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

Kenya Honda, Yusuke Ohba, Hideyuki Yanai, Hideo Hegishi, Tatsuaki Mizutani, Akinori Takaoka, Choji Taya, Tadatsugu Taniguchi

Research output: Contribution to journalArticle

654 Citations (Scopus)

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 immunity1-6. It is absolutely dependent on the transcription factor IRF-7, which interacts with and is activated by the adaptor MyD88 (ref. 7). 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)3,4,8-11, 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) 3,4,8-12. Thus, our study offers insights into the regulation of TLR9 signalling in space, potentially suggesting a new avenue for therapeutic intervention.

Original languageEnglish
Pages (from-to)1035-1040
Number of pages6
JournalNature
Volume434
Issue number7036
DOIs
Publication statusPublished - 2005 Apr 21
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • General

Cite this

Honda, K., Ohba, Y., Yanai, H., Hegishi, H., Mizutani, T., Takaoka, A., Taya, C., & Taniguchi, T. (2005). Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature, 434(7036), 1035-1040. https://doi.org/10.1038/nature03547