1. Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
2. Information and Cell Function, PRESTO, JST, Kawaguchi, Saitama 332-0012, Japan
3. Department of Laboratory Animal Science, Tokyo Metropolitan Institute of Medical Science, Honkomagome 3-18-22, Bunkyo-ku, Tokyo 113-8613, Japan
4. These authors contributed equally to this work

Correspondence to: Tadatsugu Taniguchi¹ Correspondence and requests for materials should be addressed to T.T. (Email: tada@m.u-tokyo.ac.jp).

Abstract

Robust type-I interferon (IFN-/) induction in plasmacytoid dendritic cells, through the activation of Toll-like receptor 9 (TLR9), constitutes a critical aspect of immunity^{1, 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.

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