title: GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells.
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.
authors.affiliation: Swiss Institute of Allergy and Asthma Research Davos (SIAF), Davos-Platz, Switzerland.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Mantel
authors.forename: Harmjan
authors.initials: H
authors.lastname: Kuipers
authors.forename: Onur
authors.initials: O
authors.lastname: Boyman
authors.forename: Claudio
authors.initials: C
authors.lastname: Rhyner
authors.forename: Nadia
authors.initials: N
authors.lastname: Ouaked
authors.forename: Beate
authors.initials: B
authors.lastname: Rückert
authors.forename: Christian
authors.initials: C
authors.lastname: Karagiannidis
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.forename: Rudolf W
authors.initials: RW
authors.lastname: Hendriks
authors.forename: Reto
authors.initials: R
authors.lastname: Crameri
authors.forename: Cezmi A
authors.initials: CA
authors.lastname: Akdis
authors.forename: Kurt
authors.initials: K
authors.lastname: Blaser
authors.forename: Carsten B
authors.initials: CB
authors.lastname: Schmidt-Weber
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D015847:Interleukin-4 / Q000096:biosynthesis / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D053773:Transforming Growth Factor beta1; D015847:Interleukin-4