Cytotoxic activity of human dendritic cells is differentially regulated by double-stranded RNA and CD40 ligand.
The main function of dendritic cells (DCs) is to induce adaptive immune response through Ag presentation and specific T lymphocyte activation. However, IFN-alpha- or IFN-gamma-stimulated CD11c+ blood DCs and IFN-beta-stimulated monocyte-derived DCs were recently reported to express functional TNF-related apoptosis-inducing ligand (TRAIL), suggesting that DCs may become cytotoxic effector cells of innate immunity upon appropriate stimulation. In this study, we investigate whether dsRNA and CD40 ligand (CD40L), that were characterized as potent inducers of DC maturation, could also stimulate or modulate DC cytotoxicity toward tumoral cells. We observed that dsRNA, but not CD40L, is a potent inducer of TRAIL expression in human monocyte-derived DCs. As revealed by cytotoxicity assays, DCs acquire the ability to kill tumoral cells via the TRAIL pathway when treated with dsRNA. More precisely, dsRNA is shown to induce IFN-beta synthesis that consecutively mediates TRAIL expression by the DCs. In contrast, we demonstrate that TRAIL expression in dsRNA- or IFN-alpha-treated DCs is potently inhibited after CD40L stimulation. Unexpectedly, CD40L-activated DCs still developed cytotoxicity toward tumoral cells. This latter appeared to be partly mediated by TNF-alpha induction and a yet unidentified pathway. Altogether, these results demonstrate that dsRNA and CD40L, that were originally characterized as maturation signals for DCs, also stimulate their cytotoxicity that is mediated through TRAIL-dependent or -independent mechanisms.
Vidalain
P O
PO
Laboratoire d'Immunobiologie Fondamentale et Clinique, Institut National de la Santé et de la Recherche Médicale Unité 503, 21 Avenue Tony Garnier, 69365 Lyon, France.
Azocar
O
O
Yagita
H
H
Rabourdin-Combe
C
C
Servet-Delprat
C
C
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000502:physiology*; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D009000:Monocytes / Q000276:immunology; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D019013:CD40 Antigens; D008562:Membrane Glycoproteins; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D016899:Interferon-beta