TCR/PEPTIDE/MHC INTERACTION DURING POSITIVE SELECTION

T细胞抗原识别涉及T细胞受体之间的接触， (TcR)和结合到限制性主要 组织相容性复合体（MHC）分子。 MHC限制是在 胸腺 发育中的胸腺细胞上的T细胞受体（TCR）必须 在胸腺皮质上皮上结合自身MHC分子， 胸腺细胞被阳性选择并使其完全成熟。 胸腺中的阳性选择发生在缺乏外源性 缩氨酸 与自身MHC分子结合的自身肽， 在这个过程中的作用。 然而，TCR的相对重要性： 肽与TCR：MHC接触在积极选择保持 争议 阐明这一过程的分子细节是 对我们理解基本原则至关重要， TCR识别、多种TCR库的选择、耐受性和免疫应答。 自身免疫 为了研究阳性选择过程中TCR：肽：MHC的接触， 将使用独特的系统。 一种新的MHC I类分子， 设计用于评估在生理条件下，所有TCR 在阳性选择过程中需要与肽接触，或者 有些人可能只依赖于MHC接触。 在第二个系统中， 两种1类MHC变异体的正选择功能差异 与TCR利用模式相关。 我们将分析功能 反应性和TCR序列，以将TCR定位在 在分子模拟的帮助下， 两种MHC变体的晶体结构。 定点诱变和 然后使用单链TCR转基因动物来确定 这些接触导致受限的选择模式。 上述研究 将通过测试TCR的优良功能而得到显著增强 使用最近开发的1类肽引发方法 限制性T细胞

T cell antigen recognition involves a contact between the T cell receptor (TcR) and the foreign antigenic peptide bound to the restricting major histocompatibility complex (MHC) molecule. MHC restriction is learned in the thymus. The T cell receptor (TCR) on a developing thymocyte must bind self MHC molecules on thymic cortical epithelium, in order for the thymocyte to be positively selected and allowed to complete maturation. Positive selection in the thymus occurs in the absence of foreign peptides. Self peptides, bound to self MHC molecules, play an important role in this process. However, the relative importance of TCR:self peptide versus the TCR:MHC contact during positive selection remains controversial. Elucidation of the molecular details of this process is of central importance for our understanding of fundamental principles of TCR recognition, selection of a diverse TCR repertoire, tolerance and autoimmunity. To investigate the TCR:peptide:MHC contact during positive selection, two unique systems will be used. A new MHC class I molecule was engineered to evaluate whether, under physiological conditions, all TCRs require a contact with peptides during positive selection, or whether some may rely on the MHC contact alone. In the second system, functional differences in positive selection by two class 1 MHC variants correlate to a TCR utilization pattern. We shall analyze functional reactivities and TCR sequences of these cells, to position the TCR over the selecting MHC molecule, with the help of molecular modeling and crystal structures of both MHC variants. Site-directed mutagenesis and single-chain TCR transgenic animals will then be used to determine which contacts result in restricted selection patterns. Above studies will be significantly enhanced by testing of the fine TCR repertoire using a recently developed method of peptide priming of class 1 restricted T cells.