GATA3-driven Th2 responses inhibit TGF-β1-induced FOXP3 expression and the formation of regulatory T cells

Pierre Yves Mantel, Harmjan Kuipers, Onur Boyman, Claudio Rhyner, Nadia Ouaked, Beate Rückert, Christian Karagiannidis, Bart N. Lambrecht, Rudolf W. Hendriks, Reto Crameri, Cezmi A. Akdis, Kurt Blaser, Carsten B. Schmidt-Weber

Research output: Contribution to journalArticlepeer-review

238 Scopus citations

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 (iT reg) 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)-β-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.

Original languageEnglish
Pages (from-to)2847-2861
Number of pages15
JournalPLoS Biology
Volume5
Issue number12
DOIs
StatePublished - Dec 2007
Externally publishedYes

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