Improvement of Foxp3 stability through CNS2 demethylation by TET enzyme induction and activation

Kazue Someya, Hiroko Nakatsukasa, Minako Ito, Taisuke Kondo, Kenn ichi Tateda, Takashi Akanuma, Ikuko Koya, Tsukasa Sanosaka, Jun Kohyama, Yu ichi Tsukada, Takeji Takamura-Enya, Akihiko Yoshimura

研究成果: Article査読

35 被引用数 (Scopus)

抄録

Since induced regulatory T cells (iTregs) can be produced in a large quantity in vitro, these cells are expected to be clinically useful to induce immunological tolerance in various immunological diseases. Foxp3 (Forkhead box P3) expression in iTregs is, however, unstable due to the lack of demethylation of the CpG island in the conserved non-coding sequence 2 (CNS2) of the Foxp3 locus. To facilitate the demethylation of CNS2, we over-expressed the catalytic domain (CD) of the ten-eleven translocation (TET) protein, which catalyzes the steps of the iterative demethylation of 5-methylcytosine. TET-CD over-expression in iTregs resulted in partial demethylation of CNS2 and stable Foxp3 expression. We also discovered that TET expression was enhanced under low oxygen (5%) culture conditions, which facilitated CNS2 DNA demethylation and stabilization of Foxp3 expression in a TET2- and TET3-dependent manner. In combination with vitamin C treatment, which has been reported to enhance TET catalytic activity, iTregs generated under low oxygen conditions retained more stable Foxp3 expression in vitro and in vivo and exhibited stronger suppression activity in a colitis model compared with untreated iTregs. Our data indicate that the induction and activation of TET enzymes in iTregs would be an effective method for Treg-mediated adoptive immunotherapy.

本文言語English
論文番号dxx049
ページ(範囲)365-375
ページ数11
ジャーナルInternational immunology
29
8
DOI
出版ステータスPublished - 2017 8 1

ASJC Scopus subject areas

  • 免疫アレルギー学
  • 免疫学

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