Project 2 - Specificity and repertoire of Tregs in T1D

项目摘要/摘要 1型糖尿病(T1D)是由识别和破坏胰岛组织的病理性自身反应性T细胞引起的。 然而，对自身抗原有反应的T细胞的存在不足以使疾病以自身反应的形式发生 在健康对照受试者中可以发现T细胞；因此可以使用各种方法来控制不想要的 回应。其中最重要的机制之一是调节性T细胞(Tregs)的活动，它既产生又产生 在胸腺和外周免疫系统中，作为暴露于抗原的结果。Treg中的缺陷 数量、表型和/或功能已在T1D和其他自身免疫性疾病中被描述。因为 对有限数量的AGS特异的Tregs免疫抑制占主导地位，可以有效地阻止 多克隆自身反应，Tregs是抗原特异性耐受治疗的一个有吸引力的靶点。 然而，在人类和小鼠中，Tregs识别自身AGS的特异性和特异度以及是否 它们在自身免疫性未知的个体中是不同的。 最近的研究揭示了MHC将自体多肽呈递给自身反应性T细胞的独特方面 易发生自身免疫的II类等位基因。这些特性潜在地绕过了对 胸腺中的自体反应T细胞，并导致靶组织中的自体反应。鉴于众所周知的偏斜 在tTreg的自我反应性方面，生化的复杂性可能会影响tTreg的发展和 Tregs的谱系及其在靶组织中识别自身AGS的能力--表明Ag 局部Tregs的特异性将有助于控制组织中的自身免疫。因此，识别银 树突状细胞的特异性，特别是在炎症部位，对于提高我们对树突状细胞的理解至关重要 T1D缺陷。在这个项目中，我们将通过检查总体假设来解决这个问题 促进效应器免疫的生化复杂性可能会矛盾地改变Treg的疗效和 导致Tregs在自身免疫性疾病中控制自身反应性Tconv细胞的全面失败 如T1D。我们提出了以下具体目标来解决这个问题：1：Treg的特征 针对已知的I-Ag7限制性自身抗原的特异性2：以抗原为中心的方法来定义 T1D患者Tregs的特异性。NOD小鼠和T1D小鼠Tregs新配体的鉴定 病人。 现已认识到Treg免疫调节改变是自身免疫的固有因素，但它定义了特定的 T1D患者的Treg缺陷一直是具有挑战性的。因此，定义Tregs和Tregs的特殊性和曲目 他们的反应性TCR将是发现T1D和T1D中选择性Treg缺陷的重要一步 极大地提高了我们对疾病免疫病理学的理解。此外，这将为 旨在恢复胰岛适当Treg免疫调节的治疗机会。

Project Summary/Abstract Type 1 Diabetes (T1D) is caused by pathogenic autoreactive T cells that recognize and destroy the islet tissue. However, the presence of T cells reactive to self-antigens is not sufficient for disease to occur as autoreactive T cells can be found in healthy control subjects; thus various means are available that control unwanted responses. One of the most important mechanisms is the activity of regulatory T cells (Tregs), which arise both in thymus and in the peripheral immune system as a consequence of exposure to antigens. Defects in Treg numbers, phenotype, and/or function have been described in T1D and other autoimmune diseases. Because immunosuppression by Tregs specific for a limited number of Ags is dominant and can efficiently thwart a polyclonal autoreactive response, Tregs are an attractive target for antigen-specific tolerogenic therapies. However, the specificity and repertoire of Tregs recognizing self-Ags in humans and mice and whether they are different in individuals with autoimmunity is unknown. Recent studies have uncovered unique aspects of self-peptides presentation to autoreactive T cells by MHC class II alleles predisposing to autoimmunity. These peculiarities potentially circumvent negative selection of autoreactive T cells in the thymus and lead to autoreactivity in the target tissue. Given the well-known skewing of the tTreg repertoire towards self-reactivity, biochemical complexities may affect the development and repertoire of Tregs and their ability to recognize self-Ags in the targeted tissues – suggesting that the Ag specificity of local Tregs will be instrumental in controlling autoimmunity in the tissue. Thus, identifying the Ag specificity of Tregs, especially at the site of inflammation, is critical to improve our understanding of Treg deficiencies in T1D. In this project, we will address this question by examining the overall hypothesis that the biochemical intricacies that promote effector immunity may paradoxically alter Treg efficacy and contribute to the overall failure of Tregs to control autoreactive Tconv cells in autoimmune diseases such as T1D. We propose the following Specific Aims to address this question: 1: Characterization of Treg specificity against known I-Ag7-restricted autoantigens 2: Antigen focused approach to define the specificity of Tregs in T1D patients. 3: Identification of novel ligands for Tregs in NOD mice and T1D patients. It is recognized that altered Treg immunoregulation is an inherent factor in autoimmunity but defining specific Treg defects in T1D patients has been challenging. Thus, defining the specificity and repertoire of Tregs and their reactive TCRs would be an important step towards the discovery of selective Treg defects in T1D and greatly improve our understanding of the immunopathology of disease. Moreover, it would pave the way for therapeutic opportunities aimed at restoring proper Treg immunoregulation in pancreatic islets.