Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix-loop-helix factor E2-2 and the Ets factor Spi-B

Authors

  • Maho Nagasawa,

    1. Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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  • Heike Schmidlin,

    1. Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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  • Mark G. Hazekamp,

    1. Cardiothoracic Surgery, Leiden University Medical Center, Leiden, The Netherlands
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  • Remko Schotte,

    1. Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    Current affiliation:
    1. Division of Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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  • Bianca Blom

    Corresponding author
    1. Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    • Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands Fax: +31206974156
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  • bHLH

    basic helix-loop-helix

    cDC

    conventional dendritic cells

    E2-2-i

    E2-2 RNA-i

    EICE

    ETS IRF composite DNA elements

    Flt3L

    FMS-like tyrosine kinase 3 ligand

    GFP

    green fluorescent protein

    Id2

    inhibitor of DNA binding protein 2

    IRF

    interferon regulatory factor

    pDC

    plasmacytoid dendritic cells

    Renilla-i

    Renilla RNA-i

    RNA-i

    RNA interference

    YFP

    yellow fluorescent protein

Abstract

Plasmacytoid dendritic cells (pDC) are central players in the innate and adaptive immune response against viral infections. The molecular mechanism that underlies pDC development from progenitor cells is only beginning to be elucidated. Previously, we reported that the Ets factor Spi-B and the inhibitors of DNA binding protein 2 (Id2) or Id3, which antagonize E-protein activity, are crucially involved in promoting or impairing pDC development, respectively. Here we show that the basic helix-loop-helix protein E2-2 is predominantly expressed in pDC, but not in their progenitor cells or conventional DC. Forced expression of E2-2 in progenitor cells stimulated pDC development. Conversely, inhibition of E2-2 expression by RNA interference impaired the generation of pDC suggesting a key role of E2-2 in development of these cells. Notably, Spi-B was unable to overcome the Id2 enforced block in pDC development and moreover Spi-B transduced pDC expressed reduced Id2 levels. This might indicate that Spi-B contributes to pDC development by promoting E2-2 activity. Consistent with notion, simultaneous overexpression of E2-2 and Spi-B in progenitor cells further stimulated pDC development. Together our results provide additional insight into the transcriptional network controlling pDC development as evidenced by the joint venture of E2-2 and Spi-B.

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