The methyl-CpG-binding domain 2 (MBD2) interprets DNA methylome-encoded information through binding to the methylated CpG DNA, by which it regulates target gene expression at the transcriptional level. Although derailed DNA methylation has long been recognized to trigger or promote autoimmune responses in type 1 diabetes (T1D), the exact role of MBD2 in T1D pathogenesis, however, remains poorly defined. Herein, we generated an Mbd2 knockout model in the NOD background and found that Mbd2 deficiency exacerbated the development of spontaneous T1D in NOD mice. Adoptive transfer of Mbd2^−/− CD4 T cells into NOD.scid mice further confirmed the observation. Mechanistically, Th1 stimulation rendered the Stat1 promoter to undergo a DNA methylation turnover featured by the changes of DNA methylation levels or patterns along with the induction of MBD2 expression, which then bound to the methylated CpG DNA within the Stat1 promoter, by which MBD2 maintains the homeostasis of Th1 program to prevent autoimmunity. As a result, ectopic MBD2 expression alleviated CD4 T cell diabetogenicity following their adoptive transfer into NOD.scid mice. Collectively, our data suggest that MBD2 could be a viable target to develop epigenetic-based therapeutics against T1D in clinical settings.

甲基-CpG 结合域 2 (MBD2) 通过与甲基化 CpG DNA 结合来解释 DNA 甲基化组编码的信息，从而在转录水平上调节靶基因的表达。尽管长期以来人们一直认为脱轨的 DNA 甲基化会触发或促进 1 型糖尿病 (T1D) 的自身免疫反应，但 MBD2 在 T1D 发病机制中的确切作用仍不清楚。在这里，我们在 NOD 背景中生成了Mbd2敲除模型，发现Mbd2缺乏加剧了 NOD 小鼠自发性 T1D 的发展。^{Mbd2 -/ -} CD4 T 细胞过继转移到NOD.scid小鼠中进一步证实了观察结果。从机制上讲，Th1 刺激使Stat1启动子经历 DNA 甲基化转换，其特征是 DNA 甲基化水平或模式的变化以及 MBD2 表达的诱导，然后与Stat1启动子内的甲基化 CpG DNA 结合，MBD2 通过该过程维持 Th1 程序的稳态以防止自身免疫。结果，异位 MBD2 表达减轻了 CD4 T 细胞在过继转移到NOD.scid小鼠后的致糖尿病性。总的来说，我们的数据表明 MBD2 可能是在临床环境中开发基于表观遗传的治疗 T1D 的可行目标。