Contribution of antigen presenting cells to thymic negative selection

项目总结/摘要 T细胞受体（TCR）库的选择对于产生耐受自身免疫应答的T细胞是必不可少的。 抗原，但准备保护宿主免受病原体的侵害。虽然这个选择过程被认为是 有效地去除自身反应性T细胞，自身免疫性疾病的高发病率 这表明这个过程并不完美。因此，需要更好地了解这一过程，以确定 容易导致自身免疫的机械故障。抗原呈递细胞的异质群体 在胸腺驱动TCR库的选择中，APC发挥重要作用。TCR与自身肽-MHC的强相互作用 由这些APC呈递的复合物导致克隆缺失或分化成调节性T细胞（Treg）， 而弱相互作用通过正选择产生幼稚TCR库。尽管存在着多样性， APC促进胸腺选择，很少有人知道他们如何独立地促进这一过程。 因此，本项目中提出的目标旨在澄清不同APC的各自贡献 克隆缺失和Treg诱导。具体而言，这些研究的结果将进一步促进 基于T细胞库的驱动选择中的细胞特异性差异来理解中枢耐受性。 目的1将使用细胞类型特异性MHC消融来确定不同的APC亚群如何影响克隆缺失 以及胸腺中早期和晚期的Treg分化。此外，拟议的实验将 区分特定的APC亚群是否更好地装备，以有助于自身反应性抗体的阴性选择。 胸腺细胞目的2将评估异质性树突状细胞群体在肿瘤中的空间分布， 胸腺这一目标将提供重要的洞察力，以了解亚组特异性定位如何决定耐受性， 胸腺中存在非重叠抗原。总的来说，这些结果将大大有助于 了解特定的APC群体如何驱动克隆缺失和调节性T细胞发育， 一种非冗余的方式。此外，该应用程序提供了一个严格的，明确的科学框架，以促进 本申请中概述的职业目标是成为一名成功的医生科学家。

PROJECT SUMMARY/ABSTRACT Selection of the T cell receptor (TCR) repertoire is essential for producing T cells that are tolerant to self- antigens, but poised to defend the host against pathogens. Although this selection process is considered effective at removing self-reactive T cells from the repertoire, the high incidence of autoimmune diseases indicates that this process is not perfect. Thus, greater understanding of this process is needed to identify the mechanistic failures that predispose to autoimmunity. Heterogeneous populations of antigen presenting cells (APCs) in the thymus drive selection of the TCR repertoire. Strong TCR interactions with self-peptide–MHC complexes presented by these APCs result in clonal deletion or differentiation into regulatory T cells (Treg), whereas weak interactions produce the naïve TCR repertoire via positive selection. Despite the diversity in APCs that facilitate thymic selection, little is known about how they contribute independently to this process. Therefore, the aims proposed in this project are designed to clarify the respective contributions of distinct APC subsets to clonal deletion and Treg induction. Specifically, the results from these studies will further the understanding of central tolerance based on cell-specific differences in driving selection of the T cell repertoire. Aim 1 will use cell type specific MHC ablation to determine how distinct APC subsets impact clonal deletion and Treg differentiation at early and late stages in the thymus. Furthermore, the proposed experiments will distinguish if specific APC subsets are better equipped to contribute to negative selection of autoreactive thymocytes. Aim 2 will evaluate the spatial distribution of heterogeneous dendritic cell populations in the thymus. This aim will provide important insight into how subset-specific localization may dictate tolerance to non-overlapping antigens presented in the thymus. Collectively, these results will substantially contribute to the understanding of how specific APC populations drive both clonal deletion and regulatory T cell development in a non-redundant manner. Moreover, this application provides a rigorous, defined scientific framework to foster the career goals outlined in this application for becoming a successful physician scientist.