TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines
TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines
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DOI：
10.1038/nature06537
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发表时间：
2008-02-07
期刊：
影响因子：
64.8
通讯作者：
Akira, Shizuo
中科院分区：
文献类型：
--
作者：
Ishii, Ken J.;Kawagoe, Tatsukata;Akira, Shizuo
成功的疫苗不仅含有保护性抗原，还含有引发先天免疫激活的佐剂成分，这是其最佳免疫原性所必需的（1，2）。在DNA疫苗的情况下（3），其由质粒DNA组成;然而，佐剂元件及其导致编码的抗原特异性T-和B-细胞应答的细胞内和细胞间先天免疫信号传导途径仍不清楚.在此，我们证明了TANK结合激酶1（TBK 1），一种非经典的I κ B激酶，在体内介导DNA疫苗的佐剂效应，并且是其在小鼠中的免疫原性所必需的。诱导抗原特异性B和T细胞需要质粒DNA激活的TBK 1依赖性信号传导和所得的I型干扰素受体介导的信号传导，这甚至在缺乏通过众所周知的CpG DNA传感器- Toll样受体9（TLR 9）或Z-DNA结合蛋白1的先天免疫信号传导的情况下发生。（ZBP 1，也称为DAI，最近报道为潜在的B型DNA传感器（4））。此外，骨髓转移实验表明，TBK 1介导的造血细胞信号传导对于抗原特异性B和CD 4（+）T细胞的诱导至关重要，而在非造血细胞中，TBK 1是CD 8（+）T细胞诱导所必需的。这些数据表明TBK 1是DNA疫苗诱导免疫原性的关键信号分子，通过造血和非造血细胞差异控制DNA激活的先天免疫信号。
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 vaccines(3), 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 I kappa B 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(4)). Moreover, bone- marrow-transfer experiments revealed that TBK1- mediated signalling in haematopoietic cells was critical for the induction of antigenspecific 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 nonhaematopoietic cells.