STAT6 Inhibits TGF-beta1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor.
It has been shown that transforming growth factor beta1 (TGF-beta1) is critical in the generation of CD4(+)CD25(+)Foxp3(+)-inducible regulatory T cells (iTregs) from naïve CD4(+)T cells. However, in contrast to natural Tregs, TGF-beta1-induced iTregs rapidly lose both Foxp3 expression and suppression activity. We found that TGF-beta1-induced Foxp3 levels were maintained by the addition of the anti-interleukin 4 (IL-4) antibody or by STAT6 gene deletion. Thus, IL-4 is an important suppressor of Foxp3 induction, and T helper 2 development is a major cause for the disappearance of iTreg during long culture. Using promoter analysis in EL4 cells and primary T cells, we identified a silencer region containing a STAT6 binding site. STAT6 binding to this site reduced TGF-beta1-mediated Foxp3 promoter activation and chromatin modification. Retinoic acid has also been shown to suppress loss of Foxp3 induced by TGF-beta1. Retinoic acid in the presence of TGF-beta1 reduced STAT6 binding to the Foxp3 promoter and enhanced histone acetylation, thereby reverting the effect of IL-4. We propose that antagonistic agents for neutralizing IL-4 could be a novel strategy to facilitate inducible Treg cell generation and the promotion of tolerance in Th2-dominated diseases such as allergy.
Takaki
Hiromi
H
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582.
Ichiyama
Kenji
K
Koga
Keiko
K
Chinen
Takatoshi
T
Takaesu
Giichi
G
Sugiyama
Yuki
Y
Kato
Shigeaki
S
Yoshimura
Akihiko
A
Kobayashi
Takashi
T
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006967:Hypersensitivity / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007108:Immune Tolerance / Q000235:genetics; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000276:immunology; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000494:pharmacology*
D000906:Antibodies; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018168:Receptors, Retinoic Acid; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D053773:Transforming Growth Factor beta1; D015847:Interleukin-4