Abstract
The type-I interferon (IFN-α/β) 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 induction1,2,3,4. Using mice deficient in the Irf7 gene (Irf7-/- mice), we show that the transcription factor IRF-7 is essential for the induction of IFN-α/β genes via the virus-activated, MyD88-independent pathway and the TLR-activated, MyD88-dependent pathway. Viral induction of MyD88-independent IFN-α/β 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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Acknowledgements
We thank J. Vilcek, H. Rosen, H. Ohno, F. Nakatsu, A. Nakano, L. Cantley, T. Saito, T. Seya, W.-C. Yeh and M. Lamphier for advice; S. Akira for MyD88 mutant mice; K. Yokote for Smad3 mutant mice; G. Trinchieri for pDC-specific antibody; and M. Shishido for technical assistance. This work was supported in part by a grant for Advanced Research on Cancer and a Grant-In-Aid for Scientific Research on Propriety Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Uehara Memorial Foundation, the Sumitomo Foundation, and the Nakajima Foundation. H.Y. is a research fellow of the Japan Society for the Promotion of Science. H.N. was supported by an Ishidu Shun Memorial Scholarship.
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Supplementary information
Supplementary Figure S1
Flow cytometric analysis of splenocytes in IRF-7-/- mice. (PDF 212 kb)
Supplementary Figure S2
Impaired IFN induction in IRF-7-/- MEFs. (PDF 252 kb)
Supplementary Figure S3
Impaired IFN induction in IRF-7-/- pDCs. (PDF 299 kb)
Supplementary Figure S4
Immune response in IRF-7-/- mice. (PDF 131 kb)
Supplementary Notes
Contains details of the Supplementary Methods, legends to accompany Supplementary Figures S1-S4 and additional references. (DOC 67 kb)
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Honda, K., Yanai, H., Negishi, H. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772–777 (2005). https://doi.org/10.1038/nature03464
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DOI: https://doi.org/10.1038/nature03464
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