Cytotoxic Activity of Human Dendritic Cells Is Differentially Regulated by Double-Stranded RNA and CD40 Ligand

Abstract

The main function of dendritic cells (DCs) is to induce adaptive immune response through Ag presentation and specific T lymphocyte activation. However, IFN-α- or IFN-γ-stimulated CD11c+ blood DCs and IFN-β-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-β synthesis that consecutively mediates TRAIL expression by the DCs. In contrast, we demonstrate that TRAIL expression in dsRNA- or IFN-α-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-α 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.

Killer dendritic cells: mechanisms of action and therapeutic implications for cancer

“…36 Crosslinking of CD40 molecules (using rhCD40L) expressed by DC enhances the ability of these APC to inhibit the growth of tumor cell lines via a (TNF-a-dependent) apoptotic mechanism in coculture experiments. 37,38 As a cautionary note, however, a number of carcinomas (cell lines and tissue specimens) may themselves express CD40, and the growth and survival of these tumor cell lines can be inhibited directly by rhCD40L. 44,45 This may suggest that at least some of the KDC anti-tumor effects observed by Joo et al 37 may be KDC-independent.…”

Activated human umbilical cord blood dendritic cells kill tumor cells without damaging normal hematological progenitor cells

“…Our study confirmed that mature CBDC are more active than immature CBDC in killing tumor cells, as recently reported for mature DC derived from adult bone marrow or peripheral blood. (19) The mechanisms and biological significance of such activated CBDC were not clear. Several recent studies suggest that the tumoricidal activity of activated immune cells were mediated by involvement of an apopotosis-inducing pathway, especially the TNF family pathway.…”

The ‘kiss of death’ by dendritic cells to cancer cells

“…69,70 Human blood cDCs acquire the ability to kill tumor cells via TRAIL expression or TNF-a secretion, upon IFN-a or IFN-g stimulation, 52,71 and monocyte-derived DCs upon IFN-b stimulation or measles virus infection. 72,73 Immature DCs have also been shown to kill freshly isolated tumors. [74][75][76] Although in vitro-derived immature DCs kill target cells very efficiently at low effector/target ratios via an apoptotic mechanism involving DNA fragmentation, mitochondrial dysfunction, and late membrane disruption, the level of cytotoxicity found in the freshly isolated, immature DCs remains low and questionable.…”

“…Furthermore, the cytotoxicity may be a function of DC maturation since LPS or IFN-g enhances the cytotoxicity of DCs, 70 whereas CD40L or TNF-a does not enhance or even abrogate the killing activity. 76 Furthermore, Vidalain et al 73 showed that poly(I:C) stimulation of the monocyte-derived human DCs leads to an increased cytotoxic activity, via type-I IFN-mediated TRAIL upregulation on DCs. Surprisingly, CD40L-activated DCs with no upregulation of TRAIL expression remained cytotoxic to certain types of tumor cells.…”

“…It appears that TNF-a, TRAIL, and FasL are differentially induced on the surface of the killer DCs according to the nature of the stimulating signals. 73 Thus, the type of stimulating reagents used would be tailored to the tumoricidal activity of activated DCs toward a specific tumor.…”