CD8+ CTL RECOGNITION OF MHC CLASS 1

MHC 1 类的 CD8 CTL 识别

• 批准号: 6199417
• 负责人: JANET M CONNOLLY
• 金额: $ 25.15万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6199417
• 关键词: CD8 molecule; MHC class I antigen; autoantigens; autoimmunity; cytotoxic T lymphocyte; genetically modified animals; laboratory mouse; leukocyte activation /transformation; lymphopoiesis; thymus; tissue /cell culture; tumor antigens; virus antigen

DESCRIPTION (Adapted from the Investigator's abstract): The hallmark of the immune system is the remarkable ability to discriminate between self and foreign proteins displayed as peptides bound to self-major histocompatibility complex (MHC) molecules. T lymphocytes acquire this ability during development in the thymus in which low avidity interactions between T-cell receptors (TCRs) and self-MCH/peptide result in positive selection. High avidity interactions in the thymus result in negative selection and deletion of potentially autoreactive T-cell repertoire that is self-tolerant and self-MHC restricted. TCR affinity, MHC/peptide density and co-receptor engagement contribute to the overall avidity of the interaction between T-cells and antigen presenting cell (APC). This avidity sets up a balance between positive and negative selection and establishes the activation requirements of peripheral T-cells. The overall goal of this application is to correlate the thymic selection environment with the functional phenotype of the peripheral CD8T cell repertoire. Specificity of peripheral CD8 T-cells. To do this they will alter class I expression or CD8 interaction during thymic development and determine how it affects the ability of peripheral CD8 T-cells to distinguish APC expressing different levels of class I/peptide complexes. To address these questions, unique MHC Class I transgenic mice that express a single class I allele will be engineered. Using these mice, the diversity of the CD8 T-cell repertoire selected by a single class I allele, in the absence of other class I molecules, will be characterized. These analyses will probe mechanisms of tolerance to self-antigens and avoidance of autoimmune responses. Furthermore these studies will determine factors influencing activation requirements of self-restricted responses to tumor antigens and infectious virus as well as how individual MHC alleles contribute to alloreactive responses and transplantation tolerance.

描述（改编自研究者摘要）： 免疫系统是区分自我和 外源蛋白显示为与自身主要组织相容性结合的肽 复合物（MHC）分子。T淋巴细胞在发育过程中获得这种能力 在胸腺中，T细胞受体（TCR）之间的低亲合力相互作用 和自身MCH/肽导致正选择。高亲合力相互作用， 胸腺导致潜在负选择和缺失 自身耐受和自身MHC限制的自身反应性T细胞库。 TCR亲和力、MHC/肽密度和共受体接合有助于免疫应答。 T细胞和抗原呈递细胞之间相互作用的总体亲合力 （APC）。这种贪婪在积极选择和消极选择之间建立了一种平衡 并建立外周T细胞的活化要求。整体 本申请的目的是将胸腺选择环境与 外周CD 8 T细胞库的功能表型。特异性 外周CD 8 T细胞。为此，他们将改变I类表达或CD 8 胸腺发育过程中的相互作用，并确定它如何影响能力， 的外周CD 8 T细胞，以区分表达不同水平的 I类/肽复合物。为了解决这些问题，独特的MHC I类 将对表达单个I类等位基因的转基因小鼠进行工程改造。使用 在这些小鼠中，通过单一的免疫选择，CD 8 T细胞库的多样性 I类等位基因，在不存在其他I类分子的情况下，将是 表征了这些分析将探索对以下物质的耐受机制 自身抗原和避免自身免疫反应。此外，这些研究 将确定影响自限性激活要求的因素 对肿瘤抗原和感染性病毒的反应以及个体MHC 等位基因有助于同种异体反应和移植耐受。