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

K Honda, Y Ohba, H Yanai, H Negishi, T Mizutani… - Nature, 2005 - nature.com
K Honda, Y Ohba, H Yanai, H Negishi, T Mizutani, A Takaoka, C Taya, T Taniguchi
Nature, 2005nature.com
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 immunity,,,,,. 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 …
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 immunity,,,,,. 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),,,,,, 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),,,,,,. Thus, our study offers insights into the regulation of TLR9 signalling in space, potentially suggesting a new avenue for therapeutic intervention.
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