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Interactions among the transcription factors Runx1, RORγt and Foxp3 regulate the differentiation of interleukin 17–producing T cells

Nature Immunology volume 9, pages 1297–1306 (2008)Cite this article

A Corrigendum to this article was published on 01 February 2009

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Abstract

The molecular mechanisms underlying the differentiation of interleukin 17–producing T helper cells (TH-17 cells) are still poorly understood. Here we show that optimal transcription of the gene encoding interleukin 17 (Il17) required a 2-kilobase promoter and at least one conserved noncoding (enhancer) sequence, CNS-5. Both cis-regulatory elements contained regions that bound the transcription factors RORγt and Runx1. Runx1 influenced TH-17 differentiation by inducing RORγt expression and by binding to and acting together with RORγt during Il17 transcription. However, Runx1 also interacts with the transcription factor Foxp3, and this interaction was necessary for the negative effect of Foxp3 on TH-17 differentiation. Thus, our data support a model in which the differential association of Runx1 with Foxp3 and with RORγt regulates TH-17 differentiation.

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Figure 1: Mouse Il17 promoter activity.
Figure 2: CNS-5 is a RORγt-dependent enhancer element for Il17 transcription.
Figure 3: Runx1 upregulates Il17 transcription.
Figure 4: Runx1 is required for IL-17 expression in CD4+ T cells.
Figure 5: Runx1 acts together with RORγt to induce IL-17 production.
Figure 6: RORγt and Runx1 bind to the Il17 promoter and enhancer.
Figure 7: Runx1 promotes RORγt expression.
Figure 8: Interaction of Runx1, RORγt and Foxp3 regulates TH-17 cell differentiation.
Figure 9: RORγt binds to both Runx1 and Foxp3.

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Change history

  • 14 November 2008

    NOTE: In the version of this article initially published, two panels in Figure 9a were horizontally inverted. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank S. Goenka for reading the manuscript and for technical suggestions for the reporter assay; M. Ono (Kyoto University) for Runx1 and Foxp3 expression plasmids; Y. He (Duke University) for the MSCV-hCD2-RORγt plasmid; G.J. Kersh (Emory University) for the Myc-RORγt-GFP plasmid; G.P. Nolan (Stanford University) for Phoenix cells; D.R. Littman (New York University) for monoclonal anti-RORγt; Y. Huang and Z.Y. Hu for technical support in real time PCR experiments; and X.Y. Yan for help with making reporter constructs.

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  1. Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Fuping Zhang, Guangxun Meng & Warren Strober

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  1. Fuping Zhang
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  2. Guangxun Meng
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Contributions

F.Z. and W.S. designed experiments; F.Z. did all of the experiments and wrote the manuscript; G.M. contributed Supplementary Fig. 3 and was involved in coimmunoprecipitation experiments; and W.S. directed the project and helped to write the manuscript.

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Correspondence to Warren Strober.

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Supplementary Figures 1–8 and Supplementary Table 1 (PDF 615 kb)

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Zhang, F., Meng, G. & Strober, W. Interactions among the transcription factors Runx1, RORγt and Foxp3 regulate the differentiation of interleukin 17–producing T cells. Nat Immunol 9, 1297–1306 (2008). https://doi.org/10.1038/ni.1663

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