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Control of the differentiation of regulatory T cells and TH17 cells by the DNA-binding inhibitor Id3

Nature Immunology volume 12, pages 86–95 (2011)Cite this article

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Abstract

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 (Treg 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 TH17 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 TH17 cells.

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Figure 1: Id3 regulates the generation of Foxp3+ Treg cells.
Figure 2: Id3−/− T cells fails to generate Foxp3+ Treg cells in response to TGF-β1.
Figure 3: Enrichment of E2A at the Foxp3 promoter.
Figure 4: Binding of E2A to the Foxp3 promoter is required for activation of Foxp3 by TGF-β1.
Figure 5: Id3 deficiency increases GATA-3.
Figure 6: Id3−/− CD4+ T cells differentiate into TH17 cells in response to TGF-β1 in vitro.
Figure 7: Id3 regulates TH17 cells in HDM-induced asthma.

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Acknowledgements

We thank Y.H. Chen, Q. Ruan and M. Tone (University of Pennsylvania) for Foxp3 constructs and EL4 LAF cells. Supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research (US National Institutes of Health).

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Author notes

  1. Takashi Maruyama and Jun Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Mucosal Immunology Unit, Oral Infection and Immunity Branch, National Institutes of Health, Bethesda, Maryland, USA

    Takashi Maruyama, Jun Li, Joanne E Konkel, Pin Zhang, Brian F Zamarron & WanJun Chen

  2. Oral Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA

    Jose P Vaque & J Silvio Gutkind

  3. Department of Microbiology and Molecular Biology, George Mason University, Manassas, Virginia, USA

    Weifeng Wang, Dongyang Yu & Yuntao Wu

  4. Department of Immunology, Duke University, Durham, North Carolina, USA

    Baojun Zhang & Yuan Zhuang

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  1. Takashi Maruyama
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Contributions

T.M. and J.L. designed and did experiments, analyzed data and contributed to the writing of the manuscript; J.P.V. designed and did ChIP experiments, analyzed data and contributed to the writing of the manuscript; J.E.K. did experiments, analyzed data and contributed to the writing of the manuscript; Y.W. designed and W.W. and D.Y. did the luciferase, E2A-knockdown and Id3 immunoblot experiments and analyzed data; B.Z. and Y.Z. generated and identified mice doubly deficient in E2A and HEB and provided critical input; P.Z. and B.F.Z. did experiments; J.S.G. supervised and designed the ChIP study and contributed to the writing of the manuscript; and W.C. conceived of the research, directed the study, designed experiments, analyzed data and wrote the manuscript.

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Correspondence to WanJun Chen.

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Maruyama, T., Li, J., Vaque, J. et al. Control of the differentiation of regulatory T cells and TH17 cells by the DNA-binding inhibitor Id3. Nat Immunol 12, 86–95 (2011). https://doi.org/10.1038/ni.1965

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