Spatiotemporal regulation of MyD88–IRF-7 signalling for robust type-I interferon induction

Kenya Honda, Yusuke Ohba, Hideyuki Yanai, Hideo Negishi, Tatsuaki Mizutani, Akinori Takaoka, Choji Taya and Tadatsugu Taniguchi ()
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Kenya Honda: University of Tokyo
Yusuke Ohba: University of Tokyo
Hideyuki Yanai: University of Tokyo
Hideo Negishi: University of Tokyo
Tatsuaki Mizutani: University of Tokyo
Akinori Takaoka: University of Tokyo
Choji Taya: Tokyo Metropolitan Institute of Medical Science
Tadatsugu Taniguchi: University of Tokyo

Nature, 2005, vol. 434, issue 7036, 1035-1040

Abstract: Abstract Robust type-I interferon (IFN-α/β) induction in plasmacytoid dendritic cells, through the activation of Toll-like receptor 9 (TLR9), constitutes a critical aspect of immunity1,2,3,4,5,6. It is absolutely dependent on the transcription factor IRF-7, which interacts with and is activated by the adaptor MyD88. How plasmacytoid dendritic cells, but not other cell types (such as conventional dendritic cells), are able to activate the MyD88–IRF-7-dependent IFN induction pathway remains unknown. Here we show that the spatiotemporal regulation of MyD88–IRF-7 signalling is critical for a high-level IFN induction in response to TLR9 activation. The IFN-inducing TLR9 ligand, A/D-type CpG oligodeoxynucleotide (CpG-A)3,4,8,9,10,11, is retained for long periods in the endosomal vesicles of plasmacytoid dendritic cells, together with the MyD88–IRF-7 complex. However, in conventional dendritic cells, CpG-A is rapidly transferred to lysosomal vesicles. We further show that conventional dendritic cells can also mount a robust IFN induction if CpG-A is manipulated for endosomal retention using a cationic lipid. This strategy also allows us to demonstrate endosomal activation of the IFN pathway by the otherwise inactive TLR9 ligand B/K-type oligodeoxynucleotide (CpG-B)3,4,8,9,10,11,12. Thus, our study offers insights into the regulation of TLR9 signalling in space, potentially suggesting a new avenue for therapeutic intervention.

Date: 2005
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DOI: 10.1038/nature03547

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