ROLE OF CD8 IN T CELL ACTIVATION & THYMIC SELECTION

TCR/CD3复合体是由以下分子组成的多聚体复合体 负责抗原结合信号转导。最近的证据 提示在与抗原提呈细胞相互作用的T细胞上，CD8 或者，CD4分子与这种复合体联系在一起。CD8和CD4 分子与蛋白酪氨酸激酶p56lck相关，因此 活化的T细胞CD8或CD4可能通过TCR/CD3介导信号转导 很复杂。已经开发了许多系统来调查这一角色 CD8或其他分子在T细胞识别和激活中的作用。许多. 这些系统依赖于CD8抗体的治疗来模拟 结合生理配体的作用。我们觉得一个更理想的系统 研究CD8的作用是一种生理状况，在这种情况下 唯一的变量是CD8参与度。通过我们最近的研究， 确定了MHC I类分子上与CD8相互作用的区域，我们 已经建立了一套系统来检测CD8对T细胞的贡献 与生理配体相互作用对抗原提呈的激活 细胞。同一T细胞克隆对免疫应答的比较分析 与表达野生型或突变型分子的APC的相互作用 将使我们能够定义CD8介导的信号的贡献 转导至T细胞激活。我们将分析T细胞在 该系统通过使用指示激活的可测量参数 PtdInsP2水解途径；蛋白酪氨酸激酶活性；以及 受体重新分配，并将这些事件与诱导 T细胞的效应器功能。此外，转基因的衍生 表达野生型或突变型I类分子的小鼠系 将使我们能够研究CD8在胸腺选择事件中的作用。我们 我觉得这些研究构成了一种强有力的方法来定义 CD8介导的信号转导在不同时间激活T细胞中的作用 分化阶段。

The TCR/CD3 complex is a multimeric complex composed of molecules which are responsible for antigen binding signal transduction. Recent evidence suggest that on T cells interacting with antigen presenting cells, the CD8 or CD4 molecules become associated with this complex. The CD8 and CD4 molecules are associated with a protein tyrosine kinase, p56lck, thus on activated T cells CD8 or CD4 may mediate signalling through the TCR/CD3 complex. A number of systems have been developed to investigate the role of CD8, or other molecules, in T cell recognition and activation. Many of these systems have relied upon treatment with antibodies to CD8 to mimic the effect of binding physiologic ligand. We feel that a more ideal system to investigate the role of CD8 is a physiological situation in which the only variable is CD8 engagement. Through our recent studies which identified the region on MHC class I molecules which interacts with CD8, we have established a system to examine the contribution of CD8 to T cell activation upon interaction with physiologic ligand on antigen presenting cells. A comparative analysis of the response of the same T cell clone to interaction with APC's expressing either the wild type or mutant molecule will allow us to define the contribution of Cd8 mediated signal transduction to T cell activation. We will analyze T cell activation in this system by using measurable parameters indicative of the activation of the PtdInsP2 hydrolysis pathway; protein tyrosine kinase activity; and receptor redistribution, and correlate these events with induction of effector function in the T cell. Furthermore, the derivation of transgenic mouse lines which express either the wild type or mutant class I molecule will enable us to examine the role of CD8 in thymic selection events. We feel that these studies constitute a powerful approach to define the role of CD8 mediated signal transduction in activation of T cells at different stages of differentiation.