Thymic medullary epithelial cell turnover and control of immune tolerance

项目总结/摘要 一个正常和强大的免疫系统依赖于一个多样化的T细胞库的发展， 对自身组织的耐受性。胸腺是T细胞发育和教育的关键部位， 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。内 胸腺，自身免疫调节（Aire）基因是维持免疫耐受的关键因素， 通过将其鉴定为人类自身免疫综合征中的缺陷基因， 多腺体综合征1型。Aire在特化的胸腺髓质上皮细胞（mTEC）中起作用， 促进数百种自身抗原的表达，以去除正在发展的自身反应性T细胞， 这一过程被称为负选择。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mTEC，我们称之为Aire表达后（post-Aire-expressing）。 Aire）细胞。这些细胞似乎分为2个亚群：（1）与Hassall's相关的角质形成细胞样细胞， （2）一种类似于特化肠簇细胞的簇样细胞。这些细胞表现出不同的 与常规mTEC相比具有中等水平的自身抗原表达的基因表达， 提示它们可能在介导胸腺中的T细胞耐受中发挥独特和互补的作用。 我们已经开发了一套强大的遗传工具和小鼠报告细胞系，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后Aire细胞代表了胸腺细胞的一个独特亚群， 介导致耐受性T细胞群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 胸腺簇细胞的细胞特性和细胞发育的关键途径，（2）检查后- Aire mTEC对T细胞选择和胸腺细胞发育的影响，以及（3）评估后 使mTEC在体内免疫耐受。这些研究将使我们能够揭示发展， 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， 以及诱导其他重要的免疫调节因子，如T调节和不变的自然杀伤细胞。在 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 用于自身免疫性疾病的预防。

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.