Function of Aire-dependent regulatory T cells in immune tolerance

 描述（由申请人提供）：免疫系统已经进化为保护宿主免受病原体侵害，同时限制对自身组织的附带损害。后一个过程称为免疫耐受，由多种机制强制执行。“隐性”耐受性通过对自身抗原表现出过度反应性的淋巴细胞的缺失或功能失活而赋予。或者，“显性”耐受性由抑制细胞如Foxp3+调节性T细胞（TcB）强制执行，其反式作用以抑制自身反应性淋巴细胞。免疫耐受的破坏与许多自身免疫性疾病有关，如糖尿病、狼疮和类风湿性关节炎。此外，免疫耐受促进同种异体移植的接受，并限制抗肿瘤免疫疗法的功效。因此，人们对确定赋予显性和隐性免疫耐受的机制非常感兴趣，希望可以操纵这些过程以获得临床益处。在自身免疫调节因子（Aire）功能缺失突变的人类和小鼠中的证据表明，Aire在维持免疫耐受中起着关键作用。Aire是一种转录调节因子，促进胸腺上皮细胞异位表达优先编码组织限制性抗原的转录本。以前的研究已经证明，Aire驱动的组织限制性抗原的表达可以诱导对这些自身抗原反应的胸腺细胞的缺失，这表明Aire在实施隐性缺失耐受中起着至关重要的作用。然而，我们最近的工作表明，Aire是胸腺发育的多种Treg特异性所必需的，这表明Aire也可能在建立由一个亚组的Tlag介导的显性耐受中起作用。我们的发现，一些，但不是所有的，T细胞依赖于Aire在胸腺中的发展表明，Treg库可能被分为那些识别Aire依赖性抗原（Airedep T细胞），和那些识别Aire非依赖性抗原（Airedep T细胞），提高了两者之间的“分工”的可能性。本研究的目的是确定Airedep Tumor在免疫耐受中的作用，并阐明不同抗原呈递细胞的作用。 亚群在协调Airedep Tumor的发展和体内平衡中的作用。我们的中心假设是，Airedep Tumor对维持器官特异性免疫耐受至关重要。我们将通过追求以下目标来检验我们的中心假设。在目的1中，我们将阐明Airedep Treg在抑制自身免疫中的功能作用，并确定Aire对外周Treg库的影响。在目标2中，我们将确定抗原呈递细胞类型在协调胸腺发育和外周血Airedep Tumor稳态中的作用。这些原则的阐明将解决我们理解的机制，精心策划的免疫耐受的建立的主要差距。

 DESCRIPTION (provided by applicant): The immune system has evolved to protect the host from pathogens, while limiting collateral damage to self-tissues. This latter process, termed immune tolerance, is enforced by multiple mechanisms. "Recessive" tolerance is imparted by the deletion or functional inactivation of lymphocytes exhibiting excessive reactivity to self-antigens. Alternatively, "dominant" tolerance is enforced by suppressor cells, such as Foxp3+ regulatory T cells (Tregs), which act in trans to suppress autoreactive lymphocytes. Breakdown of immune tolerance is associated with numerous autoimmune diseases, such as diabetes, lupus, and rheumatoid arthritis. Furthermore, immune tolerance promotes the acceptance of allogeneic transplants, and limits the efficacy of anti-tumor immune therapies. Therefore, there is great interest in defining the mechanisms imparting dominant and recessive immune tolerance, in the hopes that these processes can be manipulated for clinical benefit. Evidence in humans and mice with loss-of-function mutations in autoimmune regulator (Aire) demonstrates a critical role for Aire in the maintenance of immune tolerance. Aire is a transcriptional regulato that promotes the ectopic expression of transcripts preferentially encoding tissue-restricted antigens by epithelial cells in the thymus. Previous studies have demonstrated that the Aire-driven expression of tissue-restricted antigens can induce the deletion of thymocytes reactive to these autoantigens, suggesting that Aire serves a crucial role in enforcing recessive, deletional tolerance. However, our recent work demonstrates that Aire is required for the thymic development of multiple Treg specificities, suggesting that Aire may also function in the establishment of dominant tolerance mediated by a subset of Tregs. Our finding that some, but not all, Tregs are dependent on Aire for development in the thymus suggests that the Treg repertoire may be divided into those that recognize Aire-dependent antigens (Airedep Tregs), and those that recognize Aire-independent antigens (Aireindep Tregs), raising the possibility of a "division of labor" between the two. The objectives of this proposal are to determine the function of Airedep Tregs in immune tolerance, and to elucidate the role of distinct antigen presenting cell subsets in orchestrating the development and homeostasis of Airedep Tregs. It is our central hypothesis that Airedep Tregs are critical for the maintenance of organ-specific immune tolerance. We will test our central hypothesis by pursuing the following aims. In Aim 1, we will elucidate the functional role of Airedep Tregs in the suppression of autoimmunity, and determine the impact of Aire on the peripheral Treg repertoire. In Aim 2, we will determine the role of antigen presenting cell types in coordinating the thymic development and peripheral homeostasis of Airedep Tregs. The elucidation of these principles will address major gaps in our understanding of the mechanisms that orchestrate the establishment of immune tolerance.