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TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines

Nature volume 451, pages 725–729 (2008)Cite this article

Abstract

Successful vaccines contain not only protective antigen(s) but also an adjuvant component that triggers innate immune activation and is necessary for their optimal immunogenicity1,2. In the case of DNA vaccines3, this consists of plasmid DNA; however, the adjuvant element(s) as well as its intra- and inter-cellular innate immune signalling pathway(s) leading to the encoded antigen-specific T- and B-cell responses remain unclear. Here we demonstrate in vivo that TANK-binding kinase 1 (TBK1), a non-canonical IκB kinase, mediates the adjuvant effect of DNA vaccines and is essential for its immunogenicity in mice. Plasmid-DNA-activated, TBK1-dependent signalling and the resultant type-I interferon receptor-mediated signalling was required for induction of antigen-specific B and T cells, which occurred even in the absence of innate immune signalling through a well known CpG DNA sensor—Toll-like receptor 9 (TLR9) or Z-DNA binding protein 1 (ZBP1, also known as DAI, which was recently reported as a potential B-form DNA sensor4). Moreover, bone-marrow-transfer experiments revealed that TBK1-mediated signalling in haematopoietic cells was critical for the induction of antigen-specific B and CD4+ T cells, whereas in non-haematopoietic cells TBK1 was required for CD8+ T-cell induction. These data suggest that TBK1 is a key signalling molecule for DNA-vaccine-induced immunogenicity, by differentially controlling DNA-activated innate immune signalling through haematopoietic and non-haematopoietic cells.

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Figure 1: Optimal DNA vaccine immunogenicity requires type-I interferons.
Figure 2: Tbk1 -/- mice failed to elicit antigen-specific T- and B-cell responses after DNA vaccination.
Figure 3: Contribution of haematopoietic and non-haematopoietic cells to DNA-vaccine-induced immunogenicity.
Figure 4: Effects of ZBP1 deficiency on the innate immune activation by B-DNA and the adaptive immune responses to DNA vaccine.

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References

  1. Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature 449, 819–826 (2007)

    Article  CAS  ADS  Google Scholar 

  2. Pulendran, B. & Ahmed, R. Translating innate immunity into immunological memory: implications for vaccine development. Cell 124, 849–863 (2006)

    Article  CAS  Google Scholar 

  3. Donnelly, J. J., Ulmer, J. B., Shiver, J. W. & Liu, M. A. DNA vaccines. Annu. Rev. Immunol. 15, 617–648 (1997)

    Article  CAS  Google Scholar 

  4. Takaoka, A. et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448, 501–505 (2007)

    Article  CAS  ADS  Google Scholar 

  5. Mata-Haro, V. et al. The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science 316, 1628–1632 (2007)

    Article  CAS  ADS  Google Scholar 

  6. Krieg, A. M. Therapeutic potential of Toll-like receptor 9 activation. Nature Rev. Drug Discov. 5, 471–484 (2006)

    Article  CAS  ADS  Google Scholar 

  7. Gavin, A. L. et al. Adjuvant-enhanced antibody responses in the absence of Toll-like receptor signaling. Science 314, 1936–1938 (2006)

    Article  CAS  ADS  Google Scholar 

  8. Janssen, E. et al. Efficient T cell activation via a Toll–interleukin 1 receptor-independent pathway. Immunity 24, 787–799 (2006)

    Article  CAS  Google Scholar 

  9. Yang, Z. Y. et al. A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice. Nature 428, 561–564 (2004)

    Article  CAS  ADS  Google Scholar 

  10. Wang, R. et al. Induction of CD4+ T cell-dependent CD8+ type 1 responses in humans by a malaria DNA vaccine. Proc. Natl Acad. Sci. USA 98, 10817–10822 (2001)

    Article  CAS  ADS  Google Scholar 

  11. Gurunathan, S., Klinman, D. M. & Seder, R. A. DNA vaccines: immunology, application, and optimization. Annu. Rev. Immunol. 18, 927–974 (2000)

    Article  CAS  Google Scholar 

  12. Spies, B. et al. Vaccination with plasmid DNA activates dendritic cells via Toll-like receptor 9 (TLR9) but functions in TLR9-deficient mice. J. Immunol. 171, 5908–5912 (2003)

    Article  CAS  Google Scholar 

  13. Babiuk, S. et al. TLR9-/- and TLR9+/+ mice display similar immune responses to a DNA vaccine. Immunology 113, 114–120 (2004)

    Article  CAS  Google Scholar 

  14. Tudor, D. et al. TLR9 pathway is involved in adjuvant effects of plasmid DNA-based vaccines. Vaccine 23, 1258–1264 (2005)

    Article  CAS  Google Scholar 

  15. Ulmer, J. B., Wahren, B. & Liu, M. A. Gene-based vaccines: recent technical and clinical advances. Trends Mol. Med. 12, 216–222 (2006)

    Article  CAS  Google Scholar 

  16. Widera, G. et al. Increased DNA vaccine delivery and immunogenicity by electroporation in vivo . J. Immunol. 164, 4635–4640 (2000)

    Article  CAS  Google Scholar 

  17. Takeshita, F. et al. Toll-like receptor adaptor molecules enhance DNA-raised adaptive immune responses against influenza and tumors through activation of innate immunity. J. Virol. 80, 6218–6224 (2006)

    Article  CAS  Google Scholar 

  18. Ishii, K. J. & Akira, S. Innate immune recognition of, and regulation by, DNA. Trends Immunol. 27, 525–532 (2006)

    Article  CAS  Google Scholar 

  19. Okabe, Y., Kawane, K., Akira, S., Taniguchi, T. & Nagata, S. Toll-like receptor-independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation. J. Exp. Med. 202, 1333–1339 (2005)

    Article  CAS  Google Scholar 

  20. Ishii, K. J. et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nature Immunol. 7, 40–48 (2006)

    Article  CAS  Google Scholar 

  21. Stetson, D. B. & Medzhitov, R. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24, 93–103 (2006)

    Article  CAS  Google Scholar 

  22. Le Bon, A. & Tough, D. F. Links between innate and adaptive immunity via type I interferon. Curr. Opin. Immunol. 14, 432–436 (2002)

    Article  CAS  Google Scholar 

  23. Baccala, R., Hoebe, K., Kono, D. H., Beutler, B. & Theofilopoulos, A. N. TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nature Med. 13, 543–551 (2007)

    Article  CAS  Google Scholar 

  24. Hemmi, H. et al. The roles of two IκB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J. Exp. Med. 199, 1641–1650 (2004)

    Article  CAS  Google Scholar 

  25. Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000)

    Article  CAS  ADS  Google Scholar 

  26. Condon, C., Watkins, S. C., Celluzzi, C. M., Thompson, K. & Falo, L. D. DNA-based immunization by in vivo transfection of dendritic cells. Nature Med. 2, 1122–1128 (1996)

    Article  CAS  Google Scholar 

  27. Sasaki, S., Amara, R. R., Yeow, W. S., Pitha, P. M. & Robinson, H. L. Regulation of DNA-raised immune responses by cotransfected interferon regulatory factors. J. Virol. 76, 6652–6659 (2002)

    Article  CAS  Google Scholar 

  28. Koyama, S. et al. Differential role of TLR- and RLR-signaling in the immune responses to influenza A virus infection and vaccination. J. Immunol. 179, 4711–4720 (2007)

    Article  CAS  Google Scholar 

  29. Ishii, K. J. et al. CpG-activated Thy1.2+ dendritic cells protect against lethal Listeria monocytogenes infection. Eur. J. Immunol. 35, 2397–2405 (2005)

    Article  CAS  Google Scholar 

  30. Kaisho, T. et al. IκB kinase α is essential for mature B cell development and function. J. Exp. Med. 193, 417–426 (2001)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank T. Horii, K. Suzuki and S. Sasaki for suggestions, and Y. Fujita for technical support. This study was supported by Grant-in-Aid for Scientific Research (B) (to K.J.I.) from the Ministry of Education, Culture, Sports, Science and Technology in Japan.

Author Contributions K.J.I., C.C. and S.A. designed the research and analysed data. K.J.I., S.K. and C.C. performed most experiments. T.K. generated ZBP-1-deficient mice and performed the related experiments. K.M. and O.T. performed the bone-marrow-transfer experiments. S.U., T.K. and H.K. provided mutant mice. F.T. provided critical materials and advice. K.J.I., C.C. and S.A. prepared the manuscript.

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Author notes

  1. Ken J. Ishii and Tatsukata Kawagoe: These authors contributed equally to this work.

Authors and Affiliations

  1. Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Agency (JST),,

    Ken J. Ishii, Taro Kawai, Osamu Takeuchi & Shizuo Akira

  2. Department of Molecular Protozoology,,

    Ken J. Ishii

  3. Laboratory of Host Defense, WPI Immunology Frontier Research Center,,

    Ken J. Ishii, Tatsukata Kawagoe, Shohei Koyama, Himanshu Kumar, Taro Kawai, Satoshi Uematsu, Osamu Takeuchi, Cevayir Coban & Shizuo Akira

  4. Department of Host Defense,,

    Tatsukata Kawagoe, Shohei Koyama, Kosuke Matsui, Himanshu Kumar, Taro Kawai, Satoshi Uematsu, Osamu Takeuchi, Cevayir Coban & Shizuo Akira

  5. The 21st Century Center of Excellence (COE), Combined Program on Microbiology and Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan ,

    Cevayir Coban & Shizuo Akira

  6. Department of Molecular Biodefense Research, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan,

    Fumihiko Takeshita

  7. Respiratory Oncology and Molecular Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi 980-8575, Japan ,

    Shohei Koyama

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Correspondence to Ken J. Ishii or Shizuo Akira.

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Ishii, K., Kawagoe, T., Koyama, S. et al. TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature 451, 725–729 (2008). https://doi.org/10.1038/nature06537

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