TCR/CD3 COMPLEX AND T CELL DEVELOPMENT

TCR/CD3 复合物和 T 细胞发育

• 批准号: 6163968
• 负责人: CHIH-PIN LIU
• 金额: $ 27.88万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6163968
• 关键词: CD3 molecule; T cell receptor; T lymphocyte; antibody receptor; biological signal transduction; cell differentiation; cytokine; genetically modified animals; gut associated lymphoid tissue; laboratory mouse; laboratory rabbit; mucosal immunity; protein biosynthesis; receptor expression; thymus; tissue /cell culture

The major goal of this proposal is to understand the role of T cell receptor/CD3 complexes (TCR complex) in which the zetu chain is missing or replaced with the FcRgamma molecule on T cell development and function. The zetu chain homodimer of conventional TCR complexes plays a major role for expression of the complexes and in TCR mediated signaling events. However, a number of CD4- negative normal T cells such as CD8alphaalpha+ gut intraepithelial lymphocytes express alternative TCR complexes containing only one or no zetu chain but a related molecule, FcRgamma. Interestingly, these T cells tend to express potentially autoreactive TCRs but they do not cause autoimmunity. The development and function of T cells expressing alternative TCR complex are unclear, but they may develop extrathymically. Alternative TCR complexes are generally expressed at lower levels than are conventional TCR complexes. In our transgenic mice in which all their T cells express alternative TCR complexes, the complexes are expressed at even lower levels on CD4+ than on CD8+ cells. Conversely, conventional TCR complexes are expressed at higher levels on CD4+ cells than on CD8+ cells in normal mice. It is hypothesized that FcRgamma evokes different downstream signaling pathways than does zetu and thus it may alter the behavior of T cells. Experiments in Specific Aim A are designed to determine the molecular and cellular mechanisms that regulate the expression level of TCR in T cells. These studies are to find out what signaling pathways are associated with alterative TCR complexes and their influences on TCR expression and function of T cells. Further experiments in Aim B will be performed to understand the role of alternative TCR complex on T cell development and function. The experiments will analyze the roles of thymus, the cytokine secretion patterns, and the influence of alternative TCR complex on T cell reactivity. Finally, Aim C is proposed to study gut associated lymphoid tissues which is not only the largest lymphoid organ but it plays a central role in mucosal immunity. We will generate TCR transgenic mice as an animal model to study the development of T cells bearing TCRs derived from the CD8alphaalpha+ gut intraepithelial lymphocytes which express alterative TCR complexes. The knowledge gained from the studies will provide important insights into the development of normal T cells bearing alternative TCR complexes and their roles in the systemic and mucosal immunity against tumors, infections, and in autoimmune diseases.

该提案的主要目标是了解T细胞的作用， 受体/CD 3复合物（TCR复合物），其中zetu链缺失 或在T细胞发育中被FcR γ分子取代， 功能 常规TCR复合物的zetu链同源二聚体起作用， 复合物的表达和TCR介导的免疫应答中的主要作用 信号事件。 然而，许多CD 4阴性的正常T细胞 如表达CD 8 α α +肠上皮内淋巴细胞 替代的TCR复合物，其仅含有一个或不含有zetu链，但含有一个或多个zetu链。 相关分子FcR γ。 有趣的是，这些T细胞倾向于 表达潜在的自身反应性TCR，但它们不会引起 自身免疫T细胞的发育和功能表达 替代的TCR复合体尚不清楚，但它们可能会发展 胸腺外的。替代性TCR复合物通常在以下表达： 水平低于传统的TCR复合物。 在我们的转基因 所有的T细胞都表达替代性TCR复合物的小鼠， 复合物在CD 4+细胞上的表达水平甚至低于在CD 8+细胞上的表达水平。 相反，常规TCR复合物以更高水平表达， 在正常小鼠中，对CD 4+细胞的作用比对CD 8+细胞的作用大。它是假设 FcRgamma与zetu相比引发不同的下游信号通路 从而改变T细胞的行为。 具体实验 目的A旨在确定分子和细胞机制 调节T细胞中TCR的表达水平。 这些研究 找出与TCR改变相关的信号通路 复合物及其对T细胞TCR表达和功能的影响 细胞 将进行目标B中的进一步实验以理解 替代性TCR复合物对T细胞发育和功能的作用。 的 实验将分析胸腺的作用，细胞因子的分泌， 模式，以及替代性TCR复合物对T细胞的影响 反应性 最后，提出目的C是研究肠道相关淋巴组织， 它不仅是最大的淋巴器官， 在粘膜免疫中的中心作用。 我们将培育TCR转基因小鼠 作为研究携带TCR的T细胞发育的动物模型 来源于CD 8 α α +肠上皮内淋巴细胞， 表达可变TCR复合物。 从研究中获得的知识 将为正常T细胞的发育提供重要的见解 携带替代TCR复合物及其在全身和 在抗肿瘤、感染和自身免疫性疾病中的粘膜免疫。