Project 2 - Specificity and repertoire of Tregs in T1D

项目总结/摘要 1型糖尿病（T1 D）是由识别和破坏胰岛组织的致病性自身反应性T细胞引起的。 然而，对自身抗原反应的T细胞的存在不足以使疾病以自身反应性发生。 可以在健康对照受试者中发现T细胞;因此可以使用各种手段来控制不需要的T细胞。 应答最重要的机制之一是调节性T细胞（Tcells）的活性， 在胸腺和外周免疫系统中作为暴露于抗原的结果。Treg缺陷 在T1 D和其他自身免疫性疾病中已经描述了数量、表型和/或功能。因为 特异性针对有限数量的Ag的T细胞的免疫抑制是显性的，并且可以有效地阻止 多克隆自身反应性应答，是抗原特异性致耐受性疗法的有吸引力的靶标。 然而，在人类和小鼠中识别自身抗原的特异性和库以及是否 它们在具有自身免疫性的个体中是不同的是未知的。 最近的研究揭示了自身肽通过MHC呈递给自身反应性T细胞的独特方面 易患自身免疫的II类等位基因。这些特性潜在地规避了负选择， 胸腺中的自身反应性T细胞并导致靶组织中的自身反应性。考虑到众所周知的 tTreg库的自身反应性，生化复杂性可能会影响发展， T细胞抗原库及其在靶组织中识别自身抗原的能力-这表明， 局部T细胞的特异性将有助于控制组织中的自身免疫。因此，确定Ag Treg的特异性，特别是在炎症部位，对于提高我们对Treg的理解至关重要 T1 D的缺陷在这个项目中，我们将通过检查整体假设来解决这个问题， 促进效应免疫的生物化学复杂性可能矛盾地改变Treg功效， 导致Tconv在自身免疫性疾病中控制自身反应性Tconv细胞的总体失败 例如T1 D。我们提出以下具体目标来解决这个问题：1：Treg的表征 对已知的I-Ag 7限制性自身抗原的特异性2：抗原聚焦方法来定义 T1 D患者中TlD的特异性。3：NOD小鼠和T1 D中TlR的新型配体的鉴定 患者 已认识到改变的Treg免疫调节是自身免疫中的固有因素，但定义了特异性免疫调节。 T1 D患者的Treg缺陷一直具有挑战性。因此，定义TcR的特异性和库， 他们的反应性TCR将是发现T1 D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 这些治疗机会旨在恢复胰岛中适当的Treg免疫调节。

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.