論文

査読有り
2017年3月

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

PLOS ONE
  • Yutaka Saito
  • ,
  • Chie Sugimoto
  • ,
  • Toutai Mituyama
  • ,
  • Hiroshi Wakao

12
3
開始ページ
e0174699
終了ページ
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1371/journal.pone.0174699
出版者・発行元
PUBLIC LIBRARY SCIENCE

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.

リンク情報
DOI
https://doi.org/10.1371/journal.pone.0174699
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/28346544
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367832
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000399174300071&DestApp=WOS_CPL
URL
http://europepmc.org/abstract/med/28346544
URL
http://orcid.org/0000-0002-1110-6375
ID情報
  • DOI : 10.1371/journal.pone.0174699
  • ISSN : 1932-6203
  • ORCIDのPut Code : 32153026
  • PubMed ID : 28346544
  • PubMed Central 記事ID : PMC5367832
  • Web of Science ID : WOS:000399174300071

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