Thymic medullary epithelial cell turnover and control of immune tolerance

项目摘要/摘要 正常和强大的免疫系统依赖于各种T细胞的发展，这些T细胞是 对自身组织的耐受性。胸腺是T细胞发育和教育促进的关键部位 对自身的耐受性，从而预防自身免疫性疾病，如1型糖尿病或多发性硬化症。在 胸腺是自身免疫调节(Aire)基因，在维持免疫耐受中起关键作用 被鉴定为人类自身免疫综合征自身免疫缺陷基因的证据 多腺性综合征1型。AIRE作用于特化的髓质胸腺上皮细胞(MTECs)，以 促进数百种自身抗原的表达，以消除发育中的自身反应性T细胞 细胞在一个被称为负选择的过程中。然而，最近，我们发现了新的种群 从以前表达Aire的细胞发展而来的mTECs，我们称之为Aire表达后(Post-Aire-Expression，POST-AIRE) AIRE)细胞。这些细胞似乎分为两个亚群：(1)与Hassall病有关的角质形成细胞样细胞 小体和(2)簇状细胞，类似于专门的肠绒毛细胞。这些细胞显示出明显的 与传统的mTEC相比，具有中等水平自身抗原表达的基因表达， 提示它们在调节胸腺T细胞耐受中可能起着独特和互补的作用。 我们已经开发了一套强大的遗传工具和老鼠报告系，使我们能够标记、跟踪和 纯化这些独特的细胞，以研究它们在胸腺中的功能及其对免疫的贡献 宽容。我们假设胸腺中的Aire后细胞代表胸腺的一个独特的子集 介导耐受性T细胞群体成熟和发育的上皮细胞。 因此，我们建议通过以下具体目标来检验这一假设：(1)定义标记语 研究胸腺簇状细胞的细胞特性和细胞发育的关键途径，(2)检测体外培养的胸腺绒毛细胞 AIRE MTEC对T细胞选择和胸腺细胞发育的影响，以及(3)评估后T细胞选择和胸腺细胞发育的贡献。 MTECs对体内免疫耐受的影响。这些研究将使我们能够揭示 这些新细胞在胸腺内的功能以及它们对T细胞选择和成熟的贡献 以及其他重要免疫调节因子的诱导，如T调节性和不变自然杀伤细胞。在……里面 通过这种方式，我们希望了解这些细胞在促进免疫耐受中的作用以及它们如何 用于预防自身免疫性疾病。

Project Summary/Abstract A normal and robust immune system relies on the development of a diverse repertoire of T cells that are tolerant of self-tissues. The thymus is a critical site for the development and education of T cell to promote tolerance to self and thus prevent autoimmune diseases, such as Type 1 diabetes or multiple sclerosis. Within the thymus, the Autoimmune Regulator (Aire) gene is a key player in the maintenance of immune tolerance as evident by its identification as the defective gene in the human autoimmune syndrome Autoimmune Polyglandular Syndrome Type 1. Aire acts within specialized medullary thymic epithelial cells (mTECs) to promote the expression of hundreds of self-antigens for the purpose of removing developing self-reactive T cells in a process known as negative selection. Recently however, we have uncovered new populations of mTECs that develop from cells that formerly expressed Aire that we have termed post-Aire-expressing (post- Aire) cells. These cells appear to fall into 2 subsets: (1) a keratinocyte-like cell that is associated with Hassall's corpuscles and (2) a tuft-like cell similar to specialized intestinal tuft cells. These cells show distinct patterns of gene expression with intermediate levels of self-antigen expression compared to conventional mTECs, suggesting that they may play a distinct and complementary role in mediating T cell tolerance in the thymus. We have developed a powerful set of genetic tools and mouse reporter lines that allows us to mark, follow and purify these unique cells in order to study their function in the thymus and their contribution to immune tolerance. We hypothesize that post-Aire cells in the thymus represent a unique subset of thymic epithelial cells that mediate the maturation and development of tolerogenic T cell populations. Therefore, we propose to test this hypothesis through the following specific aims: (1) Define markers of cell identity and key pathways of cell development in thymic tuft cells, (2) Examine the effect of post- Aire mTEC's on T cell selection and thymocyte development, and (3) Assess the contributions of post- Aire mTECs to immune tolerance in vivo. These studies will allow us to uncover the development and function of these novel cells within the thymus as well as their contribution to T cell selection and maturation as well as induction of other important immune regulators, such as T regulatory and invariant natural killer cells. In this way, we hope to understand the role of these cells in the promoting immune tolerance and how they may be employed in the prevention of autoimmune disease.