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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Interleukin-17
Regulatory T-Lymphocytes
Cytokines
Antigen-Presenting Cells
Colitis
Homeostasis
T-Lymphocytes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production. / Takahashi, Reiko; Nishimoto, Shuhei; Muto, Go; Sekiya, Takashi; Tamiya, Taiga; Kimura, Akihiro; Morita, Rimpei; Asakawa, Mayako; Chinen, Takatoshi; Yoshimura, Akihiko.

In: Journal of Experimental Medicine, Vol. 208, No. 10, 26.09.2011, p. 2055-2067.

Research output: Contribution to journalArticle

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, vol. 208, no. 10, pp. 2055-2067. https://doi.org/10.1084/jem.20110428
Takahashi, Reiko ; Nishimoto, Shuhei ; Muto, Go ; Sekiya, Takashi ; Tamiya, Taiga ; Kimura, Akihiro ; Morita, Rimpei ; Asakawa, Mayako ; Chinen, Takatoshi ; Yoshimura, Akihiko. / SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production. In: Journal of Experimental Medicine. 2011 ; Vol. 208, No. 10. pp. 2055-2067.
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