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Journal of Virology, January 2008, p. 196-206, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01640-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Lymphocytoid Choriomeningitis Virus Activates Plasmacytoid Dendritic Cells and Induces a Cytotoxic T-Cell Response via MyD88{triangledown}

Andreas Jung,1,2 Hiroki Kato,1 Yutaro Kumagai,1 Himanshu Kumar,1 Taro Kawai,1,3 Osamu Takeuchi,1,3 and Shizuo Akira1,3*

Research Institute for Microbial Diseases, Department of Host Defense, Osaka University, Osaka, Japan,1 Department of Neonatology, Campus Mitte, Charité-Universitaetsmedizin Berlin, Berlin, Germany,2 ERATO, Japan Science and Technology Agency, Osaka, Japan3

Received 26 July 2007/ Accepted 4 October 2007

Toll-like receptors (TLRs) and retinoic acid-inducible gene I-like helicases (RLHs) are two major machineries recognizing RNA virus infection of innate immune cells. Intracellular signaling for TLRs and RLHs is mediated by their cytoplasmic adaptors, i.e., MyD88 or TRIF and IPS-1, respectively. In the present study, we investigated the contributions of TLRs and RLHs to the cytotoxic T-lymphocyte (CTL) response by using lymphocytoid choriomeningitis virus (LCMV) as a model virus. The generation of virus-specific cytotoxic T lymphocytes was critically dependent on MyD88 but not on IPS-1. Type I interferons (IFNs) are known to be important for the development of the CTL response to LCMV infection. Serum levels of type I IFNs and proinflammatory cytokines were mainly dependent on the presence of MyD88, although IPS-1–/– mice showed a decrease in IFN-{alpha} levels but not in IFN-β and proinflammatory cytokine levels. Analysis of Ifna6+/GFP reporter mice revealed that plasmacytoid dendritic cells (DCs) are the major source of IFN-{alpha} in LCMV infection. MyD88–/– mice were highly susceptible to LCMV infection in vivo. These results suggest that recognition of LCMV by plasmacytoid DCs via TLRs is responsible for the production of type I IFNs in vivo. Furthermore, the activation of a MyD88-dependent innate mechanism induces a CTL response, which eventually leads to virus elimination.

* Corresponding author. Mailing address: WPI Immunology Frontier Research Center, Laboratory of Host Defense, Osaka University, 3-1 Yamada-oka, Suita 565-0871, Osaka, Japan. Phone: 81-6-6879 8303. Fax: 81-6-6879 8305. E-mail: sakira{at}biken.osaka-u.ac.jp

{triangledown} Published ahead of print on 17 October 2007.

Journal of Virology, January 2008, p. 196-206, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01640-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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