TCR PARAMETERS OF TREG FUNCTION IN AUTOIMMUNITY

摘要 T细胞受体(TCR)决定着T细胞在发育、稳态/稳态和抗原刺激过程中的命运。 在外围地区。最近深度测序技术的扩展揭示了以前被低估的TCR 抗原特异性T细胞反应的多样性。TCR多样性提示T细胞功能多样化的可能性 TCR参数决定T细胞命运的反应：T辅助细胞谱系发育、T细胞激活或T细胞 发育成调节性T细胞谱系。为了理解在TCR中观察到的这种多样性的含义 对于曲目研究，我们需要将这种方法与TCRs的功能分析结合起来。我们建议使用一种 结合技术先进的方法分析控制Foxp3 T细胞发育的TCR参数 并在自身免疫中发挥作用。 1型糖尿病的发生主要是由自身反应性T细胞驱动的，这种T细胞专门识别和靶向胰岛素 产生用于破坏的贝塔细胞。我们之前已经发表过，β细胞反应性TCR在它们的能力上存在差异 诱导小鼠胰岛T调节细胞(Tregs)蓄积。多项研究表明， 导致Treg选择、扩展和存活的TCR信号的强度是独一无二的，不同于T效应T 细胞。然而，一个独特的Treg TCR谱系的功能含义，如抗原特异性，Treg蓄积， 在自身免疫性糖尿病中，它们的调节表型的功能和稳定性在很大程度上是未知的。我们假设 不同的胰岛浸润性树的TCR谱系具有内在的功能差异。拟议的研究将 系统地鉴定胰岛浸润性Treg TCR的TCR谱系、功能和信号特征。我们会 用TCR逆转录方法结合尖端遗传小鼠模型检测胰岛素的功能 在存在或不存在胰岛素表位的单一TCR和竞争环境中的反应性Treg TCR。这个 这项建议的最终目标是揭示Treg特异性TCR参数在自身免疫中的功能暗示。 从这项研究中获得的见解可能会对我们理解Treg背后的机制产生重大影响 自身免疫的功能和失败，并揭示了改善Tregs发育或内稳态的潜在途径 相关的抗原特异性。

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.