Project 1 - Central thymic tolerance as a major checkpoint in T1D

项目摘要/摘要 作为发育中的胸腺细胞的负选择和调节性T细胞(Treg)的产生的场所， 胸腺在免疫耐受的多层网络中起着关键作用。一个发展中的T的命运 细胞的亲和力取决于TCR与多肽-MHC复合体的相互作用 识别亲和力最高的相互作用导致缺失或Treg诱导而亲和力较低 导致T细胞存活和分化的相互作用。自身免疫调节因子(Aire)是一种重要的 胸腺内外周自身抗原表达的转录调节因子，以及Aire的丢失导致 特殊髓质中胸腺抗原表达减少或缺失导致的阴性选择缺陷 胸腺上皮细胞(MTECs)。有几条证据表明，这一过程在 1型糖尿病的发病机制。在这里，我们将使用1型糖尿病作为模型疾病系统，以进一步 揭示胰岛素特异性T细胞是如何从胸腺中产生的，胸腺既是T效应器又是T调节细胞。 我们的具体目标是： 目的：探讨Aire和胸腺胰岛素表达在胸腺InSb(9-23)特异性T细胞缺失中的作用。 目的：确定Aire表达筛选的胸腺Foxp3+T调节细胞的谱系和特异性 细胞。 这些研究将与PPG项目2(蓝石)和项目3(Kappler)密切合作进行，以及 将有助于我们更好地理解在1型胸腺中T细胞库是如何形成的 糖尿病。

Project Summary/Abstract As the site of both negative selection of developing thymocytes and generation of regulatory T cells (Tregs), the thymus plays a critical role in the multi-layered network of immune tolerance. The fate of a developing T cell is dependent on the affinity of the interaction between the TCR and the peptide-MHC complex it recognizes, with the highest affinity interactions resulting in deletion or Treg induction and lower affinity interactions resulting in T cell survival and differentiation. The Autoimmune Regulator (Aire) is a major transcriptional regulator of peripheral self-antigen expression within the thymus, and loss of Aire leads to defects in negative selection due to reduced or absent thymic antigen expression in specialized medullary thymic epithelial cells (mTECs). Several lines of evidence point to this process as playing an important role in the pathogenesis of type 1 diabetes. Here, we will use type 1 diabetes as a model disease system to further unravel how insulin-specific T cells arise from the thymus that are both T effectors and T regulatory cells. Our specific aims are: AIM1: Define the role of Aire and thymic insulin expression on the thymic deletion of insB(9-23) specific T cells. AIM2: Define the repertoire and specificity of thymic Foxp3+ T regulatory cells selected by Aire-expressing cells. These studies will be performed in close collaboration with PPG projects 2 (Bluestone) and 3 (Kappler) and will help improve our understanding of how the T cell repertoire is shaped in the thymus in the setting of type 1 diabetes.