CONTROL OF T4 AND T8 GENE EXPRESSION IN T LYMPHOCYTES

T淋巴细胞个体发生的特点是其表达的一系列变化 细胞表面的某些糖蛋白。其中的两种蛋白质， 命名为T4和T8的基因在结构和进化上都与 免疫球蛋白。T4和T8基因的激活发生在早期 T细胞发育，以及绝大多数未成熟的胸腺淋巴细胞 同时表达这两种分子。然而，成熟的T细胞总是 只表达这些蛋白质中的一种：辅助T细胞通常 而大多数抑制性/细胞毒性T细胞表达T8。我们的 目标是确定控制T4和T8的基因调控元件 转录，特别强调其分子机制 在不同的T细胞亚群中产生其选择性表达。这 知识的价值不仅在于理解人的活动如何 特定的真核基因是受调控的，但也在阐明 分子水平T淋巴细胞分化和获取的过程 它们在免疫方面的正常功能。 利用重组DNA技术，我们提出了对其结构的分析 以及人类T4和T8基因的转录功能，两者都在其 天然染色质环境和导入淋巴组织和 非淋巴样受体细胞。这些基因中的选定部分将是 系统删除、修改或链接到中的异源启动子 以便描绘出有助于 转录调控。我们将研究其作用机制。 这些监管要素以及它们之间的相互作用 以及细胞内的环境。通过比较以下监管要素 T4和T8对那些控制免疫球蛋白表达的人，我们希望了解 这两个相关的基因系统是如何在进化中分化成为 分别由T细胞和B细胞谱系唯一表达。最后， 我们将利用在这些实验中获得的知识来扩展我们的 对基因调控的分析达到更基本的水平： 控制T细胞的反式作用因子的分离和鉴定 淋巴细胞基因以组织特异性或亚群特异性的方式表达。

T lymphocyte ontogeny is marked by a series of changes in the expression of certain glycoproteins on the cell surface. Two of these proteins, designated T4 and T8, are structurally and evolutionarily related to the immunoglobulins. Activation of the T4 and T8 genes occurs during early T-cell development, and the vast majority of immature thymic lymphocytes express both molecules simultaneously. Mature T-cells, however, invariably express only one or the other of these proteins: helper T-cells generally bear surface T4, whereas most suppressor/cytotoxic T-cells express T8. Our goal is to identify the genetic regulatory elements that control T4 and T8 transcription, with particular emphasis upon the molecular mechanisms which produce their selective expression in different T-cell subsets. This knowledge will be of value not only in understanding how the activity of specific eukaryotic genes is regulated, but also in elucidating at a molecuar level the process by which T lymphocytes differentiate and acquire their normal functions in immunity. Using techniques of recombinant DNA, we propose to analyze the structure and transcriptional function of the human T4 and T8 genes, both in their native chromatin environments and after transfection into lymphoid and non-lymphoid recipient cells. Selected portions of these genes will be systematically deleted, modified, or linked to heterologous promoters in order to delineate the precise sequence elements that contribute to transcriptional regulation. We will investigate the mechanisms of action of these regulatory elements, as well as their interactions with each other and with the intracellular milieu. By comparing the regulatory elements of T4 and T8 to those controlling immunoglobulin expression, we hope to learn how these two related gene systems have diverged in evolution to become uniquely expressed by the T- and B-cell lineages, respectively. Finally, we will use the knowledge gained in these experiments to extend our analysis of gene regulation to an even more fundamental level: the isolation and characterization of trans-acting factors that control T lymphocyte gene expression in a tissue-specific or subset-specific fashion.