Zhang Qian, Liang Zhanfeng, Zhang Jiayu, Lei Tong, Dong Xue, Su Huiting, Chen Yifang, Zhang Zhaoqi, Tan Liang, Zhao Yong
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
Front Cell Dev Biol. 2021 Mar 29;9:655552. doi: 10.3389/fcell.2021.655552. eCollection 2021.
Although some advances have been made in understanding the molecular regulation of mTEC development, the role of epigenetic regulators in the development and maturation of mTEC is poorly understood. Here, using the TEC-specific knockout mice, we found the deacetylase Sirtuin 6 () is essential for the development of functionally competent mTECs. First of all, TEC-specific deletion dramatically reduces the mTEC compartment, which is caused by reduced DNA replication and subsequent impaired proliferation ability of -deficient mTECs. Secondly, deficiency specifically accelerates the differentiation of mTECs from CD80Aire immature population to CD80Aire intermediate mature population by promoting the expression of . Finally, ablation in TECs markedly interferes the proper expression of tissue-restricted antigens (TRAs) and impairs the development of thymocytes and nTreg cells. In addition, TEC conditional knockout of results in severe autoimmune disease manifested by reduced body weight, the infiltration of lymphocytes and the presence of autoantibodies. Collectively, this study reveals that the expression of epigenetic regulator in TECs is crucial for the development and differentiation of mTECs, which highlights the importance of Sirt6 in the establishment of central immune tolerance.
尽管在理解mTEC发育的分子调控方面已经取得了一些进展，但表观遗传调节因子在mTEC发育和成熟中的作用仍知之甚少。在这里，我们使用TEC特异性敲除小鼠，发现去乙酰化酶Sirtuin 6（Sirt6）对于功能健全的mTECs的发育至关重要。首先，TEC特异性缺失显著减少了mTEC区室，这是由于DNA复制减少以及随后Sirt6缺陷型mTECs的增殖能力受损所致。其次，Sirt6缺陷通过促进Nr4a1的表达，特异性地加速了mTECs从CD80Aire未成熟群体向CD80Aire中间成熟群体的分化。最后，TECs中Sirt6的缺失显著干扰了组织限制性抗原（TRA）的正常表达，并损害了胸腺细胞和nTreg细胞的发育。此外，TEC条件性敲除Sirt6会导致严重的自身免疫性疾病，表现为体重减轻、淋巴细胞浸润和自身抗体的存在。总的来说，这项研究表明TECs中表观遗传调节因子Sirt6的表达对于mTECs的发育和分化至关重要，这突出了Sirt6在建立中枢免疫耐受中的重要性。
