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T cell factor 1 initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-γ

Nature Immunology volume 10, pages 992–999 (2009)Cite this article

Abstract

The differentiation of activated CD4+ T cells into the T helper type 1 (TH1) or TH2 fate is regulated by cytokines and the transcription factors T-bet and GATA-3. Whereas interleukin 12 (IL-12) produced by antigen-presenting cells initiates the TH1 fate, signals that initiate the TH2 fate are not completely characterized. Here we show that early GATA-3 expression, required for TH2 differentiation, was induced by T cell factor 1 (TCF-1) and its cofactor β-catenin, mainly from the proximal Gata3 promoter upstream of exon 1b. This activity was induced after T cell antigen receptor (TCR) stimulation and was independent of IL-4 receptor signaling through the transcription factor STAT6. Furthermore, TCF-1 blocked TH1 fate by negatively regulating interferon-γ (IFN-γ) expression independently of β-catenin. Thus, TCF-1 initiates TH2 differentiation of activated CD4+ T cells by promoting GATA-3 expression and suppressing IFN-γ expression.

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Figure 1: Initial GATA-3 expression in TCR-activated CD4+ T cells is from Gata3-1b transcripts.
Figure 2: TCF-1 and β-catenin act together to regulate the production of GATA-3 from Gata3-1b transcripts.
Figure 3: TCF-1 and β-catenin bind TCF-1 sites upstream of Gata3 exon 1b.
Figure 4: TCF-1 and β-catenin act together to promote IL-4 production and TH2 differentiation.
Figure 5: TCF-1- and β-catenin-induced IL-4 production by CD4+ T cells is Notch independent.
Figure 6: TCF-1 negatively regulates IFN-γ production independently of β-catenin.
Figure 7: TCF-1 regulates TH2 responses in vivo.

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Acknowledgements

We thank R. Wersto and team for cell sorting; the animal facility of the National Institute on Aging for maintaining animals; S. Luo and team for genotyping; H. Clevers (Hubrecht Institute) for TCF-1-deficient mice; W. Pear (University of Pennsylvania) for the dnMAML retroviral construct; and N. Taylor, A. Singer, R. Bosselut, R. Sen and A. Bhandoola for critically reading the manuscript. Supported by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health and the Oak Ridge Institute for Science and Education's Research Associates Program of the National Institutes of Health.

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Authors and Affiliations

  1. Lymphocyte Development Unit, Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA

    Qing Yu, Archna Sharma, M Zulfiquer Hossain, Theresa M Salay, Karen E Leeds, Hansen Du & Jyoti Misra Sen

  2. Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Sun Young Oh, Hyung-Geun Moon & Zhou Zhu

  3. Microbiology and Molecular Genetics, University of California at Irvine, Irvine, California, USA

    Beibei Wu & Marian L Waterman

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Contributions

Q.Y. and J.M.S. designed and orchestrated the study and wrote the manuscript; Q.Y., A.S., M.Z.H., T.M.S. and K.E.L. did all the in vivo and in vitro experiments; S.Y.O., H.-G.M. and Z.Z. contributed to the analysis of OVA-injected mice in vivo; H.D. did electrophoretic mobility-shift assays; and B.W. and M.L.W. provided reagents and advice.

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Correspondence to Jyoti Misra Sen.

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Yu, Q., Sharma, A., Oh, S. et al. T cell factor 1 initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-γ. Nat Immunol 10, 992–999 (2009). https://doi.org/10.1038/ni.1762

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