Saito Yutaka, Sugimoto Chie, Mituyama Toutai, Wakao Hiroshi
Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Koto-ku, Tokyo, Japan.
Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology (AIST), Shinjuku-ku, Tokyo, Japan.
PLoS One. 2017 Mar 27;12(3):e0174699. doi: 10.1371/journal.pone.0174699. eCollection 2017.
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.
黏膜相关恒定T细胞（MAIT细胞）是一类固有样T细胞，在宿主抵御传染病的防御过程中发挥关键作用，并且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，源自MAIT细胞的诱导多能干细胞（iPSC）可选择性地重新分化为MAIT细胞，而不改变其抗原特异性。这种选择性分化是在细胞治疗和/或再生医学中使用MAIT细胞的先决条件。然而，这一现象背后的分子机制仍不清楚。在此，我们对iPSC分化过程中的MAIT细胞进行了甲基化组和转录组分析。我们的多组学分析显示，重组激活基因（RAG1和RAG2）和DNA核苷酸外转移酶（DNTT）高度甲基化，且在整个分化过程中其表达均受到抑制。由于这些基因对于T细胞受体（TCR）基因座的V（D）J重组至关重要，这表明新生的MAIT细胞可避免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基因的抑制通过两层得以确保：一层是通过对RAG基因转录因子的调控，另一层是通过RAG基因座处的DNA甲基化。总之，我们的研究为iPSC来源的MAIT细胞选择性分化过程中抗原特异性不变提供了一种可能的解释。
