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+ Dendritic Cells via the IPS-1 and TRIF-Dependent Pathways1
,¶,
,
* Laboratory of Host Defense,
Laboratory of Gastrointestinal Immunology, World Premier International Immunology Frontier Research Center,
Global Centers of Excellence Program, Frontier Biomedical Science Underlying Organelle Network Biology, and
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka, Japan; and
¶ Department of Surgery, Shiga University of Medical Science, Seta-tsukinowacho, Otsu, Shiga, Japan
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-β (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-
to poly I:C in NK cells in vitro. Moreover CD8
+ conventional dendritic cells (cDCs), but not CD8– 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- production in NK cells. Taken together, poly I:C activates the IPS-1- and TRIF-dependent pathways in CD8+ cDCs, which in turn leads to NK cell activation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Special Coordination Funds of the Japanese Ministry of Education, Culture, Sports, Science and Technology, and grants from the Ministry of Health, Labour and Welfare in Japan, the Global Center of Excellence Program of Japan, and the National Institutes of Health (P01 AI070167). H.K. was supported by a postdoctoral fellowship (grant number P08123) from the Japan Society for the Promotion of Science, Japan.
2 Address correspondence and reprint requests to Dr. Shizuo Akira, Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka, Japan. E-mail address: sakira{at}biken.osaka-u.ac.jp
3 Abbreviations used in this paper: DC, dendritic cell; RIG-I, retinoic acid-inducible gene-I; RLR, RIG-I-like receptor; MDA5, melanoma differentiation-associated gene 5; CARD, caspase-recruit domain; IPS-1, IFNβ promoter stimulator-1; IKK, I
B kinase; TBK1, TANK-binding kinase 1; TRAF, TNF receptor associated factor; IRF, IFN-regulatory factor; TRIF, Toll/IL-1R domain-containing adaptor inducing IFN; poly I:C, polyinosinic-polycytidylic acid; pDC, plasmacytoid DC; cDC, conventional dendritic cell; qPCR, quantitative real-time PCR.
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