ROLE OF CD8 IN T CELL ACTIVATION & THYMIC SELECTION

CD8 在 T 细胞激活中的作用

• 批准号: 3142445
• 负责人: TERRY A POTTER
• 金额: $ 18.51万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-09-01 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3142445
• 关键词: CD8 molecule; MHC class I antigen; T cell receptor; antigen presenting cell; biological signal transduction; calcium flux; cell differentiation; cell mediated lymphocytolysis test; clone cells; cytotoxic T lymphocyte; genetically modified animals; laboratory mouse; laboratory rabbit; leukocyte activation /transformation; phosphatidylinositols; polymerase chain reaction; protein tyrosine kinase; radiotracer; thymus

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.

TCR/CD 3复合物是由分子组成的多聚体复合物，所述分子 负责抗原结合信号转导。 最近的证据 表明在与抗原呈递细胞相互作用的T细胞上，CD 8 或者CD 4分子与这个复合体结合。 CD 8和CD 4 分子与蛋白酪氨酸激酶p56 lck相关，因此， 活化的T细胞CD 8或CD 4可以通过TCR/CD 3介导信号传导 复杂. 已经开发了一些系统来调查 CD 8或其他分子在T细胞识别和激活中的作用。 许多 这些系统依赖于用抗CD 8抗体的治疗来模拟 结合生理配体的作用。 我们认为一个更理想的系统 研究CD 8的作用是一种生理情况， 唯一的变量是CD 8接合。 通过我们最近的研究， 在鉴定了与CD 8相互作用的MHC I类分子区域后， 我们建立了一个系统来检测CD 8对T细胞的贡献， 与生理配体相互作用后激活抗原呈递 细胞 同一T细胞克隆对不同浓度的抗肿瘤药物的反应比较分析 与表达野生型或突变分子的APC的相互作用 将使我们能够确定Cd 8介导的信号的贡献 转导至T细胞活化。 我们将分析T细胞活化， 该系统通过使用指示激活的可测量参数 PtdInsP 2水解途径;蛋白酪氨酸激酶活性;和 受体再分布，并将这些事件与诱导 T细胞中的效应子功能。 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 将使我们能够检查CD 8在胸腺选择事件中的作用。 我们 我觉得这些研究构成了一个强有力的方法来定义的作用， CD 8介导的信号转导在T细胞活化中的作用 分化阶段。