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-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.
Perrot
Ivan
I
Innate-Pharma, Marseille, France.
Deauvieau
Florence
F
Massacrier
Catherine
C
Hughes
Nicola
N
Garrone
Pierre
P
Durand
Isabelle
I
Demaria
Olivier
O
Viaud
Nicolas
N
Gauthier
Laurent
L
Blery
Mathieu
M
Bonnefoy-Berard
Nathalie
N
Morel
Yannis
Y
Tschopp
Jurg
J
Alexopoulou
Lena
L
Trinchieri
Giorgio
G
Paturel
Carine
C
Caux
Christophe
C
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
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