TCR PARAMETERS OF TREG FUNCTION IN AUTOIMMUNITY

自身免疫中TREG功能的TCR参数

• 批准号: 10029618
• 负责人: Maria Bettini
• 金额: $ 22.62万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-20 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10029618
• 关键词: Address; Affinity; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigenic Specificity; Antigens; Autoantigens; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Beta Cell; Cell Lineage; Cells; Characteristics; Dependence; Development; Diabetes Mellitus; Epitopes; Eragrostis; FOXP3 gene; Failure; Flow Cytometry; Genetic; Goals; Homeostasis; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Knowledge; Lead; Microscopy; Modeling; Mus; Mutate; Pathogenicity; Peripheral; Phenotype; Population; Positioning Attribute; Publishing; Receptor Signaling; Regulatory T-Lymphocyte; Role; Signal Transduction; Specificity; System; T cell response; T-Cell Activation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Technology; Testing; Transgenic Organisms; Work; antigen-specific T cells; beta Chain Antigen T Cell Receptor; competitive environment; deep sequencing; effector T cell; improved; in vivo; insight; islet; mouse model; trafficking; vector

ABSTRACT T cell receptor (TCR) dictates T cell fate decision during development, steady state/homeostasis, and antigenic stimulation in periphery. Recent expansion of deep sequencing technologies has uncovered a previously underappreciated TCR diversity within antigen specific T cell responses. TCR diversity suggests a potential for functionally diverse T cell response where TCR parameters command T cell fate decisions: T helper lineage development, T cell activation, or T cell development into a regulatory T cell lineage. In order to understand the implications of this diversity observed in TCR repertoire studies, we need to combine such approaches with functional analysis of TCRs. We are proposing to utilize a combination of technologically advanced approaches to dissect TCR parameters that control Foxp3+ T cell development and function in autoimmunity. Development of type 1 diabetes is driven primarily by self-reactive T cells, which specifically recognize and target insulin producing beta cells for destruction. We have previously published that beta cell reactive TCRs vary in their ability to induce accumulation of T regulatory cells (Tregs) in the pancreatic islets of mice. Multiple studies suggest that the strength of the TCR signal leading to Treg selection, expansion, and survival is unique and distinct from T effector T cells. However, functional implications of a unique Treg TCR repertoire, such as antigenic specificity, Treg accumulation, function, and stability of their regulatory phenotype in autoimmune diabetes are largely unknown. We hypothesize that distinct TCR repertoire of islet infiltrating Tregs has intrinsic functional differences. The proposed study will systematically characterize TCR repertoire, function, and signaling characteristic of islet infiltrating Treg TCRs. We will use TCR retrogenic approach in combination with cutting edge genetic mouse models to test the function of insulin reactive Treg TCRs in single TCR and competitive environments in the presence or absence of insulin epitope. The ultimate goal of this proposal is to uncover functional implications of Treg specific TCR parameters in autoimmunity. Insights gained from this study may lead to a significant impact on our understanding of the mechanisms behind Treg function and failure in autoimmunity, and reveal potential avenues to improve development or homeostasis of Tregs with relevant antigenic specificities.

抽象的 T细胞受体（TCR）决定了在发育过程中的T细胞命运决定，稳态/稳态和抗原刺激 在外围。最新的深序技术扩展已经发现了先前未被充分重视的TCR 抗原特异性T细胞反应中的多样性。 TCR多样性提出了功能多样的T细胞的潜力 响应TCR参数命令T细胞命运决策：T辅助谱系开发，T细胞激活或T细胞 发展成调节性T细胞谱系。为了了解TCR中观察到的这种多样性的含义 曲目研究，我们需要将这种方法与TCR的功能分析相结合。我们建议利用 技术先进方法的结合，以剖析控制FOXP3+ T细胞开发的TCR参数 和自身免疫中的功能。 1型糖尿病的发展主要由自反应性T细胞驱动，该细胞专门识别和靶向胰岛素 产生β细胞进行破坏。我们以前已经发表过，β细胞反应性TCR的能力有所不同 诱导小鼠胰岛中T调节细胞（Tregs）的积累。多项研究表明 TCR信号的强度导致Treg选择，膨胀和存活是独特的，并且与T效应T不同 细胞。但是，独特的Treg TCR库的功能含义，例如抗原特异性，Treg积累， 自身免疫性糖尿病中其调节表型的功能和稳定性在很大程度上未知。我们假设这一点 胰岛浸润Treg的独特TCR库具有内在的功能差异。拟议的研究将 系统地表征了TCR库，功能和信号传导特征的特征。我们将 使用TCR后源方法与尖端遗传小鼠模型结合使用胰岛素的功能 在存在或不存在胰岛素表位的单个TCR和竞争环境中的反应性Treg TCR。这 该提案的最终目标是发现自身免疫中TREG特定TCR参数的功能含义。 从这项研究中获得的见解可能会对我们对Treg背后机制的理解产生重大影响 自身免疫性的功能和失败 相关的抗原特异性。