Abstract：
Since its discovery, Aire has been the topic of numerous studies in its role as a transcriptional regulator in the thymus where it promotes the \"promiscuous\" expression of a large repertoire of tissue-restricted antigens (TRAs) that are normally expressed only in the immune periphery. This process occurs in specialized medullary thymic epithelial cells (mTECs) and mediates the elimination of self-reactive T cells or promotes their conversion to the Foxp3+ regulatory T cell lineage, both of which are required for the prevention of autoimmunity. In recent years, there has been increasing interest in the role of extrathymic Aire expression in peripheral organs. The focus has primarily been on the identification of the cellular source(s) and mechanism(s) by which extrathymic AIRE affects tolerance-related or other physiological processes. A cadre of OMICs tools including single cell RNA sequencing and novel transgenic models to trace Aire expression to perform lineage tracing experiments have shed light on a phenomenon that is more complex than previously thought. In this chapter, we provide a deeper analysis of how extrathymic Aire research has developed and progressed, how cellular sources were identified, and how the function of AIRE was determined. Current data suggests that extrathymic AIRE fulfills a function that differs from what has been observed in the thymus and strongly argues that its main purpose is to regulate transcriptional programs in a cell content-dependent manner. Surprisingly, there is data that also suggests a non-transcriptional role of extrathymic AIRE in the cytoplasm. We have arrived at a potential turning point that will take the field from the classical understanding of AIRE as a transcription factor in control of TRA expression to its role in immunological and non-immunological processes in the periphery.
摘要：
自从它被发现,Aire在胸腺中作为转录调节因子的作用一直是众多研究的主题，在胸腺中，Aire可促进大量组织限制性抗原（TRA）的“混杂”表达，这些抗原通常仅在免疫外周中表达。这个过程发生在专门的髓质胸腺上皮细胞（mTEC）中，并介导自身反应性T细胞的消除或促进其转化为Foxp3调节性T细胞谱系，两者都是预防自身免疫所必需的。近年来,人们对胸腺外Aire表达在外周器官中的作用越来越感兴趣。重点主要是鉴定胸腺外AIRE影响耐受性相关或其他生理过程的细胞来源和机制。包括单细胞RNA测序和追踪Aire表达以进行谱系追踪实验的新型转基因模型在内的OMIC工具已经揭示了比以前认为的更复杂的现象。在这一章中,我们对胸腺外Aire研究的发展和进展进行了更深入的分析，细胞来源是如何被识别的，以及如何确定AIRE的功能。当前的数据表明，胸腺外AIRE具有与胸腺中观察到的功能不同的功能，并强烈认为其主要目的是以细胞含量依赖性方式调节转录程序。令人惊讶的是,有数据也提示了胸腺外AIRE在细胞质中的非转录作用.我们已经到达了一个潜在的转折点，该转折点将使该领域从对AIRE作为控制TRA表达的转录因子的经典理解转变为其在外周免疫和非免疫过程中的作用。
