Epigenetic silencing of V(D)J recombination is a major determinant for selective differentiation of mucosal-associated invariant t cells from induced pluripotent stem cells.
Epigenetic silencing of V(D)J recombination is a major determinant for selective differentiation of mucosal-associated invariant t cells from induced pluripotent stem cells.
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DOI：
10.1371/journal.pone.0174699
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Wakao H
中科院分区：
文献类型：
--
作者：
Saito Y;Sugimoto C;Mituyama T;Wakao H
粘膜相关不变T细胞(MAITs)是一类先天的T细胞，在宿主抵抗感染性疾病中起着关键作用，也与自身免疫性疾病、代谢性疾病和癌症有关。最近的研究表明，来源于MAITs的诱导多能干细胞(IPSCs)可以选择性地重新分化为MAITs，而不会改变其抗原特异性。这种选择性分化是MAITs用于细胞治疗和/或再生医学的先决条件。然而，这种现象背后的分子机制仍不清楚。在此，我们进行了MAITs与IPSCs分化过程中的甲基组和转录组分析。我们的多组学分析表明，重组激活基因(RAG1和RAG2)和DNA核苷酸转移酶(DNTT)高度甲基化，它们的表达在分化过程中受到抑制。由于这些基因对于T细胞受体(TCR)基因座的V(D)J重组是必不可少的，这表明新生的MAITs被阻止了可能改变其抗原特异性的进一步重排。重要的是，我们发现RAG的抑制在两个层面上得到保证：一个是RAG转录因子的调节，另一个是RAG基因座位上的DNA甲基化。综上所述，我们的研究为MAITs和IPSCs选择性分化的抗原特异性提供了可能的解释。
Mucosal-associated invariant T cells (MAITs) are innate-like T cells that play a pivotal role in the host defense against infectious diseases, and are also implicated in autoimmune diseases, metabolic diseases, and cancer. Recent studies have shown that induced pluripotent stem cells (iPSCs) derived from MAITs selectively redifferentiate into MAITs without altering their antigen specificity. Such a selective differentiation is a prerequisite for the use of MAITs in cell therapy and/or regenerative medicine. However, the molecular mechanisms underlying this phenomenon remain unclear. Here, we performed methylome and transcriptome analyses of MAITs during the course of differentiation from iPSCs. Our multi-omics analyses revealed that recombination-activating genes (RAG1 and RAG2) and DNA nucleotidylexotransferase (DNTT) were highly methylated with their expression being repressed throughout differentiation. Since these genes are essential for V(D)J recombination of the T cell receptor (TCR) locus, this indicates that nascent MAITs are kept from further rearrangement that may alter their antigen specificity. Importantly, we found that the repression of RAGs was assured in two layers: one by the modulation of transcription factors for RAGs, and the other by DNA methylation at the RAG loci. Together, our study provides a possible explanation for the unaltered antigen specificity in the selective differentiation of MAITs from iPSCs.