POSITIVE SELECTION BY SINGLE CLASS II MHC/PEPTIDE MOTIFS

描述（改编自研究者摘要）：总体目标 本申请旨在确定自衍生肽的重要性 在体内胸腺中的CD 4 + T细胞的阳性选择中。 在胸腺中， 携带可与自身MHC/肽相互作用的受体的胸腺细胞 选择复合物使其成熟。 此外，胸腺细胞也 强烈与自身MHC/肽复合物被消除， 自我攻击 自身衍生肽在阴性对照中的重要性 胸腺的选择是无可争议的 肽在免疫中的作用 积极选择的过程并不像消极选择那样清晰 选择. 目前，没有数据表明，积极的选择 对天然MHC/肽配体的作用主要是肽特异性的。 这 应用程序使用最近建立的体内模型，其中所有类 II MHC分子（Ab）被单个肽E（52-68）（Ep）占据， 研究在该MHC/肽复合物上选择的CD 4 + T细胞的特异性。 具体目标1中的实验被设计为确定库， 通过单一II类MHC/肽选择的CD 4 + T细胞的特异性 复杂. 特别是，研究者将研究CD 4+的谱系 通过单一II类MHC/肽阳性选择的T细胞 复合物和阴性选择相同的II类MHC与野生型 缩氨酸 Aim 2的具体任务是分离TCR基因， 在AbEp上体内选择的具有鉴定的抗原特异性的TCR 复杂. 这些基因将使他能够构建TCR转基因小鼠 已知TCR对选择（AbEp）和激活都具有特异性 （AbPCC）。 最后，这种转基因TCR将在表达 不同量的阳性选择的AbEp肽配体。 此外，将确定这种转基因TCR是否可以被移植到人。 被其他自身衍生的MHC/肽复合物阳性选择或 抗原性AbPCC复合物。 从这方面的研究中获得的知识 应用程序将提供重要的洞察力的选择过程 CD 4 + T细胞在体内的表达，并可为T细胞的操作提供基础。 剧目-一个具有重要医学意义的问题。

DESCRIPTION (Adapted from the Investigator's abstract): The overall aim of this application is to determine the significance of self-derived peptides in positive selection of CD4+ T-cells in the thymus in vivo. In the thymus, thymocytes bearing receptors that can interact with self MHC/peptide complexes are selected to mature. Furthermore, thymocytes that interact too strongly with self MHC/peptide complexes are eliminated as potentially autoaggressive. The importance of self-derived peptides in negative selection in the thymus is indisputable. The role of peptides in the process of positive selection is not as clear as it is in negative selection. Currently, there are no data that show that positive selection on natural MHC/peptide ligands is primarily peptide specific. This application uses the recently established in vivo model, in which all class II MHC molecules (Ab) are occupied by a single peptide E(52-68) (Ep), to study the specificity of CD4+ T-cells selected on this MHC/peptide complex. Experiments in Specific Aim 1 are designed to determine the repertoire and specificity of CD4+ T-cells selected by a single class II MHC/peptide complex. In particular, the investigator will study the repertoire of CD4+ T-cells that were positively selected by a single class II MHC/peptide complex and negatively selected on the same class II MHC with wild-type peptides. The specific task of Aim 2 is to isolate TCR genes that encode TCRs with identified antigen-specificity, selected in vivo on the AbEp complex. These genes will allow him to construct a TCR transgenic mouse with TCR of known specificity for both selection (AbEp) and activation (AbPCC). Finally, this transgenic TCR will be tested in mice that express different amounts of the positively selected AbEp peptide ligand. Furthermore, it will be determined whether this transgenic TCR can be positively selected by other self-derived MHC/peptide complexes or on antigenic AbPCC complex. The knowledge gained from studies in this application will provide important insight into the selection processes of CD4+ T-cells in vivo, and may provide a basis for manipulation of the T-cell repertoire - an issue of great medical importance.