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.

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。