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.

项目摘要（摘要）： I型糖尿病（T1D）是一种早期发作自身免疫性疾病，最终导致胰岛素的靶向破坏 在Langerhans的胰岛中发现的细胞。前两个遗传易感性 与1型糖尿病的发育相关的决定因素与抗原表现和抗原有关 可用性（HLA和INS-VNTR）。这些和其他易感性等位基因的识别突出了潜力 对胰岛抗原的中央和周围耐受性的不足。因此，研究重点是基本 自身免疫性T细胞选择的各个方面对于确定导致丧失的关键机制至关重要 中央公差。目前尚不清楚T细胞之间的细胞内信号传导和转录曲线如何不同 选择自然表达的高亲和力宠物（潜在的自身免疫抗原）与低亲和力 胸腺发育过程中的肽（正常阳性选择）。失去自我耐受的机制 似乎是多方面的，并且理解不佳。现在有证据表明，除了易感性等位基因外， 自身免疫性糖尿病也与用作新抗原的翻译后修饰的表位有关 助手的自我耐受性丧失。致病性T细胞，该细胞针对新抗原在 胰腺可以通过称为无知的过程避免胸腺选择。非肥胖糖尿病小鼠 模型提供了一个体内系统，以剖析胸腺中自动反应性T细胞发育的机制 在人类中是不可行的。与模型抗原建立的系统不同，点头鼠标提供一般 易感背景，关键靶抗原进行翻译后修饰，导致 赞助糖尿病的发展。因此，研究自身免疫性TCR的选择至关重要 赞助商自发地逃脱了NOD小鼠的负选择。这种方法的限制是有限的 可用的自身抗原特异性TCR转基因NOD小鼠的数量。该申请利用了我们的优势 以及产生胰岛素特异性TCR后源性小鼠的经验以及我们对 胸腺细胞发育和TCR信号传导。因此，此应用程序的范围将仅限于并集中在 在上面，解剖特定的信号传导机制，允许胸腺选择自身免疫胰岛素和 染色体素反应性II限制了TCR。在拟议的工作的目标1中，我们将使用INSB：9-23 TCR 接触突变体P16A，以确定高和低的正选择的细胞机制 胰岛素反应性胸腺细胞。在AIM 2中，我们将确定早期胸腺抗原暴露在新生儿中的影响 对胰岛抗原的寿命耐受性的小鼠。从这些研究中收集的信息可能具有重要的 影响我们对自动反应性T细胞如何避免缺失以及抗原特异性Treg的理解的影响 发生发展，导致新的方法建立对胰岛抗原的耐受性。