cells and low avidity interactions will induce Th2 cells. The overall goal of this proposal is to determine how signaling pathways initiated by TcR ligation with differing affinity peptides affect the developmental regulation of Thl and Th2 differentiation in the absence of a dominant pre-existing cytokine microenvironment. Previous studies in this laboratory have shown that the organization of the TcR signaling complex in differentiatingand committed Thl and Th2 cells differs. We hypothesize that T cells may discriminate between different potency signals by altering the composition of the macromolecular signaling complexes which will regulate the outcome of T cell activation. In Aim 1, we will define the components of the signaling complexes in Thl and Th2 cells before, during, and after T cell activation and determine how these components are assembled during differentiation and/or activation. In Aim 2, we will determine if the failure to induce Th2 differentiation following strong TcR signaling is due to signals that inhibit Th2 generation by studying the regulation and binding of Th2 associated transcription factors. Understanding the factors that related Thl and Th2 responses in situations in which the cytokine microenvironment does not play a dominant role is relevant to our understanding of allergicinflammation.