Regulatory T cells suppress CD4+ T cells through NFAT-dependent transcriptional mechanisms

Authors

  • Daniel S Shin,

    1. Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
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    • These authors contributed equally to this work
  • Ayana Jordan,

    1. Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
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    • These authors contributed equally to this work
  • Samik Basu,

    1. Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
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  • Rajan M Thomas,

    1. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania and Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA
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  • Sanmay Bandyopadhyay,

    1. Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
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  • Edwin F de Zoeten,

    1. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania and Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA
    Current affiliation:
    1. Digestive Health Institute, Children's Hospital, University of Colorado School of Medicine, Denver, CO, USA
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  • Andrew D Wells,

    1. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania and Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA
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  • Fernando Macian

    Corresponding author
    1. Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
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Abstract

Regulatory T cells (Tregs) control autoreactive T cells by inhibiting activation-induced proliferation and cytokine expression. The molecular mechanisms responsible for the inactivation of effector T cells by Tregs remain yet to be fully characterized. We report that T-helper cells stimulated in the presence of Tregs quickly activate NFAT1 and have increased NFAT1-dependent expression of the transcription repressor Ikaros. NFAT1 deficiency or dominant-negative Ikaros compromises Treg-mediated inhibition of T-helper cells in vitro and in vivo. Thus, our results place NFAT-dependent mechanisms as general regulators of T-cell tolerance and show that Treg-mediated suppression of T-helper cells results from the activation of NFAT-regulated gene expression.

Synopsis

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This study shows that regulatory T cells activate NFAT1-dependent gene expression in stimulated T-helper cells, including the transcription of Ikaros, which is required for optimal T-helper cell suppression in vitro and in vivo.

  • Activation of T-helper cells in the presence of tTregs induces the NFAT1-dependent expression if Ikaros, likely as a result of the downmodulation of costimulatory ligands in antigen-presenting cells.
  • NFAT1-deficient CD4+ T cells or T cells expressing a dominant-negative form of Ikaros are resistant to tTreg-mediated suppression.

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