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Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity.
Nature Immunology ( IF 27.7 ) Pub Date : 2020-06-22 , DOI: 10.1038/s41590-020-0700-y
Shinya Tanaka 1, 2, 3 , Wataru Ise 1 , Takeshi Inoue 1 , Ayako Ito 1 , Chisato Ono 2 , Yoshihito Shima 4 , Shuhei Sakakibara 5 , Manabu Nakayama 6 , Kentaro Fujii 1 , Ikuo Miura 7 , Jafar Sharif 8 , Haruhiko Koseki 8, 9 , Pandelakis A Koni 10 , Indu Raman 11 , Quan-Zhen Li 11 , Masato Kubo 3, 12 , Katsunori Fujiki 13 , Ryuichiro Nakato 13 , Katsuhiko Shirahige 13 , Hiromitsu Araki 14 , Fumihito Miura 14 , Takashi Ito 14 , Eiryo Kawakami 15, 16 , Yoshihiro Baba 1, 2 , Tomohiro Kurosaki 1, 17
Affiliation  

A contribution of epigenetic modifications to B cell tolerance has been proposed but not directly tested. Here we report that deficiency of ten–eleven translocation (Tet) DNA demethylase family members Tet2 and Tet3 in B cells led to hyperactivation of B and T cells, autoantibody production and lupus-like disease in mice. Mechanistically, in the absence of Tet2 and Tet3, downregulation of CD86, which normally occurs following chronic exposure of self-reactive B cells to self-antigen, did not take place. The importance of dysregulated CD86 expression in Tet2- and Tet3-deficient B cells was further demonstrated by the restriction, albeit not complete, on aberrant T and B cell activation following anti-CD86 blockade. Tet2- and Tet3-deficient B cells had decreased accumulation of histone deacetylase 1 (HDAC1) and HDAC2 at the Cd86 locus. Thus, our findings suggest that Tet2- and Tet3-mediated chromatin modification participates in repression of CD86 on chronically stimulated self-reactive B cells, which contributes, at least in part, to preventing autoimmunity.



中文翻译:

B 细胞中的 Tet2 和 Tet3 是抑制 CD86 和防止自身免疫所必需的。

已经提出了表观遗传修饰对 B 细胞耐受性的贡献,但没有直接测试。在这里,我们报告了 B 细胞中 10-11 易位 (Tet) DNA 脱甲基酶家族成员 Tet2 和 Tet3 的缺乏导致 B 细胞和 T 细胞过度活化、自身抗体产生和小鼠狼疮样疾病。从机制上讲,在缺乏 Tet2 和 Tet3 的情况下,CD86 的下调(通常发生在自我反应性 B 细胞长期暴露于自身抗原后)并未发生。在 Tet2 和 Tet3 缺陷的 B 细胞中,CD86 表达失调的重要性通过对抗 CD86 阻断后异常 T 和 B 细胞活化的限制(尽管不完全)得到进一步证明。Tet2 和 Tet3 缺陷的 B 细胞减少了组蛋白脱乙酰酶 1 (HDAC1) 和 HDAC2 在Cd86位点。因此,我们的研究结果表明,Tet2 和 Tet3 介导的染色质修饰参与抑制慢性刺激的自反应 B 细胞上的 CD86,这至少部分有助于预防自身免疫。

更新日期:2020-06-23
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