TLR3 and Rig-like receptor on myeloid dendritic cells and Rig-like receptor on human NK cells are both mandatory for production of IFN-gamma in response to double-stranded RNA.

Cross-talk between NK cells and dendritic cells (DCs) is critical for the potent therapeutic response to dsRNA, but the receptors involved remained controversial. We show in this paper that two dsRNAs, polyadenylic- polyuridylicacid and polyinosinic-polycytidylic acid [poly(I:C)], similarly engaged human TLR3, whereas only poly(I:C) triggered human RIG-Iand MDA5. Both dsRNA enhanced NK cell activation within PBMCs but only poly(I:C) induced IFN-γ. Although myeloid DCs (mDCs) were required for NK cell activation, induction of cytolytic potential and IFN-γ production did not require contact with mDCs but was dependent on type I IFN and IL-12, respectively. Poly(I:C) but not polyadenylic- polyuridylicacid synergized with mDC-derived IL-12 for IFN-γ production by acting directly on NK cells. Finally, the requirement of both TLR3and Rig-like receptor (RLR) on mDCs and RLRs but not TLR3on NK cells for IFN-γ production was demonstrated using TLR3- and Cardif-deficient mice and human RIG-I–specific activator. Thus, we report the requirement of cotriggering TLR3and RLR on mDCs and RLRs on NK cells for a pathogen product to induce potent innate cell activation.