SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production

Reiko Takahashi, Shuhei Nishimoto, Go Muto, Takashi Sekiya, Taiga Tamiya, Akihiro Kimura, Rimpei Morita, Mayako Asakawa, Takatoshi Chinen, Akihiko Yoshimura

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Abstract

Regulatory T cells (Treg cells) maintain immune homeostasis by limiting inflammatory responses. SOCS1 (suppressor of cytokine signaling 1), a negative regulator of cytokine signaling, is necessary for the suppressor functions of Treg cells in vivo, yet detailed mechanisms remain to be clarified. We found that Socs1-/- Treg cells produced high levels of IFN-γ and rapidly lost Foxp3 when transferred into Rag2-/- mice or cultured in vitro, even though the CNS2 (conserved noncoding DNA sequence 2) in the Foxp3 enhancer region was fully demethylated. Socs1-/- Treg cells showed hyperactivation of STAT1 and STAT3. Because Foxp3 expression was stable and STAT1 activation was at normal levels in Ifnγ-/-Socs1-/- Treg cells, the restriction of IFN-γ-STAT1 signaling by SOCS1 is suggested to be necessary for stable Foxp3 expression. However, Ifnγ-/-Socs1-/- Treg cells had hyperactivated STAT3 and higher IL-17A (IL-17) production compared with Ifnγ-/-Socs1+/+ Treg cells and could not suppress colitis induced by naive T cells in Rag2-/- mice. In vitro experiments suggested that cytokines produced by Socs1-/- Treg cells and Ifnγ-/-Socs1-/- Treg cells modulated antigen-presenting cells for preferential Th1 and Th17 induction, respectively. We propose that SOCS1 plays important roles in Treg cell integrity and function by maintaining Foxp3 expression and by suppressing IFN-γ and IL-17 production driven by STAT1 and STAT3, respectively.

Original languageEnglish
Pages (from-to)2055-2067
Number of pages13
JournalJournal of Experimental Medicine
Volume208
Issue number10
DOIs
Publication statusPublished - 2011 Sep 26

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Takahashi, R., Nishimoto, S., Muto, G., Sekiya, T., Tamiya, T., Kimura, A., Morita, R., Asakawa, M., Chinen, T., & Yoshimura, A. (2011). SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production. Journal of Experimental Medicine, 208(10), 2055-2067. https://doi.org/10.1084/jem.20110428