Foxp3+ T-regulatory cells require DNA methyltransferase 1 expression to prevent development of lethal autoimmunity
Foxp3+ T-regulatory cells require DNA methyltransferase 1 expression to prevent development of lethal autoimmunity
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DOI：
10.1182/blood-2012-08-451765
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发表时间：
2013-05-02
期刊：
影响因子：
20.3
通讯作者：
Hancock, Wayne W.
中科院分区：
文献类型：
--
作者：
Wang, Liqing;Liu, Yujie;Hancock, Wayne W.
使用Foxp3+ T调节（Treg）细胞进行细胞治疗的方案，特别是同种异体干细胞移植后，目前正在由各个小组开发和测试。DNA甲基转移酶（Dnmt）酶的抑制剂已被提倡作为在体内注射之前促进和稳定Foxp3在经历体外扩增的Tcells中表达的手段。我们研究了有条件地删除Treg分离株中与Foxp3共免疫沉淀的两种Dnmt酶的影响。Dnmt1的缺失，而不是Dnmt3a，减少了外周T细胞的数量和功能，并损害了常规T细胞在极化条件下向Foxp3+ T细胞的转化。重要的是，在其Tendon中有条件缺失Dnmt 1的小鼠在3至4周龄时死于自身免疫，除非通过围产期转移野生型Tendon来拯救它们。条件性Dnmt1缺失不影响Foxp3内CpG位点的甲基化，但降低了整体DNA甲基化，并改变了数百个促炎基因和其他基因的Treg表达。因此，Dnmt 1对于维持Treg发育和功能的核心基因程序是必需的，并且其在Treg谱系内的缺失导致致死性自身免疫。这些数据表明，在考虑使用DNMT抑制剂开发基于Treg的细胞疗法时，可能需要谨慎。
Protocols to use Foxp3+ T-regulatory (Treg) cells for cellular therapy, especially postallogeneic stem cell transplantation, are currently being developed and tested by various groups. Inhibitors of DNA methyltransferase (Dnmt) enzymes have been advocated as a means to promote and stabilize Foxp3 expression in Tregs undergoing expansion in vitro before their injection in vivo. We investigated the effects of conditionally deleting two Dnmt enzymes that co-immunoprecipitated with Foxp3 in Treg isolates. Deletion of Dnmt1, but not Dnmt3a, decreased the numbers and function of peripheral Tregs and impaired conversion of conventional T cells into Foxp3+ Tregs under polarizing conditions. Importantly, mice with conditional deletion of Dnmt1 in their Tregs died of autoimmunity by 3 to 4 weeks of age unless they were rescued by perinatal transfer of wildtype Tregs. Conditional Dnmt1 deletion did not affect methylation of CpG sites within Foxp3 but decreased global DNA methylation and altered Treg expression of several hundred pro-inflammatory and other genes. Hence, Dnmt1 is necessary for maintenance of the core gene program underlying Treg development and function, and its deletion within the Treg lineage leads to lethal autoimmunity. These data suggest that caution may be warranted when considering the use of DNMT inhibitors in development of Treg-based cellular therapies.