Smad2 and Smad3 are redundantly essential for the TGF-β-mediated regulation of regulatory T plasticity and Th1 development

Tomohito Takimoto, Yu Wakabayashi, Takashi Sekiya, Naoko Inoue, Rimpei Morita, Kenji Ichiyama, Reiko Takahashi, Mayako Asakawa, Go Muto, Tomoaki Mori, Eiichi Hasegawa, Saika Shizuya, Toshiro Hara, Masatoshi Nomura, Akihiko Yoshimura

Research output: Contribution to journalArticlepeer-review

198 Citations (Scopus)

Abstract

Although it has been well established that TGF-β plays a pivotal role in immune regulation, the roles of its downstream transcription factors, Smad2 and Smad3, have not been fully clarified. Specifically, the function of Smad2 in the immune system has not been investigated because of the embryonic lethality of Smad2-deficient mice. In this study, we generated T cell-specific Smad2 conditional knockout (KO) mice and unexpectedly found that Smad2 and Smad3 were redundantly essential for TGF-β-mediated induction of Foxp3-expressing regulatory T cells and suppression of IFN-γ production in CD4+ T cells. Consistent with these observations, Smad2/Smad3-double KO mice, but not single KO mice, developed fatal inflammatory diseases with higher IFN-γ production and reduced Foxp3 expression in CD4+ T cells at the periphery. Although it has been suggested that Foxp3 induction might underlie TGF-β-mediated immunosuppression, TGF-β still can suppress Th1 cell development in Foxp3-deficient T cells, suggesting that the Smad2/3 pathway inhibits Th1 cell development with Foxp3-independent mechanisms. We also found that Th17 cell development was reduced in Smad-deficient CD4+ T cells because of higher production of Th17-inhibotory cytokines from these T cells. However, TGF-β-mediated induction of RORγt, a master regulator of Th17 cell, was independent of both Smad2 and Smad3, suggesting that TGF-β regulates Th17 development through Smad2/3-dependent and -independent mechanisms.

Original languageEnglish
Pages (from-to)842-855
Number of pages14
JournalJournal of Immunology
Volume185
Issue number2
DOIs
Publication statusPublished - 2010 Jul 15

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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