title: 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.
abstract: 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.
authors.affiliation: Innate-Pharma, Marseille, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Perrot
authors.forename: Florence
authors.initials: F
authors.lastname: Deauvieau
authors.forename: Catherine
authors.initials: C
authors.lastname: Massacrier
authors.forename: Nicola
authors.initials: N
authors.lastname: Hughes
authors.forename: Pierre
authors.initials: P
authors.lastname: Garrone
authors.forename: Isabelle
authors.initials: I
authors.lastname: Durand
authors.forename: Olivier
authors.initials: O
authors.lastname: Demaria
authors.forename: Nicolas
authors.initials: N
authors.lastname: Viaud
authors.forename: Laurent
authors.initials: L
authors.lastname: Gauthier
authors.forename: Mathieu
authors.initials: M
authors.lastname: Blery
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bonnefoy-Berard
authors.forename: Yannis
authors.initials: Y
authors.lastname: Morel
authors.forename: Jurg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Lena
authors.initials: L
authors.lastname: Alexopoulou
authors.forename: Giorgio
authors.initials: G
authors.lastname: Trinchieri
authors.forename: Carine
authors.initials: C
authors.lastname: Paturel
authors.forename: Christophe
authors.initials: C
authors.lastname: Caux
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D007371:Interferon-gamma / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011063:Poly A-U / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000494:pharmacology; D011971:Receptors, Immunologic; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D007371:Interferon-gamma; D011063:Poly A-U; D011070:Poly I-C; D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; D051196:Toll-Like Receptor 3; C512612:MAVS protein, mouse; C452820:RIGI protein, human; C503356:Ddx58 protein, mouse; C452815:IFIH1 protein, human