title: 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 immunogenicity. In the case of DNA vaccines, 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 IkappaB 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 sensor). 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.
authors.affiliation: Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Agency (JST). kenishii@biken.osaka-u.ac.jp
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.forename: Tatsukata
authors.initials: T
authors.lastname: Kawagoe
authors.forename: Shohei
authors.initials: S
authors.lastname: Koyama
authors.forename: Kosuke
authors.initials: K
authors.lastname: Matsui
authors.forename: Himanshu
authors.initials: H
authors.lastname: Kumar
authors.forename: Taro
authors.initials: T
authors.lastname: Kawai
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Takeshita
authors.forename: Cevayir
authors.initials: C
authors.lastname: Coban
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology; D002678:Chimera / Q000276:immunology; D004247:DNA / Q000276:immunology; D018274:Electroporation; D005347:Fibroblasts; D006023:Glycoproteins / Q000172:deficiency; D007113:Immunity, Innate / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*
chemical_list: D006023:Glycoproteins; D007370:Interferon Type I; D016601:RNA-Binding Proteins; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D019444:Vaccines, DNA; C402632:Zbp1 protein, mouse; D053633:Receptor, Interferon alpha-beta; D004247:DNA; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases