Thymic medullary epithelial cell turnover and control of immune tolerance

描述（由申请方提供）：维持免疫耐受性对于预防自身免疫至关重要。胸腺髓质上皮细胞（mTEC）是一种有助于促进免疫耐受的关键细胞。mTEC的关键子集在自身免疫调节因子（Aire）基因的控制下表达广泛的组织限制性抗原。Aire被鉴定为自身免疫综合征1型自身免疫多腺体综合征中的缺陷基因，并强调了该基因和mTEC细胞群对于维持耐受性的至关重要性。mTEC’s的Aire表达亚群通过帮助促进TRA’s向发育中的胸腺细胞的展示以用于负选择和可能的调节性T细胞的正选择来促进自身耐受性。在胸腺内，mTEC隔室似乎处于动态周转状态，但参与这种周转的分子途径和细胞群仍有待确定，特别是在胸腺发育后的成年期。除了它们的周转之外，mTEC在胸腺中诱导和选择调节性T细胞（Treg）中的作用仍有待明确描述。最近，我们已经开发了一套强大的遗传工具，以帮助解剖和检查的营业额mTEC的和他们的控制Treg选择，包括细胞消融系统和细胞命运映射系统。这两种系统都可以在时间上进行控制，并允许在成人和新生儿环境中测试细胞周转动力学。我们假设mTEC区室是由表达Aire的前体细胞再生的细胞的动态区室，并且该细胞区室也是Treg选择的重要贡献者。 为了测试这些问题，我们的具体目标是：1）确定成年小鼠中mTEC周转和再生的机制，2）鉴定mTEC在引导调节性T细胞诱导和发育中的作用，以及3）评估Aire表达细胞消融对自身免疫发展的功能后果。总之，我们的研究将有助于确定哪些因素和细胞有助于mTEC的周转和替换，它们在Treg诱导中的潜在作用，以及mTEC的长期维持是否对免疫耐受至关重要。

DESCRIPTION (provided by applicant): The maintenance of immune tolerance is critical for the prevention of autoimmunity. A key cell that helps promote immune tolerance is the thymic medullary epithelial cell (mTEC). A critical subset of mTEC's expresses a wide array of tissue restricted antigens under the control of the Autoimmune Regulator (Aire) gene. Aire was identified as the defective gene in the autoimmune syndrome Autoimmune Polyglandular Syndrome Type 1 and highlights the critical importance of this gene and the mTEC cell population for the maintenance of tolerance. The Aire-expressing subset of mTEC's promotes self-tolerance by helping promote the display of TRA's to developing thymocytes for negative selection and perhaps the positive selection of regulatory T cells. Within the thymus, the mTEC compartment appears to be in a state of dynamic turnover, but what molecular pathways and cell populations that are involved in this turnover remain to be determined especially in adulthood after thymic development. In addition to their turnover, the role of mTEC's in the induction and selection of regulatory T cells (Treg's) in the thymus remains to be clearly delineated. Recently, we have developed a powerful set of genetic tools to help dissect and examine the turnover of mTEC's and their control of Treg selection including a cell ablation system and cell fate mapping system. Both systems can be temporally controlled and allow for testing cell turnover dynamics in the adult and neonatal settings. We hypothesize that the mTEC compartment is a dynamic compartment of cells that is regenerated by precursor cells that express Aire and that this cell compartment is also an important contributor to the selection of Treg's. To test these questions our specific aims are: 1) Determine the mechanism(s) of mTEC turnover and regeneration in adult mice, 2) Identify the role of mTECs in guiding regulatory T cell induction and development, and 3) Assess the functional consequences of Aire-expressing cell ablation on the development of autoimmunity. Taken together our studies will help determine what factors and cells contribute to the turnover and replacement of mTEC's, their potential role in the induction of Treg's, and whether the long term maintenance of mTEC's are critical for immune tolerance.