The epigenetic regulator Uhrf1 facilitates the proliferation and maturation of colonic regulatory T cells

Yuuki Obata, Yukihiro Furusawa, Takaho A. Endo, Jafar Sharif, Daisuke Takahashi, Koji Atarashi, Manabu Nakayama, Satoshi Onawa, Yumiko Fujimura, Masumi Takahashi, Tomokatsu Ikawa, Takeshi Otsubo, Yuki I. Kawamura, Taeko Dohi, Shoji Tajima, Hiroshi Masumoto, Osamu Ohara, Kenya Honda, Shohei Hori, Hiroshi OhnoHaruhiko Koseki, Kouji Hase

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Abstract

Intestinal regulatory T cells (T reg cells) are necessary for the suppression of excessive immune responses to commensal bacteria. However, the molecular machinery that controls the homeostasis of intestinal T reg cells has remained largely unknown. Here we report that colonization of germ-free mice with gut microbiota upregulated expression of the DNA-methylation adaptor Uhrf1 in T reg cells. Mice with T cell-specific deficiency in Uhrf1 (Uhrf1 fl/fl Cd4-Cre mice) showed defective proliferation and functional maturation of colonic T reg cells. Uhrf1 deficiency resulted in derepression of the gene (Cdkn1a) that encodes the cyclin-dependent kinase inhibitor p21 due to hypomethylation of its promoter region, which resulted in cell-cycle arrest of T reg cells. As a consequence, Uhrf1 fl/fl Cd4-Cre mice spontaneously developed severe colitis. Thus, Uhrf1-dependent epigenetic silencing of Cdkn1a was required for the maintenance of gut immunological homeostasis. This mechanism enforces symbiotic host-microbe interactions without an inflammatory response.

Original languageEnglish
Pages (from-to)571-579
Number of pages9
JournalNature Immunology
Volume15
Issue number6
DOIs
Publication statusPublished - 2014

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ASJC Scopus subject areas

  • Immunology

Cite this

Obata, Y., Furusawa, Y., Endo, T. A., Sharif, J., Takahashi, D., Atarashi, K., Nakayama, M., Onawa, S., Fujimura, Y., Takahashi, M., Ikawa, T., Otsubo, T., Kawamura, Y. I., Dohi, T., Tajima, S., Masumoto, H., Ohara, O., Honda, K., Hori, S., ... Hase, K. (2014). The epigenetic regulator Uhrf1 facilitates the proliferation and maturation of colonic regulatory T cells. Nature Immunology, 15(6), 571-579. https://doi.org/10.1038/ni.2886