A cGAS-Independent STING/IRF7 Pathway Mediates the Immunogenicity of DNA Vaccines.
A cGAS-Independent STING/IRF7 Pathway Mediates the Immunogenicity of DNA Vaccines.
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DOI：
10.4049/jimmunol.1501836
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发表时间：
2016-01-01
期刊：
影响因子：
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通讯作者：
Lu S
中科院分区：
文献类型：
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作者：
Suschak JJ;Wang S;Fitzgerald KA;Lu S
自从20多年前发现DNA疫苗以来，人们就知道DNA疫苗可以作为佐剂。我们最近的研究报道了Aim2作为DNA疫苗的传感器参与引发抗原特异性抗体反应。我们的研究结果表明，除了TLR9途径外，还存在先前未被识别的先天免疫应答途径，该途径主要由DNA疫苗的CpG基序激活。我们的数据进一步证明了I型IFN通过Aim2途径在DNA疫苗诱导的免疫应答中是必需的，但确切的下游分子机制尚未确定。在当前的研究中，我们研究了假定的DNA传感器环GMP-AMP合成酶（cGas）以及下游干扰素调节因子（Irf） 3和7在DNA接种引起的I型IFN诱导和抗原特异性免疫应答中的作用。我们的研究结果表明，DNA疫苗诱导的依赖于irf7的信号传导，作为Sting通路的一部分，对于产生先天细胞因子信号传导和抗原特异性B细胞和T细胞反应至关重要。相比之下，Irf3在这一途径中并不像预期的那么重要，更令人惊讶的是，DNA疫苗引发的免疫反应在体内并不依赖cGas。本报告中提供的数据为DNA疫苗接种所涉及的先天免疫机制提供了更多细节，并进一步丰富了我们对DNA疫苗在产生抗原特异性免疫反应方面的潜在效用的理解。
It is known since the discovery of DNA vaccines more than 20 years ago that DNA vaccines can function as adjuvants. Our recent study reported the involvement of Aim2 as the sensor of DNA vaccines in eliciting antigen-specific antibody responses. Our findings indicated the presence of previously unrecognized innate immune response pathways in addition to the TLR9 pathway, which is mainly activated by the CpG motifs of DNA vaccines. Our data further demonstrated the requirement of type I IFN in DNA vaccine-induced immune responses via the Aim2 pathway, but the exact downstream molecular mechanism was not characterized. In the current study, we investigated the roles of the putative DNA sensor cyclic GMP-AMP synthase (cGas), as well as the downstream interferon regulatory factors (Irf) 3 and 7 in type I IFN induction and antigen-specific immune responses elicited by DNA vaccination. Our results showed that DNA vaccine induced, Irf7-dependent signaling, as part of the Sting pathway, was critical for generation of both innate cytokine signaling and antigen-specific B and T cell responses. In contrast, Irf3 was not as critical as expected in this pathway and more surprisingly, immune responses elicited by DNA vaccines were not cGas dependent in vivo. Data presented in the current report provide more details on the innate immune mechanisms involved in DNA vaccination and further enrich our understanding on the potential utility of DNA vaccines in generating antigen-specific immune responses.