Smad2/3 and IRF4 play a cooperative role in IL-9-producing T cell induction

Taiga Tamiya, Kenji Ichiyama, Hitoshi Kotani, Tomohiro Fukaya, Takashi Sekiya, Takashi Shichita, Kiri Honma, Katsuyuki Yui, Toshifumi Matsuyama, Takako Nakao, Satoru Fukuyama, Hiromasa Inoue, Masatoshi Nomura, Akihiko Yoshimura

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Abstract

IL-9 is a pleiotropic cytokine that can regulate autoimmune and allergic responses. Th9 cells can develop from naive T cells or Th2 cells through stimulation by TGF-β in vitro. In this study, we demonstrated that Smad2 and Smad3 are necessary for IL-9 production from T cells in an OVA-induced asthma model using T cell-specific Smad2- and Smad3-deficient mice. Smad2 and Smad3 were also redundantly essential for TGF-β signaling to induce histone modifications for Il9 transcription. Although Smad2/3 was recruited to the Il9 promoter by TGF-β stimulation, they are not sufficient to activate the Il9 promoter. By the screening the transcription factors, we found that IFN regulatory factor 4 (IRF4) was essential for the Smad2/3-mediated Il9 promoter activation. In addition, Smad2/3 physically interacted with IRF4, and Smad2/3 did not bind to the Il9 promoter and could not induce Th9 in IRF4-deficient T cells. Similarly, IRF4 could not stimulate Il9 transcription in the absence of Smad2/3, and TGF-β enhanced IRF4 recruitment to the Il9 promoter in a Smad2/3-dependent manner. We propose that Smad2/3 and IRF4 cooperatively transactivate the Il9 promoter and play an important role in regulating allergic immune responses by inducing Th9 cells.

Original languageEnglish
Pages (from-to)2360-2371
Number of pages12
JournalJournal of Immunology
Volume191
Issue number5
DOIs
Publication statusPublished - 2013 Sep 1

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Interferon Regulatory Factor-3
Interleukin-9
T-Lymphocytes
Transcription Factor 7-Like 2 Protein
Histone Code
Th2 Cells
Autoimmunity
Transcription Factors
Asthma
Cytokines

ASJC Scopus subject areas

  • Immunology

Cite this

Tamiya, T., Ichiyama, K., Kotani, H., Fukaya, T., Sekiya, T., Shichita, T., ... Yoshimura, A. (2013). Smad2/3 and IRF4 play a cooperative role in IL-9-producing T cell induction. Journal of Immunology, 191(5), 2360-2371. https://doi.org/10.4049/jimmunol.1301276

Smad2/3 and IRF4 play a cooperative role in IL-9-producing T cell induction. / Tamiya, Taiga; Ichiyama, Kenji; Kotani, Hitoshi; Fukaya, Tomohiro; Sekiya, Takashi; Shichita, Takashi; Honma, Kiri; Yui, Katsuyuki; Matsuyama, Toshifumi; Nakao, Takako; Fukuyama, Satoru; Inoue, Hiromasa; Nomura, Masatoshi; Yoshimura, Akihiko.

In: Journal of Immunology, Vol. 191, No. 5, 01.09.2013, p. 2360-2371.

Research output: Contribution to journalArticle

Tamiya, T, Ichiyama, K, Kotani, H, Fukaya, T, Sekiya, T, Shichita, T, Honma, K, Yui, K, Matsuyama, T, Nakao, T, Fukuyama, S, Inoue, H, Nomura, M & Yoshimura, A 2013, 'Smad2/3 and IRF4 play a cooperative role in IL-9-producing T cell induction', Journal of Immunology, vol. 191, no. 5, pp. 2360-2371. https://doi.org/10.4049/jimmunol.1301276
Tamiya T, Ichiyama K, Kotani H, Fukaya T, Sekiya T, Shichita T et al. Smad2/3 and IRF4 play a cooperative role in IL-9-producing T cell induction. Journal of Immunology. 2013 Sep 1;191(5):2360-2371. https://doi.org/10.4049/jimmunol.1301276
Tamiya, Taiga ; Ichiyama, Kenji ; Kotani, Hitoshi ; Fukaya, Tomohiro ; Sekiya, Takashi ; Shichita, Takashi ; Honma, Kiri ; Yui, Katsuyuki ; Matsuyama, Toshifumi ; Nakao, Takako ; Fukuyama, Satoru ; Inoue, Hiromasa ; Nomura, Masatoshi ; Yoshimura, Akihiko. / Smad2/3 and IRF4 play a cooperative role in IL-9-producing T cell induction. In: Journal of Immunology. 2013 ; Vol. 191, No. 5. pp. 2360-2371.
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