Thymic medullary epithelial cell turnover and control of immune tolerance

描述（由申请人提供）：维持免疫耐受对于预防自身免疫至关重要。帮助促进免疫耐受的关键细胞是胸腺髓上皮细胞（mTEC）。mTEC的一个关键亚群在自身免疫调节因子（Aire）基因的控制下表达多种组织限制性抗原。Aire被确定为自身免疫性综合征自身免疫性多腺综合征1型的缺陷基因，并强调了该基因和mTEC细胞群对维持耐受性的关键重要性。mTEC的air表达亚群通过帮助促进TRA向发育中的胸腺细胞的展示来促进自我耐受性，以进行负选择，也可能是调节性T细胞的正选择。在胸腺内，mTEC室似乎处于动态转换状态，但参与这种转换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。除了它们的转换，mTEC's在胸腺中诱导和选择调节性T细胞（Treg's）中的作用仍有待明确描述。最近，我们开发了一套强大的遗传工具来帮助解剖和检查mTEC的转换及其对Treg选择的控制，包括细胞消融系统和细胞命运定位系统。这两种系统都可以暂时控制，并允许在成人和新生儿环境中测试细胞周转动态。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。为了验证这些问题，我们的具体目标是：1)确定成年小鼠mTEC转换和再生的机制，2)确定mTEC在引导调节性T细胞诱导和发育中的作用，以及3)评估air表达细胞消融对自身免疫发展的功能后果。综上所述，我们的研究将有助于确定哪些因素和细胞有助于mTEC的更新和替换，它们在诱导Treg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.