IRF-7 is the master regulator of type-I interferon-dependent immune responses (original) (raw)

Nature volume 434, pages 772–777 (2005) Cite this article

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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Author notes

  1. Kenya Honda and Hideyuki Yanai: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, 113-0033, Tokyo, Japan
    Kenya Honda, Hideyuki Yanai, Hideo Negishi, Masataka Asagiri, Tatsuaki Mizutani, Naoya Shimada, Yusuke Ohba, Akinori Takaoka & Tadatsugu Taniguchi
  2. Institute of Medical Sciences, University of Tokyo, Shirokanedai 4-6-1, Minato-ku, 108-8639, Tokyo, Japan
    Mitsuharu Sato & Nobuaki Yoshida
  3. Information and Cell Function, PRESTO, JST, Kawaguchi, Saitama, 332-0012, Japan
    Yusuke Ohba

Authors

  1. Kenya Honda
  2. Hideyuki Yanai
  3. Hideo Negishi
  4. Masataka Asagiri
  5. Mitsuharu Sato
  6. Tatsuaki Mizutani
  7. Naoya Shimada
  8. Yusuke Ohba
  9. Akinori Takaoka
  10. Nobuaki Yoshida
  11. Tadatsugu Taniguchi

Corresponding author

Correspondence toTadatsugu Taniguchi.

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The authors declare that they have no competing financial interests.

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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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