title: Rapamycin has suppressive and stimulatory effects on human plasmacytoid dendritic cell functions.
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.
authors: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Centre, Rotterdam, the Netherlands.
authors: P P C
authors: PP
authors: Boor
authors: H J
authors: HJ
authors: Metselaar
authors: S
authors: S
authors: Mancham
authors: L J W
authors: LJ
authors: van der Laan
authors: J
authors: J
authors: Kwekkeboom
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D015703:Antigens, CD / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007156:Immunologic Memory / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016898:Interferon-alpha / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D016207:Cytokines; D007166:Immunosuppressive Agents; D016898:Interferon-alpha; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; D007371:Interferon-gamma; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human
keywords: IFN-α; Toll-like receptor; mTOR
references: Discov Med. 2010 Mar;9(46):173-8
references: 20350481
references: Blood. 2008 Nov 1;112(9):3713-22
references: 18698004
references: J Exp Med. 2004 Jul 5;200(1):89-98
references: 15238608
references: Blood. 2009 Feb 26;113(9):2088-95
references: 19144988
references: J Interferon Cytokine Res. 1996 Oct;16(10):819-27
references: 8910767
references: Immunity. 2011 Dec 23;35(6):958-71
references: 22177923
references: Blood. 2012 Dec 13;120(25):4982-91
references: 23091295
references: J Exp Med. 2007 Jan 22;204(1):105-15
references: 17200410
references: J Exp Med. 2010 Aug 30;207(9):1891-905
references: 20696698
references: Nat Immunol. 2006 Jun;7(6):652-62
references: 16633346
references: Nature. 2009 Jul 2;460(7251):108-12
references: 19543266
references: Semin Cell Dev Biol. 2005 Feb;16(1):29-37
references: 15659337
references: Nat Rev Immunol. 2008 Aug;8(8):594-606
references: 18641647
references: Blood. 2005 Nov 15;106(10):3457-64
references: 16037393
references: J Immunol. 2004 Oct 1;173(7):4433-42
references: 15383574
references: Genes Dev. 2004 Aug 15;18(16):1926-45
references: 15314020
references: Immunity. 2008 Sep 19;29(3):352-61
references: 18799143
references: J Clin Invest. 2008 Oct;118(10):3431-9
references: 18776940
references: Am J Transplant. 2006 Oct;6(10):2332-41
references: 16889610
references: J Exp Med. 2002 Mar 18;195(6):695-704
references: 11901196
references: Am J Transplant. 2009 Dec;9(12):2655-61
references: 19788500
references: J Immunol Methods. 1992 Jul 31;152(1):15-23
references: 1379275
references: J Immunol. 2003 May 1;170(9):4465-74
references: 12707322
references: Immunity. 2008 Oct 17;29(4):565-77
references: 18848473
references: Nat Rev Drug Discov. 2011 Oct 31;10(11):868-80
references: 22037041
references: Nat Immunol. 2008 Oct;9(10):1157-64
references: 18758466
references: J Immunol. 2008 Oct 15;181(8):5396-404
references: 18832696
references: J Exp Med. 2004 Feb 16;199(4):567-79
references: 14970182
references: Nature. 2009 Jul 2;460(7251):103-7
references: 19494812
references: J Intern Med. 2009 Jan;265(1):43-57
references: 19093959
references: Curr Opin Rheumatol. 2009 Sep;21(5):443-7
references: 19584730
references: Blood. 2006 Feb 1;107(3):1031-8
references: 16219801
references: Immunol Rev. 2010 Mar;234(1):142-62
references: 20193017
references: Eur J Immunol. 2011 Jun;41(6):1663-74
references: 21469126
references: Annu Rev Immunol. 2004;22:563-98
references: 15032589
references: Immunol Today. 1996 Aug;17(8):369-72
references: 8783497