Regulation of MHC Dependence of gamma delta T cells

γ δ T 细胞 MHC 依赖性的调节

• 批准号: 7149369
• 负责人: DAVID H RAULET
• 金额: $ 37.15万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7149369
• 关键词: T cell receptor; T lymphocyte; cell differentiation; developmental immunology; gene rearrangement; gene targeting; genetic promoter element; genetic regulation; genetically modified animals; immunoglobulin genes; laboratory mouse; major histocompatibility complex; posttranslational modifications; thymus; tissue /cell culture

DESCRIPTION (provided by applicant): Gamma/delta T cells play specialized but still poorly understood roles in the immune system. Our aim is to understand their biological function and the developmental processes that produce them. The specialized roles are carried out by gamma/delta T cell subsets that express distinct Vgamma and Vdelta genes and localize to distinct barrier sites or to lymphoid tissue. T cell receptor genes are assembled by the process of V(D)J recombination, a highly developmentally regulated process. In the case of gamma/deltaT cells, a strikingly coordinated process of programmed gene rearrangement and cellular selection acts between the early fetal and adult stages within the thymus, to generate the distinct subsets of gamma/deltaT cells observed in the mature animal. One of our interests is in defining the developmental processes that supervise the production of different gamma/delta T cell subsets. Our previous studies have defined key aspects of these developmental processes, but some key molecular events remain to be defined at a molecular level. More fundamentally, although important progress has been made, the physiologic role of gamma/delta T cells in disease is still poorly understood. Our preliminary data shows that mice with a deficiency in subsets of gamma/delta T cells are highly susceptible to eye disease characterized by inflammation of the conjunctival and corneal epithelium and a type 2 immune response indicative of allergic inflammation. Our first specific aim is to determine the etiology of the disease, the components of the immune response that are dysregulated and leave to immune inflammation, and the role of gamma/delta T cells in regulating the normal immune response. Our second specific aim addresses the molecular mechanism of a genetic switch that represses rearrangement of Vgamma3 and 4 in adult thymocytes. We propose to define the roles of Vgamma promoters in repressing rearrangement of these Vgamma genes in the adult period, and the role of nuclear factors in regulating the promoters. The third aim is based on our data demonstrating that the genomic location of Vgamma genes determines the pattern of rearrangement in fetal thymocytes. We propose to test whether competition between Vgamma promoters and/or RSS, or alternatively the distance from Jgamma1, are major determinants of location-dependent rearrangement. By developing an understanding of how gamma/delta T cells are produced, and defining the disregulated immune pathology that arise when specific sets are not produced, we propose to identify the normal role of that gamma/delta T cells in preventing disease. An understanding of the role of gamma/delta T cells and the rules that govern their production will undoubtedly aid in efforts marshal the immune system for therapeutic application

描述（由申请人提供）：γ/δ T 细胞在免疫系统中发挥着专门但仍知之甚少的作用。我们的目标是了解它们的生物学功能以及产生它们的发育过程。这些专门的作用是由表达不同 Vgamma 和 Vdelta 基因并定位于不同屏障位点或淋巴组织的 gamma/delta T 细胞亚群执行的。 T 细胞受体基因通过 V(D)J 重组过程组装，这是一个高度发育调控的过程。就γ/δT细胞而言，在胸腺内的早期胎儿阶段和成体阶段之间，程序性基因重排和细胞选择的惊人协调过程起作用，以产生在成熟动物中观察到的不同的γ/δT细胞亚群。我们的兴趣之一是定义监督不同 γ/δ T 细胞亚群产生的发育过程。我们之前的研究已经定义了这些发育过程的关键方面，但一些关键的分子事件仍有待在分子水平上定义。更根本的是，尽管已经取得了重要进展，但 γ/δ T 细胞在疾病中的生理作用仍然知之甚少。我们的初步数据表明，缺乏 γ/δ T 细胞亚群的小鼠极易患眼部疾病，其特征是结膜和角膜上皮炎症以及表明过敏性炎症的 2 型免疫反应。我们的第一个具体目标是确定疾病的病因、免疫反应失调并导致免疫炎症的组成部分，以及 γ/δ T 细胞在调节正常免疫反应中的作用。我们的第二个具体目标是研究抑制成人胸腺细胞中 Vgamma3 和 4 重排的基因开关的分子机制。我们建议定义 Vgamma 启动子在抑制成年期这些 Vgamma 基因重排中的作用，以及核因子在调节启动子中的作用。第三个目标是基于我们的数据，证明 Vgamma 基因的基因组位置决定胎儿胸腺细胞的重排模式。我们建议测试 Vgamma 启动子和/或 RSS 之间的竞争，或者距 Jgamma1 的距离是否是位置依赖性重排的主要决定因素。通过了解 γ/δ T 细胞如何产生，并定义未产生特定组时出现的失调免疫病理学，我们建议确定该 γ/δ T 细胞在预防疾病中的正常作用。了解 γ/δ T 细胞的作用及其产生的规则无疑将有助于整合免疫系统以进行治疗应用