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

• Published in: The Journal of immunology (1950) 2010-08, Vol.185 (4), p.2080-2088
• Main Authors: Perrot, Ivan, Deauvieau, Florence, Massacrier, Catherine, Hughes, Nicola, Garrone, Pierre, Durand, Isabelle, Demaria, Olivier, Viaud, Nicolas, Gauthier, Laurent, Blery, Mathieu, Bonnefoy-Berard, Nathalie, Morel, Yannis, Tschopp, Jurg, Alexopoulou, Lena, Trinchieri, Giorgio, Paturel, Carine, Caux, Christophe
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Cell Line; Cells, Cultured; DEAD Box Protein 58; DEAD-box RNA Helicases; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Dendritic Cells; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - metabolism; Dose-Response Relationship, Drug; Humans; Immunology; Interferon-gamma; Interferon-gamma - metabolism; Interferon-Induced Helicase, IFIH1; Killer Cells, Natural; Killer Cells, Natural - cytology; Killer Cells, Natural - drug effects; Killer Cells, Natural - metabolism; Life Sciences; Lymphocyte Activation; Lymphocyte Activation - drug effects; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Cells; Myeloid Cells - cytology; Myeloid Cells - drug effects; Myeloid Cells - metabolism; Poly A-U; Poly A-U - pharmacology; Poly I-C; Poly I-C - pharmacology; Receptors, Immunologic; RNA, Double-Stranded; RNA, Double-Stranded - pharmacology; Toll-Like Receptor 3; Toll-Like Receptor 3 - genetics; Toll-Like Receptor 3 - metabolism; Transfection
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1000532

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-polyuridylic acid and polyinosinic-polycytidylic acid [poly(I:C)], similarly engaged human TLR3, whereas only poly(I:C) triggered human RIG-I and MDA5. Both dsRNA enhanced NK cell activation within PBMCs but only poly(I:C) induced IFN-gamma. Although myeloid DCs (mDCs) were required for NK cell activation, induction of cytolytic potential and IFN-gamma production did not require contact with mDCs but was dependent on type I IFN and IL-12, respectively. Poly(I:C) but not polyadenylic-polyuridylic acid synergized with mDC-derived IL-12 for IFN-gamma production by acting directly on NK cells. Finally, the requirement of both TLR3 and Rig-like receptor (RLR) on mDCs and RLRs but not TLR3 on NK cells for IFN-gamma production was demonstrated using TLR3- and Cardif-deficient mice and human RIG-I-specific activator. Thus, we report the requirement of cotriggering TLR3 and RLR on mDCs and RLRs on NK cells for a pathogen product to induce potent innate cell activation.