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Cutting Edge: TLR-Dependent Viral Recognition Along with Type I IFN Positive Feedback Signaling Masks the Requirement of Viral Replication for IFN- Production in Plasmacytoid Dendritic Cells¹

Yutaro Kumagai^*,,, Himanshu Kumar^*,, Shohei Koyama^*,, Taro Kawai^*,, Osamu Takeuchi^*, and Shizuo Akira^2,*,,

^* Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Department of Host Defense, Research Institute for Microbial Diseases, and Global Centers of Excellence Program, Frontier Biomedical Science Underlying Organelle Network Biology, Osaka University, Suita, Osaka, Japan

Plasmacytoid dendritic cells (pDCs) recognize RNA virus infection via TLRs and consequently produce vast amounts of type I IFN. Because nucleic acid-sensing TLRs reside in the intracellular membrane compartment, it is presumable that pDCs do not require cytoplasmic viral replication to recognize the infection. By checking Newcastle disease virus (NDV) RNA abundance in GFP⁺ and GFP^– pDCs from Ifna6gfp mice, we found that NDV replication was not detected in IFN-producing pDCs. GFP⁺ pDC was induced in response to replication-incompetent NDV. In contrast, the replication-incompetent NDV failed to induce IFN-producing pDCs in type I IFNR-deficient mice. The lack of IFNR signaling led to the replication of NDV and the subsequent RIG-I-like helicase-dependent IFN- production in pDCs. These results showed that detection of viruses via TLRs together with a type I IFN feedback system circumvents the requirement for viral replication-dependent recognition in pDCs.

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 in part by National Institutes of Health Grant AI070167. H.K. was supported by a postdoctoral fellowship 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 565-0871, Japan. E-mail address: sakira{at}biken.osaka-u.ac.jp

³ Abbreviations used in this paper: IPC, IFN-producing cell; DC, dendritic cell; cDC, conventional DC; pDC, plasmacytoid DC; HI, heat-inactivated; IPS, IFN-β promoter stimulator; IRF, IFN regulatory factor; MDA, melanoma differentiation-associated gene; NDV, Newcastle disease virus; Q-PCR, quantitative real-time PCR; RIG-I, retinoic acid-inducible gene I; RLH, RIG-I-like helicase; TRIF, Toll/IL-1R homology domain containing adaptor inducing IFN-β.