Abstract
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.
Highlights
CD4ϩCD25ϩFoxp3ϩ regulatory T cells (Tregs)3 are crucial for the maintenance of immunological tolerance [1, 2]
Naive CD4ϩCD25Ϫ T cells were isolated from mouse spleen and activated by plate-bound anti-TCR antibody, anti-IFN-␥ antibody in the presence of IL-2 (Th0 condition), TGF- ϩ IL2, or TGF- ϩ IL-2 ϩ IL-4 ϩ IL-10 (Th3 condition)
IL-4 and IL-10 were included in Th3 conditions, but not in iTreg conditions, we examined which one was responsible for the suppression of Foxp3 induction
Summary
CD4ϩCD25ϩFoxp3ϩ regulatory T cells (Tregs)3 are crucial for the maintenance of immunological tolerance [1, 2]. We identified the TGF-1-responsive enhancer region and found a particular silencer region of the Foxp3 promoter containing a STAT6 binding site. IL-4/STAT6 Suppresses TGF-1-mediated iTreg Induction in Vitro—Upon stimulation with anti-CD3 antibody and TGF-1, Foxp3 expression was induced in primary CD4ϩCD25Ϫ T cells.
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