DIFFERENTIAL ACTIVATION OF CD4+ T CELL SUBSETS

产生不同细胞因子的CD4T细胞亚群的产生受T细胞受体强度的影响 中介信号。Th1/Th2细胞分化的信号强度模型预测高亲和力 TCR与其配体的相互作用会诱导Th1细胞，低亲和力的相互作用会诱导Th2细胞。 这项建议的总体目标是确定TCR连接启动的信号通路与不同的 亲和肽影响Th1和Th2分化的发育调控 预先存在的细胞因子微环境。这个实验室以前的研究表明，组织 Th1和Th2细胞分化和融合的TCR信号复合体不同。我们假设T细胞可能 通过改变大分子信号的组成来区分不同效力的信号 调节T细胞活化结果的复合体。在目标1中，我们将定义 THL和Th2细胞在T细胞活化之前、期间和之后的信号复合体，并确定这些信号如何 组件在分化和/或激活期间组装。在目标2中，我们将确定故障是否 通过研究发现，在强TCR信号之后诱导Th2分化是由于抑制Th2生成的信号 Th2相关转录因子的调节和结合。了解与Th1和Th1相关的因素 在细胞因子微环境不起主导作用的情况下，Th2反应与我们的 了解过敏性炎症。

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.