Control of the differentiation of regulatory T cells and T(H)17 cells by the DNA-binding inhibitor Id3.
The molecular mechanisms that direct transcription of the gene encoding the transcription factor Foxp3 in CD4(+) T cells remain ill-defined. We show here that deletion of the DNA-binding inhibitor Id3 resulted in the defective generation of Foxp3(+) regulatory T cells (T(reg) cells). We identify two transforming growth factor-β1 (TGF-β1)-dependent mechanisms that were vital for activation of Foxp3 transcription and were defective in Id3(-/-) CD4(+) T cells. Enhanced binding of the transcription factor E2A to the Foxp3 promoter promoted Foxp3 transcription. Id3 was required for relief of inhibition by the transcription factor GATA-3 at the Foxp3 promoter. Furthermore, Id3(-/-) T cells showed greater differentiation into the T(H)17 subset of helper T cells in vitro and in a mouse asthma model. Therefore, a network of factors acts in a TGF-β-dependent manner to control Foxp3 expression and inhibit the development of T(H)17 cells.
Mucosal Immunology Unit, Oral Infection and Immunity Branch, National Institutes of Health, Bethesda, Maryland, USA.
Takashi
T
Maruyama
Jun
J
Li
Jose P
JP
Vaque
Joanne E
JE
Konkel
Weifeng
W
Wang
Baojun
B
Zhang
Pin
P
Zhang
Brian F
BF
Zamarron
Dongyang
D
Yu
Yuntao
Y
Wu
Yuan
Y
Zhuang
J Silvio
JS
Gutkind
WanJun
W
Chen
D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015533:Transcriptional Activation / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D051858:Forkhead Transcription Factors; D051796:Inhibitor of Differentiation Proteins; D053773:Transforming Growth Factor beta1; C498833:Foxp3 protein, mouse; C075668:Tcf3 protein, mouse; C067679:Idb3 protein, mouse