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The transcription factor musculin promotes the unidirectional development of peripheral Treg cells by suppressing the TH2 transcriptional program

Nature Immunology volume 18, pages 344353 (2017) | Download Citation

Abstract

Although master transcription factors (TFs) are key to the development of specific T cell subsets, whether additional transcriptional regulators are induced by the same stimuli that dominantly repress the development of other, non-specific T cell lineages has not been fully elucidated. Through the use of regulatory T cells (Treg cells) induced by transforming growth factor-β (TGF-β), we identified the TF musculin (MSC) as being critical for the development of induced Treg cells (iTreg cells) by repression of the T helper type 2 (TH2) transcriptional program. Loss of MSC reduced expression of the Treg cell master TF Foxp3 and induced TH2 differentiation even under iTreg-cell-differentiation conditions. MSC interrupted binding of the TF GATA-3 to the locus encoding TH2-cell-related cytokines and diminished intrachromosomal interactions within that locus. MSC-deficient (Msc−/−) iTreg cells were unable to suppress TH2 responses, and Msc−/− mice spontaneously developed gut and lung inflammation with age. MSC therefore enforced Foxp3 expression and promoted the unidirectional induction of iTreg cells by repressing the TH2 developmental program.

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Acknowledgements

We thank D. Kozoriz for cell sorting; T. Chatila for advice; M. Collins for advice and editing the manuscript; E.N. Olson (University of Texas Southwestern Medical Center at Dallas) for Msc−/− mice; L. Maggio-Price (University of Washington) for Smad3−/− mice; and A. Yoshimura (Keio University School of Medicine) for the plasmid pCMV5-Smad3. Supported by the National Multiple Sclerosis Society (Career Transition Award TA 3059-A-2 to C.W.) and the US National Institutes of Health (K99 NIH Pathway to Independence Award KAI110649A to C.W.; K01DK090105 to S.X.; and P01AI073748, P01AI056299, P01AI039671, R01NS045937 and R01 NS030843 to V.K.).

Author information

Author notes

    • Chuan Wu
    • , Valerie Dardalhon
    •  & Rafael F Franca

    Present addresses: Experimental Immunology Branch, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA (C.W.), GMM-UMR5535-CNRS, Montpellier, France (V.D.), and Department of Pharmacology, University of São Paulo, São Paulo, Ribeirao Preto, Brazil (R.F.F.).

    • Chuan Wu
    •  & Zuojia Chen

    These authors contributed equally to this work.

Affiliations

  1. Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Chuan Wu
    • , Zuojia Chen
    • , Valerie Dardalhon
    • , Sheng Xiao
    • , Theresa Thalhamer
    • , Asaf Madi
    • , Rafael F Franca
    • , Timothy Han
    •  & Vijay Kuchroo
  2. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Mengyang Liao
  3. Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA.

    • Mohammed Oukka

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Contributions

C.W. designed and performed experiments and wrote the manuscript; Z.C. performed experiments and wrote the manuscript; V.D., S.X., T.T., M.L., A.M., R.F.F., T.H. and M.O. performed experiments; A.M. analyzed the data; and V.K. supervised the study and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Chuan Wu or Vijay Kuchroo.

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https://doi.org/10.1038/ni.3667

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