GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells.

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Serval ID
serval:BIB_54B716DCFEBC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells.
Journal
PLoS Biology
Author(s)
Mantel P.Y., Kuipers H., Boyman O., Rhyner C., Ouaked N., Rückert B., Karagiannidis C., Lambrecht B.N., Hendriks R.W., Crameri R., Akdis C.A., Blaser K., Schmidt-Weber C.B.
ISSN
1545-7885[electronic]
Publication state
Published
Issued date
2007
Volume
5
Number
12
Pages
e329
Language
english
Abstract
Transcription factors act in concert to induce lineage commitment towards Th1, Th2, or T regulatory (Treg) cells, and their counter-regulatory mechanisms were shown to be critical for polarization between Th1 and Th2 phenotypes. FOXP3 is an essential transcription factor for natural, thymus-derived (nTreg) and inducible Treg (iTreg) commitment; however, the mechanisms regulating its expression are as yet unknown. We describe a mechanism controlling iTreg polarization, which is overruled by the Th2 differentiation pathway. We demonstrated that interleukin 4 (IL-4) present at the time of T cell priming inhibits FOXP3. This inhibitory mechanism was also confirmed in Th2 cells and in T cells of transgenic mice overexpressing GATA-3 in T cells, which are shown to be deficient in transforming growth factor (TGF)-beta-mediated FOXP3 induction. This inhibition is mediated by direct binding of GATA3 to the FOXP3 promoter, which represses its transactivation process. Therefore, this study provides a new understanding of tolerance development, controlled by a type 2 immune response. IL-4 treatment in mice reduces iTreg cell frequency, highlighting that therapeutic approaches that target IL-4 or GATA3 might provide new preventive strategies facilitating tolerance induction particularly in Th2-mediated diseases, such as allergy.
Keywords
Animals, Cell Differentiation, Cells, Cultured, Forkhead Transcription Factors, GATA3 Transcription Factor, Gene Expression Regulation, Humans, Interleukin-4, Kinetics, Mice, Promoter Regions, Genetic, T-Lymphocytes, Regulatory, Th2 Cells, Transforming Growth Factor beta1
Pubmed
Web of science
Open Access
Yes
Create date
31/03/2009 11:02
Last modification date
20/08/2019 14:09
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