GATA3-Driven Th2 Responses Inhibit TGF-β1–Induced FOXP3 Expression and the Formation of Regulatory T Cells

• DOI: 10.1371/journal.pbio.0050329
• Publication Date: 2007-12-20T14:40:34Z
• Authors: Pierre-Yves Mantel; Harmjan Kuipers; Onur Boyman; Claudio Rhyner; Nadia Ouaked; Beate Rückert; Christian Karagia...; Bart N Lambrecht; Rudolf W Hendriks; Reto Crameri; Cezmi A Akdis; Kurt Blaser; Carsten B Schmidt...
• Keywords: QH301-705.5; Cell Differentiation; Forkhead Transcription Factors; GATA3 Transcription Factor; EMC MM-04-42-02; T-Lymphocytes, Regulatory; EMC MM-02-72-01; 3. Good health; Transforming Growth Factor beta1; Kinetics; Mice; 03 medical and health sciences; Th2 Cells; 0302 clinical medicine; Gene Expression Regulation; Animals; Humans; Interleukin-4; Biology (General); Promoter Regions, Genetic; 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; Cells, Cultured; Research Article

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.