GATA3-Driven Th2 Responses Inhibit TGF-ß1–Induced FOXP3 Expression and the Formation of Regulatory T Cells
Pierre-Yves Mantel1, Harmjan Kuipers2, Onur Boyman3, Claudio Rhyner1, Nadia Ouaked1, Beate Rückert1, Christian Karagiannidis1, Bart N. Lambrecht2, Rudolf W. Hendriks2,4, Reto Crameri1, Cezmi A. Akdis1, Kurt Blaser1, Carsten B. Schmidt-Weber1,5*
1 Swiss Institute of Allergy and Asthma Research Davos (SIAF), Davos-Platz, Switzerland, 2 Department of Pulmonary Medicine, Erasmus Medical College, Rotterdam, The Netherlands, 3 Division of Immunology and Allergy, University Hospital of Lausanne (CHUV), Lausanne, Switzerland, 4 Department of Immunology, Erasmus Medical College, Rotterdam, The Netherlands, 5 Department of Allergy and Clinical Immunology, Imperial College London, London, United Kingdom
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)-ß–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.
Funding. This work was supported by the Swiss National Science Foundation Grant Numbers 31–65436, 3100A0–100164, and 310000–112329, the Ehmann Foundation Chur, the Saurer Foundation Zurich, and the Swiss Life Zurich.
Competing interests. The authors have declared that no competing interests exist.
Academic Editor: Philippa Marrack, National Jewish Medical and Research Center, United States of America
Citation: Mantel PY, Kuipers H, Boyman O, Rhyner C, Ouaked N, et al. (2007) GATA3-Driven Th2 Responses Inhibit TGF-ß1–Induced FOXP3 Expression and the Formation of Regulatory T Cells. PLoS Biol 5(12): e329 doi:10.1371/journal.pbio.0050329
Received: March 16, 2007; Accepted: November 6, 2007; Published: December 27, 2007
Copyright: © 2007 Mantel et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
