Poly I:C-induced activation of NK cells by CD8 alpha+ dendritic cells via the IPS-1 and TRIF-dependent pathways.
NK cells play essential roles in eliminating virally infected cells and tumor cells. Polyinosinic-polycytidylic acid (poly I:C), a double-stranded RNA analog recognized by melanoma-differentiation associated gene 5 (MDA5) and TLR3, activates NK cells in vivo. MDA5 and TLR3 signal through distinct adaptor molecules, IFN-promoter stimulator-1 (IPS-1) and Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF), respectively. However, it remains unclear how NK cells are activated by poly I:C in vivo. In this study, we demonstrate that the IPS-1-dependent and the TRIF-dependent pathways are essential for NK cell activation to poly I:C stimulation in mice, whereas deficiency in either IPS-1 or TRIF only modestly impairs the poly I:C-induced NK cell activation. Furthermore, both IPS-1 and TRIF contributed to suppression of implanted B16 tumor growth in response to poly I:C administration via NK cell activation. Presence of IPS-1 and TRIF in dendritic cells (DCs), but not NK cells, was required for production of IFN-gamma to poly I:C in NK cells in vitro. Moreover CD8alpha(+) conventional dendritic cells (cDCs), but not CD8alpha(-) cDCs, expressed genes for type I IFNs, IL-6, and IL-12p40 in response to poly I:C stimulation, and were also responsible for inducing IFN-gamma production in NK cells. Taken together, poly I:C activates the IPS-1- and TRIF-dependent pathways in CD8alpha(+) cDCs, which in turn leads to NK cell activation.
Miyake
Tohru
T
Laboratory of Host Defense.
Kumagai
Yutaro
Y
Kato
Hiroki
H
Guo
Zijin
Z
Matsushita
Kazufumi
K
Satoh
Takashi
T
Kawagoe
Tatsukata
T
Kumar
Himanshu
H
Jang
Myoung Ho
MH
Kawai
Taro
T
Tani
Tohru
T
Takeuchi
Osamu
O
Akira
Shizuo
S
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D016827:CD8 Antigens / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011070:Poly I-C / Q000494:pharmacology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D016827:CD8 Antigens; D011070:Poly I-C; C431698:CD8alpha antigen; C512612:MAVS protein, mouse; C476286:Ticam1 protein, mouse