Self-Reactive T Cell Development in Type 1 Diabetes

1 型糖尿病中的自身反应性 T 细胞发育

• 批准号: 10026565
• 负责人: Matthew Bettini
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10026565
• 关键词: Self; Reactive; Cell; Development; Type

Project Summary (Abstract): Type I Diabetes (T1D) is an early onset autoimmune disease that culminates in the targeted destruction of insulin producing  cells found within the pancreatic islets of Langerhans. The top two genetic susceptibility determinants associated with development of Type 1 Diabetes are related to antigen presentation and antigen availability (HLA and INS-VNTR). The identification of these and other susceptibility alleles highlight a potential deficiency in central and peripheral tolerance to islets antigens. Therefore, studies focused on the fundamental aspects of autoimmune T cell selection are crucial in identifying the key mechanisms that lead to the loss of central tolerance. It is still unclear how the intracellular signaling and transcriptional profiles differ between T cells selected on naturally expressed high affinity peptides (potential autoimmune antigens) versus low affinity peptides (normal positive selection) during thymic development. The mechanisms behind loss of self-tolerance appear to multifaceted and poorly understood. It is now evident that in addition to susceptibility alleles, autoimmune diabetes is also associated with post-translationally modified epitopes that serve as neo-antigens and aide in loss of self-tolerance. Pathogenic T cells that are specific for neo-antigens uniquely expressed in the pancreas may escape thymic selection by a process known as ignorance. The Non-Obese Diabetic mouse model offers an in vivo system to dissect the mechanisms of autoreactive T cell development in the thymus that is not feasible in humans. Unlike systems build on model antigens, the NOD mouse offers a genetically susceptible background where key target antigens undergo post-translational modification leading to spontaneous diabetes development. Therefore, it is of high importance to study selection of autoimmune TCRs that have spontaneously escaped negative selection in NOD mice. A limitation to such approach is the limited number of available autoantigen-specific TCR transgenic NOD mice. This application capitalizes on our strengths and experience in generating insulin specific TCR retrogenic mice as well as our in-depth knowledge of thymocyte development and TCR signaling. The scope of this application will therefore be limited to, and focused on, dissecting specific signaling mechanisms that allow thymic selection of autoimmune insulin and chromogranin reactive Class-II restricted TCRs. In Aim 1 of the proposed work, we will use the InsB:9-23 TCR contact mutant, p16A, to determine the cellular mechanisms for positive and negative selection of high and low insulin reactive thymocytes. In Aim 2, we will determine the impact of early thymic antigen exposure in neonatal mice on life-long tolerance to islet antigens. Information gathered from these studies may have a significant impact on our understanding of how autoreactive T cells escape deletion and how antigen specific Treg development occurs, leading to novel approaches to establish tolerance to islet antigens.

项目概要（摘要）： I 型糖尿病 (T1D) 是一种早发性自身免疫性疾病，最终导致胰岛素的靶向破坏 产生在朗格汉斯胰岛中发现的  细胞。前两位遗传易感性 与 1 型糖尿病发展相关的决定因素与抗原呈递和抗原有关 可用性（HLA 和 INS-VNTR）。这些和其他易感性等位基因的鉴定突出了潜在的 中枢和外周对胰岛抗原的耐受性缺陷。因此，研究主要集中在基础 自身免疫 T 细胞选择的各个方面对于确定导致 T 细胞丧失的关键机制至关重要。 中枢耐受性。目前尚不清楚 T 细胞之间的细胞内信号传导和转录谱有何不同 选择天然表达的高亲和力肽（潜在的自身免疫抗原）与低亲和力肽 胸腺发育过程中的肽（正常正选择）。自我宽容丧失背后的机制 似乎是多方面的且知之甚少。现在很明显，除了易感性等位基因之外， 自身免疫性糖尿病还与作为新抗原的翻译后修饰表位有关 并帮助失去自我宽容。特异于新抗原的致病性 T 细胞，该新抗原在 胰腺可能通过一种称为“无知”的过程来逃避胸腺选择。非肥胖糖尿病小鼠 该模型提供了一个体内系统来剖析胸腺中自身反应性 T 细胞发育的机制 在人类中是不可行的。与建立在模型抗原上的系统不同，NOD 小鼠提供了遗传性 敏感背景，其中关键靶抗原经历翻译后修饰，导致 自发性糖尿病的发展。因此，研究自身免疫TCR的选择具有重要意义。 在 NOD 小鼠中自发地逃脱了阴性选择。这种方法的局限性在于 可用自身抗原特异性 TCR 转基因 NOD 小鼠的数量。该应用程序充分利用了我们的优势 和产生胰岛素特异性 TCR 逆转录小鼠的经验以及我们对 胸腺细胞发育和 TCR 信号传导。因此，本申请的范围将限于并集中于 剖析特定的信号传导机制，允许胸腺选择自身免疫胰岛素和 嗜铬粒蛋白反应性 II 类限制性 TCR。在拟议工作的目标 1 中，我们将使用 InsB:9-23 TCR 接触突变体 p16A，以确定高和低的正向和负向选择的细胞机制 胰岛素反应性胸腺细胞。在目标 2 中，我们将确定早期胸腺抗原暴露对新生儿的影响 小鼠对胰岛抗原的终生耐受。从这些研究中收集的信息可能具有重要意义 影响我们对自身反应性 T 细胞如何逃避缺失以及抗原特异性 Treg 如何理解的影响 发育的发生，导致了建立对胰岛抗原耐受性的新方法。