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) 决定发育、稳态/稳态和抗原刺激期间 T 细胞的命运决定 在外围。最近深度测序技术的扩展发现了以前被低估的 TCR 抗原特异性 T 细胞反应的多样性。 TCR 多样性表明功能多样化 T 细胞的潜力 TCR 参数指挥 T 细胞命运决定的响应：T 辅助谱系发育、T 细胞激活或 T 细胞 发育成调节性T细胞谱系。为了理解 TCR 中观察到的这种多样性的含义 曲目研究，我们需要将这些方法与 TCR 的功能分析结合起来。我们建议利用 结合先进的技术方法来剖析控制 Foxp3+ T 细胞发育的 TCR 参数 并在自身免疫中发挥作用。 1 型糖尿病的发展主要是由自身反应性 T 细胞驱动的，这些细胞专门识别并靶向胰岛素 产生用于破坏的β细胞。我们之前曾发表过，β 细胞反应性 TCR 的能力各不相同 诱导小鼠胰岛中 T 调节细胞 (Treg) 的积累。多项研究表明 导致 Treg 选择、扩增和存活的 TCR 信号强度是独特的，与 T 效应子 T 不同 细胞。然而，独特的 Treg TCR 库的功能意义，例如抗原特异性、Treg 积累、 它们在自身免疫性糖尿病中的功能和调节表型的稳定性很大程度上是未知的。我们假设 胰岛浸润性 Tregs 的不同 TCR 库具有内在的功能差异。拟议的研究将 系统地表征胰岛浸润性 Treg TCR 的 TCR 库、功能和信号传导特征。我们将 使用TCR逆转录方法结合尖端遗传小鼠模型来测试胰岛素的功能 在存在或不存在胰岛素表位的情况下，单一 TCR 和竞争环境中的反应性 Treg TCR。这 该提案的最终目标是揭示 Treg 特异性 TCR 参数在自身免疫中的功能影响。 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 自身免疫功能和失败，并揭示改善 Tregs 发育或稳态的潜在途径 相关的抗原特异性。