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Clin Exp Immunol. 2013 Dec;174(3):389-401. doi: 10.1111/cei.12191.

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

Author information

1
Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Centre, Rotterdam, the Netherlands.

Abstract

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.

KEYWORDS:

IFN-α; Toll-like receptor; mTOR

PMID:
23968562
PMCID:
PMC3826305
DOI:
10.1111/cei.12191
[Indexed for MEDLINE]
Free PMC Article

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