Sirt6 Regulates the Development of Medullary Thymic Epithelial Cells and Contributes to the Establishment of Central Immune Tolerance.
Sirt6 Regulates the Development of Medullary Thymic Epithelial Cells and Contributes to the Establishment of Central Immune Tolerance.
复制标题
Sirt6 调节胸腺髓质上皮细胞的发育并有助于中枢免疫耐受的建立
DOI：
10.3389/fcell.2021.655552
复制
发表时间：
2021
影响因子：
5.5
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Zhang Q;Liang Z;Zhang J;Lei T;Dong X;Su H;Chen Y;Zhang Z;Tan L;Zhao Y
虽然在了解mTEC发育的分子调控方面取得了一些进展，但表观遗传调控因子在mTEC发育和成熟中的作用知之甚少。在这里，使用TEC特异性Sirt 6基因敲除小鼠，我们发现去乙酰化酶Sirtuin 6（Sirt 6）对于功能胜任的mTEC的发育是必不可少的。首先，TEC特异性Sirt 6缺失显著减少了mTEC区室，这是由DNA复制减少和随后Sirt 6缺陷型mTEC的增殖能力受损引起的。其次，Sirt 6缺陷通过促进Spib的表达特异性地加速mTEC从CD 80-Aire-未成熟群体向CD 80 +Aire-中间成熟群体的分化。最后，TEC中的Sirt 6消融显著干扰组织限制性抗原（TRAs）的适当表达，并损害胸腺细胞和nTreg细胞的发育。此外，Sirt 6的TEC条件性敲除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，这项研究揭示了表观遗传调节因子Sirt 6在TECs中的表达对于mTECs的发育和分化至关重要，这突出了Sirt 6在建立中枢免疫耐受中的重要性。
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 Sirt6 knockout mice, we found the deacetylase Sirtuin 6 (Sirt6) is essential for the development of functionally competent mTECs. First of all, TEC-specific Sirt6 deletion dramatically reduces the mTEC compartment, which is caused by reduced DNA replication and subsequent impaired proliferation ability of Sirt6-deficient mTECs. Secondly, Sirt6 deficiency specifically accelerates the differentiation of mTECs from CD80–Aire– immature population to CD80+Aire– intermediate mature population by promoting the expression of Spib. Finally, Sirt6 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 Sirt6 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 Sirt6 in TECs is crucial for the development and differentiation of mTECs, which highlights the importance of Sirt6 in the establishment of central immune tolerance.
登录
查看更多内容
DOI：
10.1084/jem.20141207
发表时间：
2014-11-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Akiyama N;Shinzawa M;Miyauchi M;Yanai H;Tateishi R;Shimo Y;Ohshima D;Matsuo K;Sasaki I;Hoshino K;Wu G;Yagi S;Inoue J;Kaisho T;Akiyama T
通讯作者：
Akiyama T
影响因子：
4.4
作者：
Anderson, M;Anderson, SK;Farr, AG
通讯作者：
Farr, AG
影响因子：
30.5
作者：
Aschenbrenner, Katharina;D'Cruz, Louise M.;Klein, Ludger
通讯作者：
Klein, Ludger
影响因子：
4.4
作者：
Christie, Darah A.;Xu, Li S.;DeKoter, Rodney P.
通讯作者：
DeKoter, Rodney P.
影响因子：
7.8
作者：
Chinn IK;Blackburn CC;Manley NR;Sempowski GD
通讯作者：
Sempowski GD