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

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25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numberdxx049
Pages (from-to)365-375
Number of pages11
JournalInternational immunology
Volume29
Issue number8
DOIs
Publication statusPublished - Aug 1 2017

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Someya, K., Nakatsukasa, H., Ito, M., Kondo, T., Tateda, K. I., Akanuma, T., Koya, I., Sanosaka, T., Kohyama, J., Tsukada, Y. I., Takamura-Enya, T., & Yoshimura, A. (2017). Improvement of Foxp3 stability through CNS2 demethylation by TET enzyme induction and activation. International immunology, 29(8), 365-375. [dxx049]. https://doi.org/10.1093/intimm/dxx049