Aire Controls Heterogeneity of Medullary Thymic Epithelial Cells for the Expression of Self-Antigens
Aire Controls Heterogeneity of Medullary Thymic Epithelial Cells for the Expression of Self-Antigens
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DOI：
10.4049/jimmunol.2100692
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发表时间：
2022-01-15
影响因子：
4.4
通讯作者：
Matsumoto, Mitsuru
中科院分区：
文献类型：
--
作者：
Nishijima, Hitoshi;Matsumoto, Minoru;Matsumoto, Mitsuru
Aire是一种转录调节因子，其缺陷导致自身免疫的发展，其缺陷与髓质胸腺上皮细胞(MTECs)组织限制性自身AGS(Tras)表达减少有关。尽管TRAS依赖于Aire表达的机制还有待研究，但由于TRAS的低水平和混杂表达，Aire靶标(S)的物理识别一直受到阻碍。我们已经解决了这个问题，方法是用增强Aire表达的基因改造小鼠。整合来自Aire增强型和Aire缺陷型mTEC的转录数据表明，包括tras在内的大部分所谓的Aire依赖基因可能不是Aire下游的直接转录靶点。相反，单细胞分析显示，Aire通过控制mTECs的异质性间接诱导TRA的表达。相反，Ccl25成为Aire的典型靶点，我们在体外和体内都证实了这一点。我们的方法已经照亮了Aire的主要目标，同时将它们与次要目标区分开来。
The deficiency of Aire, a transcriptional regulator whose defect results in the development of autoimmunity, is associated with reduced expression of tissue-restricted self-Ags (TRAs) in medullary thymic epithelial cells (mTECs). Although the mechanisms underlying Aire-dependent expression of TRAs need to be explored, the physical identification of the target(s) of Aire has been hampered by the low and promiscuous expression of TRAs. We have tackled this issue by engineering mice with augmented Aire expression. Integration of the transcriptomic data from Aire-augmented and Aire-deficient mTECs revealed that a large proportion of so-called Aire-dependent genes, including those of TRAs, may not be direct transcriptional targets downstream of Aire. Rather, Aire induces TRA expression indirectly through controlling the heterogeneity of mTECs, as revealed by single-cell analyses. In contrast, Ccl25 emerged as a canonical target of Aire, and we verified this both in vitro and in vivo. Our approach has illuminated the Aire's primary targets while distinguishing them from the secondary targets.