Spatiotemporal regulation of MyD88–IRF-7 signalling for robust type-I interferon induction (original) (raw)

Nature volume 434, pages 1035–1040 (2005)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Colonna, M., Trinchieri, G. & Liu, Y. J. Plasmacytoid dendritic cells in immunity. Nature Immunol. 5, 1219–1226 (2004)
    Article CAS Google Scholar
  2. Wagner, H. The immunobiology of the TLR9 subfamily. Trends Immunol. 25, 381–386 (2004)
    Article MathSciNet CAS Google Scholar
  3. Klinman, D. M. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nature Rev. Immunol. 4, 249–258 (2004)
    Article CAS Google Scholar
  4. Krieg, A. M. CpG motifs in bacterial DNA and their immune effects. Annu. Rev. Immunol. 20, 709–760 (2002)
    Article CAS Google Scholar
  5. Theofilopoulos, A. N., Baccala, R., Beutler, B. & Kono, D. H. Type I interferons (α/β) in immunity and autoimmunity. Annu. Rev. Immunol. 23, 307–335 (2005)
    Article CAS Google Scholar
  6. Ronnblom, L. & Alm, G. V. Systemic lupus erythematosus and the type I interferon system. Arthritis Res. Ther. 5, 68–75 (2003)
    Article Google Scholar
  7. Honda, K. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature advance online publication, 30 March 2005 (doi:10.1038/nature03464)
  8. Verthelyi, D., Ishii, K. J., Gursel, M., Takeshita, F. & Klinman, D. M. Human peripheral blood cells differentially recognize and respond to two distinct CpG motifs. J. Immunol. 166, 2372–2377 (2001)
    Article CAS Google Scholar
  9. Krug, A. et al. Identification of CpG oligonucleotide sequences with high induction of IFN-α/β in plasmacytoid dendritic cells. Eur. J. Immunol. 31, 2154–2163 (2001)
    Article CAS Google Scholar
  10. Hemmi, H., Kaisho, T., Takeda, K. & Akira, S. The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J. Immunol. 170, 3059–3064 (2003)
    Article CAS Google Scholar
  11. Kerkmann, M. et al. Activation with CpG-A and CpG-B oligonucleotides reveals two distinct regulatory pathways of type I IFN synthesis in human plasmacytoid dendritic cells. J. Immunol. 170, 4465–4474 (2003)
    Article CAS Google Scholar
  12. Krieg, A. M. et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374, 546–549 (1995)
    Article ADS CAS Google Scholar
  13. Izaguirre, A. et al. Comparative analysis of IRF and IFN-α expression in human plasmacytoid and monocyte-derived dendritic cells. J. Leukoc. Biol. 74, 1125–1138 (2003)
    Article CAS Google Scholar
  14. Coccia, E. M. et al. Viral infection and Toll-like receptor agonists induce a differential expression of type I and λ interferons in human plasmacytoid and monocyte-derived dendritic cells. Eur. J. Immunol. 34, 796–805 (2004)
    Article CAS Google Scholar
  15. Latz, E. et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nature Immunol. 5, 190–198 (2004)
    Article CAS Google Scholar
  16. Honda, K. et al. Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc. Natl Acad. Sci. USA 101, 15416–15421 (2004)
    Article ADS CAS Google Scholar
  17. Takaoka, A. et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434, 243–249 (2005)
    Article ADS CAS Google Scholar
  18. Zabner, J., Fasbender, A. J., Moninger, T., Poellinger, K. A. & Welsh, M. J. Cellular and molecular barriers to gene transfer by a cationic lipid. J. Biol. Chem. 270, 18997–19007 (1995)
    Article CAS Google Scholar
  19. Heil, F. et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303, 1526–1529 (2004)
    Article ADS CAS Google Scholar
  20. Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004)
    Article ADS CAS Google Scholar
  21. Heil, F. et al. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur. J. Immunol. 33, 2987–2997 (2003)
    Article CAS Google Scholar
  22. Hacker, H. et al. CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. EMBO J. 17, 6230–6240 (1998)
    Article CAS Google Scholar
  23. Hacker, H. et al. Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6. J. Exp. Med. 192, 595–600 (2000)
    Article CAS Google Scholar
  24. Radler, J. O., Koltover, I., Salditt, T. & Safinya, C. R. Structure of DNA-cationic liposome complexes: DNA intercalation in multilamellar membranes in distinct interhelical packing regimes. Science 275, 810–814 (1997)
    Article CAS Google Scholar
  25. Koltover, I., Salditt, T., Radler, J. O. & Safinya, C. R. An inverted hexagonal phase of cationic liposome–DNA complexes related to DNA release and delivery. Science 281, 78–81 (1998)
    Article ADS CAS Google Scholar
  26. Durrer, P., Gaudin, Y., Ruigrok, R. W., Graf, R. & Brunner, J. Photolabeling identifies a putative fusion domain in the envelope glycoprotein of rabies and vesicular stomatitis viruses. J. Biol. Chem. 270, 17575–17581 (1995)
    Article CAS Google Scholar
  27. Brunetti, C. R., Dingwell, K. S., Wale, C., Graham, F. L. & Johnson, D. C. Herpes simplex virus gD and virions accumulate in endosomes by mannose 6-phosphate-dependent and -independent mechanisms. J. Virol. 72, 3330–3339 (1998)
    CAS PubMed PubMed Central Google Scholar
  28. Leadbetter, E. A. et al. Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002)
    Article ADS CAS Google Scholar
  29. Mellman, I. Endocytosis and molecular sorting. Annu. Rev. Cell Dev. Biol. 12, 575–625 (1996)
    Article CAS Google Scholar
  30. Asselin-Paturel, C., Brizard, G., Pin, J. J., Briere, F. & Trinchieri, G. Mouse strain differences in plasmacytoid dendritic cell frequency and function revealed by a novel monoclonal antibody. J. Immunol. 171, 6466–6477 (2003)
    Article CAS Google Scholar

Download references

Acknowledgements

We thank J. Vilcek, H. Rosen, H. Ohno, F. Nakatsu, A. Nakano, M. Lamphier, L. Cantley and T. Curran for advice, S. Akira for TLR9 and MyD88 mutant mice, G. Trinchieri for the pDC-specific antibody, A. Miyawaki for Venus (a variant of YFP), H. Miyoshi for lentivirus vectors, 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, the Uehara Memorial Foundation, the Sumitomo Foundation, the Senri Life Science Foundation and the Nakajima Foundation. H.N. was supported by an Ishidu Shun Memorial Scholarship.

Author information

Author notes

  1. Kenya Honda, Yusuke Ohba 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, Tokyo, 113-0033, Japan
    Kenya Honda, Yusuke Ohba, Hideyuki Yanai, Hideo Negishi, Tatsuaki Mizutani, Akinori Takaoka & Tadatsugu Taniguchi
  2. Information and Cell Function, PRESTO, JST, Kawaguchi, Saitama, 332-0012, Japan
    Yusuke Ohba
  3. Department of Laboratory Animal Science, Tokyo Metropolitan Institute of Medical Science, Honkomagome 3-18-22, Bunkyo-ku, Tokyo, 113-8613, Japan
    Choji Taya

Authors

  1. Kenya Honda
    You can also search for this author inPubMed Google Scholar
  2. Yusuke Ohba
    You can also search for this author inPubMed Google Scholar
  3. Hideyuki Yanai
    You can also search for this author inPubMed Google Scholar
  4. Hideo Negishi
    You can also search for this author inPubMed Google Scholar
  5. Tatsuaki Mizutani
    You can also search for this author inPubMed Google Scholar
  6. Akinori Takaoka
    You can also search for this author inPubMed Google Scholar
  7. Choji Taya
    You can also search for this author inPubMed Google Scholar
  8. Tadatsugu Taniguchi
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toTadatsugu Taniguchi.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure S1

This file contains Supplementary Figure S1 a, b, c and d. (PDF 655 kb)

Supplementary Figure S2

This file contains Supplementary Figure S2 a, b, c, d and e. (PDF 1107 kb)

Supplementary Figure S3

This file contains Supplementary Figure S3 a, b, c, d and e. (PDF 612 kb)

Supplementary Figure S4

This file contains Supplementary Figure S4 a, b, c, d and e. (PDF 699 kb)

Supplementary Figure S5

This file contains Supplementary Figure S5 a, b, c, d, e, f and g. Modelling and simulation of CpG-dependent IFN induction. (PDF 95 kb)

Supplementary Video S1

Time-lapse analysis of CpG-A trafficking in bone-marrow-derived conventional dendritic cells. (MOV 1176 kb)

Supplementary Video S2

Time-lapse analysis of CpG-B trafficking in bone-marrow-derived conventional dendritic cells. (MOV 1188 kb)

Supplementary Video S3

Time-lapse analysis of CpG-A/DOTAP trafficking in bone-marrow-derived conventional dendritic cells. (MOV 3638 kb)

Supplementary Notes

This file contains the Supplementary Methods, Legends to accompany Supplementary Figures S1-S5, Supplementary Video Legends, Supplementary Discussion and additional References. (DOC 88 kb)

Rights and permissions

About this article

Cite this article

Honda, K., Ohba, Y., Yanai, H. et al. Spatiotemporal regulation of MyD88–IRF-7 signalling for robust type-I interferon induction.Nature 434, 1035–1040 (2005). https://doi.org/10.1038/nature03547

Download citation