Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity
Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity
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DOI：
10.1038/s41590-020-0700-y
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发表时间：
2020-06-22
影响因子：
30.5
通讯作者：
Kurosaki, Tomohiro
中科院分区：
文献类型：
--
作者：
Tanaka, Shinya;Ise, Wataru;Kurosaki, Tomohiro
已经提出表观遗传修饰对B细胞耐受性的贡献，但未直接测试。在这里，我们报告了10 - 11易位（泰特）DNA去甲基化酶家族成员Tet 2和Tet 3在B细胞中的缺陷导致小鼠B和T细胞的过度活化，自身抗体的产生和狼疮样疾病。从机制上讲，在Tet 2和Tet 3不存在的情况下，通常在自身反应性B细胞慢性暴露于自身抗原后发生的CD 86下调没有发生。Tet 2-和Tet 3-缺陷B细胞中失调的CD 86表达的重要性通过在抗CD 86阻断后对异常T和B细胞活化的限制（尽管不完全）进一步证明。Tet 2和Tet 3缺陷型B细胞在Cd 86位点的组蛋白脱乙酰酶1（HDAC 1）和HDAC 2积累减少。因此，我们的研究结果表明，Tet 2-和Tet 3-介导的染色质修饰参与慢性刺激的自身反应性B细胞上的CD 86的抑制，这至少部分地有助于防止自身免疫。十-十一易位（泰特）酶氧化5-甲基胞嘧啶，促进DNA去甲基化。Kurosaki和他的同事表明，B细胞特异性Tet 2和Tet 3的缺失导致小鼠狼疮样自身免疫，部分原因是B细胞CD 86表达增加和CD 4（+）T细胞活化增强。
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 theCd86locus. 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.Ten-eleven translocation (Tet) enzymes oxidize 5-methylcytosine, facilitating DNA demethylation. Kurosaki and colleagues show that B cell-specific loss of Tet2 and Tet3 leads to lupus-like autoimmunity in mice, in part through increased B cell expression of CD86 and enhanced activation of CD4(+)T cells.