GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells.
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.
Mantel
Pierre-Yves
PY
Swiss Institute of Allergy and Asthma Research Davos (SIAF), Davos-Platz, Switzerland.
Kuipers
Harmjan
H
Boyman
Onur
O
Rhyner
Claudio
C
Ouaked
Nadia
N
Rückert
Beate
B
Karagiannidis
Christian
C
Lambrecht
Bart N
BN
Hendriks
Rudolf W
RW
Crameri
Reto
R
Akdis
Cezmi A
CA
Blaser
Kurt
K
Schmidt-Weber
Carsten B
CB
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*
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