1. Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Agency (JST),
2. Department of Molecular Protozoology,
3. Laboratory of Host Defense, WPI Immunology Frontier Research Center,
4. Department of Host Defense,
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
6. Department of Molecular Biodefense Research, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan
7. Respiratory Oncology and Molecular Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi 980-8575, Japan
8. These authors contributed equally to this work.

Correspondence to: Ken J. Ishii^1,2,3,8Shizuo Akira^1,3,4,5 Correspondence and requests for materials should be addressed to K.J.I. (Email: kenishii@biken.osaka-u.ac.jp) or S.A. (Email: sakira@biken.osaka-u.ac.jp).

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 immunogenicity^{1, 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 IB 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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