Project 2 - Specificity and repertoire of Tregs in T1D

项目 2 - T1D 中 Tregs 的特异性和全部功能

• 批准号: 9151389
• 负责人: JEFFREY A BLUESTONE
• 金额: $ 40.87万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-08 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9151389
• 关键词: Address; Affect; Alleles; Antigen Targeting; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Biochemical; Bystander Suppression; Cells; Cloning; Collaborations; Computational algorithm; Computer Simulation; Coupled; Defect; Development; Disease; Endocrine; Exposure to; Failure; G6PC2 gene; Generations; HLA-DQ8 antigen; High-Throughput Nucleotide Sequencing; Human; IL2RA gene; Immune system; Immunity; Immunosuppression; In Vitro; Inbred NOD Mice; Individual; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Lead; Libraries; Ligands; Lymphoid; MHC Class II Genes; Mediating; Methods; Molecular; Molecular Structure; Mus; Organ; Pancreas; Patients; Peptide/MHC Complex; Peptides; Peripheral; Phenotype; Process; Proinsulin; Property; Regulatory T-Lymphocyte; Role; Sampling; Site; Specificity; Staining method; Stains; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Tissues; Yeasts; abstracting; autoreactive T cell; autoreactivity; base; central tolerance; diabetogenic; immunopathology; immunoregulation; improved; in vivo; islet; lymph nodes; novel; peripheral tolerance; response; screening

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.

项目概要/摘要 1 型糖尿病 (T1D) 是由识别并破坏胰岛组织的致病性自身反应性 T 细胞引起的。 然而，对自身抗原产生反应的 T 细胞的存在不足以导致疾病发生为自身反应性的 T 细胞可以在健康对照受试者中找到；因此，有各种方法可以控制不需要的 回应。最重要的机制之一是调节性 T 细胞 (Treg) 的活性，它产生于 由于暴露于抗原而在胸腺和外周免疫系统中。 Treg细胞缺陷 数量、表型和/或功能已在 T1D 和其他自身免疫性疾病中得到描述。因为 特定于有限数量 Ag 的 Tregs 的免疫抑制占主导地位，可以有效地阻止免疫抑制。 由于多克隆自身反应，Tregs 是抗原特异性耐受疗法的一个有吸引力的靶点。 然而，Tregs 在人类和小鼠中识别自身抗原的特异性和全部功能以及是否 它们在患有自身免疫的个体中有何不同尚不清楚。 最近的研究揭示了 MHC 将自身肽呈递给自身反应性 T 细胞的独特方面 易产生自身免疫的 II 类等位基因。这些特性可能会规避负面选择 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。鉴于众所周知的倾斜 tTreg 库的自身反应性、生化复杂性可能会影响其发育和 Tregs 的全部功能及其识别目标组织中自身 Ag 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，鉴定Ag Tregs 的特异性，尤其是炎症部位的特异性，对于提高我们对 Treg 的理解至关重要 T1D 的缺陷。在这个项目中，我们将通过检验总体假设来解决这个问题： 促进效应免疫的生化复杂性可能会矛盾地改变 Treg 的功效 导致Tregs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T1D。我们提出以下具体目标来解决这个问题： 1：Treg 的表征 针对已知 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 患者中 Tregs 的特异性。图 3：NOD 小鼠和 T1D 中 Tregs 的新型配体的鉴定 患者。 人们认识到 Treg 免疫调节的改变是自身免疫的固有因素​​，但定义了特定的 T1D 患者的 Treg 缺陷一直具有挑战性。因此，定义 Tregs 的特异性和全部功能 他们的反应性 TCR 将是发现 T1D 和 Treg 选择性缺陷的重要一步 极大地提高了我们对疾病免疫病理学的理解。此外，这将为 旨在恢复胰岛正常 Treg 免疫调节的治疗机会。