Cytotoxic activity of human dendritic cells is differentially regulated bydouble-stranded RNA and CD40 ligand

The main function of dendritic cells (DCs) is to induce adaptive immune res ponse through Ag presentation and specific T lymphocyte activation. However , IFN-alpha- or IFN-gamma -stimulated CD11c(+) blood DCs and IFN-beta -stim ulated monocyte-derived DCs were recently reported to express functional TN F-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 w ere 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-de rived DCs. As revealed by cytotoxicity assays, DCs acquire the ability to k ill tumoral cells via the TRAIL pathway when treated with dsRNA. More preci sely, dsRNA is shown to induce IFN-beta synthesis that consecutively mediat es TRAIL expression by the DCs. In contrast, we demonstrate that TRAIL expr ession in dsRNA- or IFN-alpha -treated DCs is potently inhibited after CD40 L stimulation. Unexpectedly, CD40L-activated DCs still developed cytotoxici ty toward tumoral cells. This latter appeared to be partly mediated by TNF- alpha induction and a yet unidentified pathway. Altogether, these results d emonstrate that dsRNA and CD40L, that were originally characterized as matu ration signals for DCs, also stimulate their cytotoxicity that is mediated through TRAIL-dependent or -independent mechanisms.