Contribution of antigen presenting cells to thymic negative selection

抗原呈递细胞对胸腺阴性选择的贡献

基本信息

批准号：
9394114
负责人：
Elise R Breed
金额：
$ 3.78万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9394114
关键词：
Ablation Adopted Affect Affinity Anatomy Animals Antigen-Presenting Cells Antigens Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity Automobile Driving B-Lymphocytes CASP3 gene Cell Death Cell Differentiation process Cells Cleaved cell Clonal Deletion Cytometry Data Defect Dendritic Cells Development Failure Fostering Frequencies Functional disorder Generations Goals Heterogeneity High Prevalence Incidence Knowledge Location MHC Class II Genes MHC Interaction Mediating Methods Mus Peptide/MHC Complex Phenotype Physicians Population Population Heterogeneity Process Regulatory T-Lymphocyte Reporter Scientist Signal Transduction Site Spatial Distribution Structure of thymic cortex Structure of thymic medulla T-Cell Receptor T-Lymphocyte TCR Activation Testing Thymic epithelial cell Thymocyte Selection Thymus Gland Tissues autoreactive T cell autoreactivity base career cell type central tolerance chronic autoimmune disease cytokine design experimental study insight novel pathogen thymocyte

项目摘要

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.

项目概要/摘要 T 细胞受体 (TCR) 库的选择对于产生耐受自身受体的 T 细胞至关重要。抗原，但准备保护宿主免受病原体侵害，尽管这种选择过程被考虑。有效清除自身反应性 T 细胞，提高自身免疫性疾病的发病率表明这个过程并不完美，因此需要更好地理解这个过程来识别。容易产生自身免疫的机械故障。胸腺中的 APC（APC）驱动 TCR 库的选择，TCR 与自肽-MHC 具有强相互作用。这些 APC 呈递的复合物导致克隆缺失或分化为调节性 T 细胞 (Treg)，而弱相互作用则通过正选择产生朴素的 TCR 库，尽管存在多样性。 APC 促进胸腺选择，但人们对它们如何独立参与这一过程知之甚少。因此，本项目提出的目标旨在阐明不同 APC 各自的贡献具体来说，这些研究的结果将进一步促进克隆删除和 Treg 诱导的子集。基于驱动 T 细胞库选择的细胞特异性差异来理解中心耐受性。目标 1 将使用细胞类型特异性 MHC 消融来确定不同的 APC 子集如何影响克隆删除此外，所提出的实验将在胸腺的早期和晚期阶段进行 Treg 分化。区分特定 APC 子集是否能够更好地促进自身反应的阴性选择目标 2 将评估异质树突状细胞群的空间分布。这一目标将为了解子集特异性定位如何决定胸腺的耐受性提供重要的见解。总的来说，这些结果将极大地促进胸腺中存在的非重叠抗原。了解特定 APC 群体如何驱动克隆缺失和调节性 T 细胞发育此外，该应用程序提供了一个严格的、明确的科学框架来促进。本申请中概述的成为一名成功的医师科学家的职业目标。