Intrinsic adjuvanting of a novel single-cycle flavivirus vaccine in the absence of type I interferon receptor signaling.
Intrinsic adjuvanting of a novel single-cycle flavivirus vaccine in the absence of type I interferon receptor signaling.
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在缺乏 I 型干扰素受体信号传导的情况下，新型单周期黄病毒疫苗的内在佐剂作用。
DOI：
10.1016/j.vaccine.2011.12.103
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发表时间：
2012
期刊：
影响因子：
5.5
通讯作者：
Milligan,GreggN
中科院分区：
文献类型：
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作者：
Winkelmann,EvandroR;Widman,DouglasG;Xia,Jingya;Ishikawa,Tomohiro;Miller-Kittrell,Mindy;Nelson,MichelleH;Bourne,Nigel;Scholle,Frank;Mason,PeterW;Milligan,GreggN
I型干扰素（IFN）对于控制致病性病毒感染至关重要，并且可以增强免疫应答。因此，它们对减毒活疫苗有效性的影响涉及限制病毒抗原表达和增强适应性免疫应答发展之间的平衡。我们研究了I型干扰素对这些参数的影响，免疫接种后的<$VAX WN，单循环黄病毒疫苗（SCFV）对西尼罗河病毒（WNV）疾病。<$VAX WN免疫的小鼠产生IFN-α，并在引流淋巴结（LN）中显示IFN刺激的基因转录增加。与野生型（wt）小鼠相比，I型IFN受体敲除小鼠（IFNAR-/-）中SCFV基因表达在感染后1-3天高出100倍以上，表明wt动物中IFN介导的SCFV基因表达的显著抑制。与野生型小鼠相比，IFNAR−/−小鼠产生几乎相同水平的WNV特异性血清IgG和WNV特异性CD 4 +T细胞应答。然而，IFNAR−/−小鼠产生的WNV特异性CD 8 +T细胞数量显著更高，并且在抗原特异性再刺激后，来自IFNAR−/−小鼠的这些T细胞中仅产生IFN-γ的百分比显著更高。这种改变的细胞因子表达与增加的抗原负荷无关，表明I型IFN受体信号传导的丧失是CD 8+效应T细胞应答质量改变的原因。总之，这些结果表明，尽管I型IFN对于dVAX WN的内在佐剂作用不是必需的，但它在形成由该SCFV引起的CD 8+效应T细胞的细胞因子分泌谱中起作用。
Type I interferons (IFNs) are critical for controlling pathogenic virus infections and can enhance immune responses. Hence their impact on the effectiveness of live-attenuated vaccines involves a balance between limiting viral antigen expression and enhancing the development of adaptive immune responses. We examined the influence of type I IFNs on these parameters following immunization with RepliVAX WN, a single-cycle flavivirus vaccine (SCFV) against West Nile virus (WNV) disease. RepliVAX WN-immunized mice produced IFN-α and displayed increased IFN-stimulated gene transcription in draining lymph nodes (LN). SCFV gene expression was over 100 fold-higher on days 1–3 post-infection in type I IFN receptor knockout mice (IFNAR−/−) compared to wild-type (wt) mice indicating a profound IFN-mediated suppression of SCFV gene expression in the wt animals. IFNAR−/−mice produced nearly equivalent levels of WNV-specific serum IgG and WNV-specific CD4+T cell responses compared to wt mice. However, significantly higher numbers of WNV-specific CD8+T cells were produced by IFNAR−/−mice and a significantly greater percentage of these T cells from IFNAR−/−mice produced only IFN-γ following antigen-specific re-stimulation. This altered cytokine expression was not associated with increased antigen load suggesting the loss of type I IFN receptor signaling was responsible for the altered quality of the CD8+effector T cell response. Together, these results indicate that although type I IFN is not essential for the intrinsic adjuvanting of RepliVAX WN, it plays a role in shaping the cytokine secretion profiles of CD8+effector T cells elicited by this SCFV.