CD8+ CTL RECOGNITION OF MHC CLASS 1

描述(改编自调查者摘要)： 免疫系统是一种非凡的区分自我和 外源蛋白显示为与自身主要组织相容性结合的多肽 络合物(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)之间的低亲和力相互作用 自身的MCH/多肽导致阳性选择。高亲和度交互作用 胸腺导致潜在的否定选择和缺失 具有自我耐受性和自身MHC限制性的自身反应性T细胞谱系。 TCR亲和力、MHC/肽密度和共受体参与有助于 T细胞与抗原提呈细胞相互作用的总体亲和力 (APC)。这种贪婪在积极和消极选择之间建立了平衡。 并建立了外周T细胞的激活要求。整体而言 这个应用程序的目标是将胸腺选择环境与 外周CD8T细胞的功能表型。的专一性 外周CD8 T细胞。为了做到这一点，他们将改变I类表达或CD8 在胸腺发育过程中的相互作用，并确定它如何影响能力 外周血CD8 T细胞表达不同水平的APC I类/多肽复合体。为了解决这些问题，独特的MHC I类 表达单一I类等位基因的转基因小鼠将被改造。vbl.使用 这些小鼠，CD8 T细胞谱系的多样性由单个 在没有其他I类分子的情况下，I类等位基因将是 特色化的。这些分析将探索对 自身抗原和避免自身免疫反应。此外，这些研究 将决定影响自限激活要求的因素 对肿瘤抗原和传染性病毒的反应以及个体MHC如何 等位基因有助于同种异体反应和移植耐受。

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.