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Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation

Author

Listed:
  • Jesse W. Williams

    (Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago)

  • Melissa Y. Tjota

    (Committee on Immunology, University of Chicago
    Medical Scientist Training Program, University of Chicago)

  • Bryan S. Clay

    (Committee on Immunology, University of Chicago)

  • Bryan Vander Lugt

    (Genentech Inc.)

  • Hozefa S. Bandukwala

    (Committee on Immunology, University of Chicago)

  • Cara L. Hrusch

    (Section of Pulmonary and Critical Care Medicine, University of Chicago)

  • Donna C. Decker

    (Section of Pulmonary and Critical Care Medicine, University of Chicago)

  • Kelly M. Blaine

    (Section of Pulmonary and Critical Care Medicine, University of Chicago)

  • Bethany R. Fixsen

    (Section of Pulmonary and Critical Care Medicine, University of Chicago)

  • Harinder Singh

    (Genentech Inc.)

  • Roger Sciammas

    (University of Chicago)

  • Anne I. Sperling

    (Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago
    Committee on Immunology, University of Chicago
    Section of Pulmonary and Critical Care Medicine, University of Chicago)

Abstract

Atopic asthma is an inflammatory pulmonary disease associated with Th2 adaptive immune responses triggered by innocuous antigens. While dendritic cells (DCs) are known to shape the adaptive immune response, the mechanisms by which DCs promote Th2 differentiation remain elusive. Herein we demonstrate that Th2-promoting stimuli induce DC expression of IRF4. Mice with conditional deletion of Irf4 in DCs show a dramatic defect in Th2-type lung inflammation, yet retain the ability to elicit pulmonary Th1 antiviral responses. Using loss- and gain-of-function analysis, we demonstrate that Th2 differentiation is dependent on IRF4 expression in DCs. Finally, IRF4 directly targets and activates the Il-10 and Il-33 genes in DCs. Reconstitution with exogenous IL-10 and IL-33 recovers the ability of Irf4-deficient DCs to promote Th2 differentiation. These findings reveal a regulatory module in DCs by which IRF4 modulates IL-10 and IL-33 cytokine production to specifically promote Th2 differentiation and inflammation.

Suggested Citation

  • Jesse W. Williams & Melissa Y. Tjota & Bryan S. Clay & Bryan Vander Lugt & Hozefa S. Bandukwala & Cara L. Hrusch & Donna C. Decker & Kelly M. Blaine & Bethany R. Fixsen & Harinder Singh & Roger Sciamm, 2013. "Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation," Nature Communications, Nature, vol. 4(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3990
    DOI: 10.1038/ncomms3990
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    Cited by:

    1. Hongkui Xiao & Isabel Ulmert & Luisa Bach & Johanna Huber & Hamsa Narasimhan & Ilia Kurochkin & Yinshui Chang & Signe Holst & Urs Mörbe & Lili Zhang & Andreas Schlitzer & Carlos-Filipe Pereira & Barba, 2024. "Genomic deletion of Bcl6 differentially affects conventional dendritic cell subsets and compromises Tfh/Tfr/Th17 cell responses," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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