Rapamycin has suppressive and stimulatory effects on human plasmacytoid dendritic cell functions

Authors

  • P. P. C. Boor,

    1. Department of Gastroenterology and Hepatology, Erasmus MC – University Medical Centre, Rotterdam, the Netherlands
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  • H. J. Metselaar,

    1. Department of Gastroenterology and Hepatology, Erasmus MC – University Medical Centre, Rotterdam, the Netherlands
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  • S. Mancham,

    1. Department of Gastroenterology and Hepatology, Erasmus MC – University Medical Centre, Rotterdam, the Netherlands
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  • L. J. W. van der Laan,

    1. Department of Surgery, Erasmus MC – University Medical Centre, Rotterdam, the Netherlands
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  • J. Kwekkeboom

    Corresponding author
    1. Department of Gastroenterology and Hepatology, Erasmus MC – University Medical Centre, Rotterdam, the Netherlands
    • Correspondence: J. Kwekkeboom, Laboratory for Gastroenterology and Hepatology, Room L-455, Erasmus MC – University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands.

      E-mail: j.kwekkeboom@erasmusmc.nl

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Summary

Plasmacytoid dendritic cells (PDC) are involved in innate immunity by interferon (IFN)-α production, and in adaptive immunity by stimulating T cells and inducing generation of regulatory T cells (Treg). In this study we studied the effects of mammalian target of rapamycin (mTOR) inhibition by rapamycin, a commonly used immunosuppressive and anti-cancer drug, on innate and adaptive immune functions of human PDC. A clinically relevant concentration of rapamycin inhibited Toll-like receptor (TLR)-7-induced IFN-α secretion potently (−64%) but TLR-9-induced IFN-α secretion only slightly (−20%), while the same concentration suppressed proinflammatory cytokine production by TLR-7-activated and TLR-9-activated PDC with similar efficacy. Rapamycin inhibited the ability of both TLR-7-activated and TLR-9-activated PDC to stimulate production of IFN-γ and interleukin (IL)-10 by allogeneic T cells. Surprisingly, mTOR-inhibition enhanced the capacity of TLR-7-activated PDC to stimulate naive and memory T helper cell proliferation, which was caused by rapamycin-induced up-regulation of CD80 expression on PDC. Finally, rapamycin treatment of TLR-7-activated PDC enhanced their capacity to induce CD4+forkhead box protein 3 (FoxP3)+ regulatory T cells, but did not affect the generation of suppressive CD8+CD38+lymphocyte activation gene (LAG)-3+ Treg. In general, rapamycin inhibits innate and adaptive immune functions of TLR-stimulated human PDC, but enhances the ability of TLR-7-stimulated PDC to stimulate CD4+ T cell proliferation and induce CD4+FoxP3+ regulatory T cell generation.

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