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LEU 2/T8 CELL DIFFERENTIATION ANTIGEN GENE

LEU 2/T8 细胞分化抗原基因

基本信息

批准号：
2900608
负责人：
JANE R PARNES
金额：
$ 19.88万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-01-01 至 2000-03-31
项目状态：
已结题

项目摘要

CD8 is a heterodimeric cell surface glycoprotein expressed on the mature T lymphocyte subset that recognizes foreign antigen in association with class I major histocompatibility complex (MHC) proteins and has cytotoxic function. The main goal of this proposal is to further elucidate the role of CD in T cell activation and development by analysis of the function of the CD8beta chain in these processes. First, the mechanisms by which CD8beta stimulates T cell responses will be explored in several ways: Binding studies to a recombinant, soluble for of class I linked to beta/2- microglobulin will be used to determine whether CD8beta it can bind directly to class I MHC proteins. Transfectants expressing various forms of CD8beta and/or CD8alpha will be used to assess the role of CD8beta in the activation-dependent increase in the avidity of binding of CD8alphabeta to class I MHC. The direct or indirect interaction between CD8beta and other surface proteins that might enhance signaling will be analyzed in coimmunoprecipitation and blotting studies. The interaction of the CD8beta cytoplasmic tail with proteins that may be involved in signaling through CD8beta will be analyzed using the yeast two-hybrid system. A second major aim is to determine the physiological significance of CD8alpha-independent expression of CD8beta that we have previously identified in fetal and adult thymocytes. The presence of such forms of CD8beta will be analyzed by cell staining and flow cytometric analysis of thymocytes and peripheral lymphoid cells in normal and mutant mice, both with and without activation stimuli. The biochemical nature of such complexes will be explored to determine whether they indeed represent the CD8beta/TCRbeta disulfide-linked heterodimers we have observed in transfected cells. The function of such a complex and the cells bearing it will be examined by mAb treatment of fetal thymic organ cultures, by thymic reconstitution experiments using this population isolated from day 14 fetal thymus and by evaluation of the signaling capacity of CD8beta/TCRbeta heterodimers. An attempt will be made to generate a mutant form of CD8beta that no longer dimerizes with TCRbeta but retains dimerization and functional capacity with CD8alpha. If obtained, such a mutant would be used to distinguish effects of these two forms of dimers during thymocyte that has been identified on transfectants and that appears to be present on a subset of thymocytes. These studies will aid in our understanding of how cytotoxic T cells are activated to kill virally infected or tumor cells and may additionally provide insight into the regulation of their developmental pathway.

CD8是一种异二聚体细胞表面糖蛋白，表达于成熟细胞上。识别外来抗原的 T 淋巴细胞亚群 I 类主要组织相容性复合体 (MHC) 蛋白，具有细胞毒性功能。该提案的主要目标是进一步阐明其作用通过分析 CD 在 T 细胞活化和发育中的功能这些过程中的 CD8beta 链。首先，其机制 CD8beta 刺激 T 细胞反应的研究将通过多种方式进行探索：与 β/2- 连接的 I 类重组可溶性酶的结合研究微球蛋白将用于确定它是否可以结合CD8beta 直接作用于 I 类 MHC 蛋白。表达各种形式的转染子 CD8beta 和/或 CD8alpha 将用于评估 CD8beta 在结合亲和力的激活依赖性增加 CD8alphabeta 至 I 类 MHC。之间直接或间接的相互作用 CD8beta 和其他可能增强信号传导的表面蛋白将在共免疫沉淀和印迹研究中进行分析。互动 CD8β 细胞质尾部的蛋白质可能参与将使用酵母双杂交来分析通过 CD8beta 的信号传导系统。第二个主要目标是确定生理意义我们之前研究过的 CD8β 的 CD8α 独立表达在胎儿和成人胸腺细胞中发现。此类形式的存在 CD8beta 将通过细胞染色和流式细胞术分析正常和突变小鼠的胸腺细胞和外周淋巴细胞有或没有激活刺激。此类物质的生化性质将探索复合物以确定它们是否确实代表我们在 CD8beta/TCRbeta 二硫键连接的异二聚体中观察到转染的细胞。这种复合体的功能和细胞的功能将通过单克隆抗体处理胎儿胸腺器官培养物进行检查，通过使用从白天分离的该群体进行胸腺重建实验 14 胎儿胸腺并通过评估信号传递能力 CD8β/TCRβ 异二聚体。将尝试生成一个 CD8beta 的突变形式不再与 TCRbeta 二聚化，但保留 CD8α 的二聚化和功能能力。如果获得的话，这样的突变体将用于区分这两种形式的二聚体的作用已在转染子上鉴定出胸腺细胞，并且似乎存在于胸腺细胞的子集上。这些研究将有助于在我们对细胞毒性 T 细胞如何被激活以杀伤的理解中病毒感染或肿瘤细胞，还可以提供深入了解对其发育路径的调节。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structure of the mouse gene encoding CD4 and an unusual transcript in brain.

编码 CD4 的小鼠基因的结构和大脑中不寻常的转录物。

DOI：
10.1073/pnas.84.21.7644
发表时间：
1987
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Gorman,SD;Tourvieille,B;Parnes,JR
通讯作者：
Parnes,JR

The CD8 alpha locus is located on the telomere side of the immunoglobulin kappa locus at a distance of 2 Mb.

CD8 α 基因座位于免疫球蛋白 kappa 基因座的端粒侧，距离 2 Mb。