RECEPTOR/LIGAND INTERACTIONS IN T CELL DIFFERENTIATION

T 细胞分化中的受体/配体相互作用

• 批准号: 2638147
• 负责人: STANISLAV VUKMANOVIC
• 金额: $ 20.24万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2638147
• 关键词: CD4 molecule; CD8 molecule; MHC class I antigen; MHC class II antigen; T cell receptor; animal breeding; cell differentiation; cytotoxic T lymphocyte; gene rearrangement; genetically modified animals; helper T lymphocyte; immune tolerance /unresponsiveness; laboratory mouse; receptor expression

DESCRIPTION (Adapted from the Investigator's abstract): The mature T-cell receptor (TCR) repertoire is formed during thymic development to fulfill two criteria: 1) peripheral T-cells must recognize foreign antigens associated with self MHC molecules, and 2) potentially harmful activity of T-cells specific for self-peptide/MHC complexes must be prevented. Tolerance to self may be achieved by physical deletion or by a variety of silencing mechanisms. In mature T-cells, the MHC restriction of the TCR matches the expression of the co-receptor molecule - MHC class I restricted TCRs are expressed by CD8+ T-cells, while MHC class II restricted TCRs are expressed by CD4+ T-cells. The aim of this application is to test if instead of CD4+CD8+ thymocyte deletion self MHC class II molecules can alter the lineage commitment and the CD8+ cell function. Preliminary data demonstrate that transgenic TCR specific for the H-Y antigen presented by H-2Db class I cross-reacts to self MHC class II. By breeding the H-Y TCR transgenic mice to background lacking or not H-21Ab, and by forcing the expression of CD4 in these backgrounds, it will be determined whether H-Y TCR-H-21Ab interaction during thymocyte maturation induces CD4+CD8- thymocyte deletion, endogenous TCR alpha rearrangement or functional unresponsiveness. To test if tolerance may obscure the stochastic component of lineage commitment, CD8 transgene will be introduced to H-Y mice on backgrounds lacking, or not, H-2IAb. To ask if tolerance can directly influence the lineage commitment the CD4 and CD8 gene shut-off in various transitional thymocyte populations on backgrounds lacking, or not, H-2IAb will be assessed. Testing functions of CD8+ T-cells in vitro and in vivo in H-Y mice on backgrounds lacking, or not, H2IAb or CD4 genes will determine whether tolerance to self MHC class II can alter the functional capacity of CD8+ T-cells and whether CD4 expression is required for the induction of tolerance, respectively. The proposed experiments should demonstrate for the first time that tolerance to self MHC class II molecules can affect the lineage commitment of thymocytes and the function of MHC class I restricted CD8+ cells. These findings should greatly contribute to our knowledge of the functional TCR repertoire formation and could be used to improve the immune defense against infectious agents and tumors.

描述（改编自调查员的摘要）：成熟的T细胞 在胸腺发育过程中形成受体（TCR）曲目以实现两个 标准：1）外围T细胞必须识别与外国抗原相关的 与自MHC分子和2）T细胞的潜在有害活性 必须防止针对自肽/MHC复合物。 对 自我可以通过身体上的删除或多种沉默来实现 机制。 在成熟的T细胞中，TCR的MHC限制与 共受体分子的表达-MHC I类限制的TCR是 由CD8+ T细胞表示，而MHC II类限制的TCR表示 由CD4+ T细胞。 此应用程序的目的是测试是否而不是 CD4+ CD8+胸腺细胞缺失自MHC II类分子可以改变 谱系承诺和CD8+细胞功能。 初步数据证明了 TCR特有的转基因TCR特异性H-Y抗原I类I类 与自我MHC II类交叉反应。 通过育种H-Y TCR转基因小鼠 对于缺乏或不是H-21AB的背景，并通过强迫CD4的表达 这些背景将确定H-Y TCR-H-21AB相互作用是否 在胸腺细胞成熟期间诱导CD4+CD8-胸腺细胞缺失，内源性 TCR alpha重排或功能无响应性。 测试是否 公差可能会掩盖谱系承诺的随机组成部分CD8 转基因将在缺乏背景的H-Y小鼠中介绍 H-2IAB。 询问宽容是否可以直接影响血统承诺 各种过渡性胸腺细胞种群中的CD4和CD8基因关闭 在缺乏的背景下，将评估H-2IAB。 测试功能 在缺乏背景的H-Y小鼠中，体外和体内的CD8+ T细胞的缺乏或 不是，H2IAB或CD4基因将确定对自我MHC类的耐受性 II可以改变CD8+ T细胞的功能能力以及CD4是否 诱导耐受性需要表达。 这 提出的实验应首次证明对 自我MHC II类分子会影响胸腺细胞的谱系承诺 以及MHC I类限制CD8+细胞的功能。 这些发现 应该大大促进我们对功能性TCR曲目的了解 形成，可用于改善对感染性的免疫防御 特工和肿瘤。