1. Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
2. Institute of Medical Sciences, University of Tokyo, Shirokanedai 4-6-1, Minato-ku, Tokyo 108-8639, Japan
3. Information and Cell Function, PRESTO, JST, Kawaguchi, Saitama 332-0012, Japan
4. These authors contributed equally to this work

Correspondence to: Tadatsugu Taniguchi¹ Correspondence and requests for materials should be addressed to T.T. (Email: tada@m.u-tokyo.ac.jp).

Abstract

The type-I interferon (IFN-/) response is critical to immunity against viruses and can be triggered in many cell types by cytosolic detection of viral infection, or in differentiated plasmacytoid dendritic cells by the Toll-like receptor 9 (TLR9) subfamily, which generates signals via the adaptor MyD88 to elicit robust IFN induction^{1, 2, 3, 4}. Using mice deficient in the Irf7 gene (Irf7^-/- mice), we show that the transcription factor IRF-7 is essential for the induction of IFN-/ genes via the virus-activated, MyD88-independent pathway and the TLR-activated, MyD88-dependent pathway. Viral induction of MyD88-independent IFN-/ genes is severely impaired in Irf7^-/- fibroblasts. Consistently, Irf7^-/- mice are more vulnerable than Myd88^-/- mice to viral infection, and this correlates with a marked decrease in serum IFN levels, indicating the importance of the IRF-7-dependent induction of systemic IFN responses for innate antiviral immunity. Furthermore, robust induction of IFN production by activation of the TLR9 subfamily in plasmacytoid dendritic cells is entirely dependent on IRF-7, and this MyD88–IRF-7 pathway governs the induction of CD8⁺ T-cell responses. Thus, all elements of IFN responses, whether the systemic production of IFN in innate immunity or the local action of IFN from plasmacytoid dendritic cells in adaptive immunity, are under the control of IRF-7.

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