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

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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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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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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