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

Research output: Contribution to journalArticlepeer-review

85 Citations (Scopus)


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
Issue number5
Publication statusPublished - 2013 Sept 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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