Differentially imprinted innate immunity by mucosal boost vaccination determines antituberculosis immune protective outcomes, independent of T-cell immunity
Differentially imprinted innate immunity by mucosal boost vaccination determines antituberculosis immune protective outcomes, independent of T-cell immunity
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DOI：
10.1038/mi.2012.103
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发表时间：
2013-05-01
影响因子：
8
通讯作者：
Xing, Z.
中科院分区：
文献类型：
--
作者：
Jeyanathan, M.;Damjanovic, D.;Xing, Z.
同源和异源肠胃外初粘膜加强免疫在对抗结核病和艾滋病等粘膜感染方面显示出巨大的前景。然而，它们的免疫机制仍然不明确。特别是，目前尚不清楚 T 细胞和先天免疫是否可能独立地受到这些免疫方式的影响以及它如何影响免疫保护结果。使用两种基于病毒的结核疫苗（腺病毒（Ad）和水泡性口炎病毒（VSV）载体），我们发现虽然同源（Ad/Ad）和异源（Ad/VSV）呼吸道粘膜加强免疫在肺部引起相似的T细胞反应，但它们导致了截然不同的免疫保护结果。与基于Ad的加强免疫相比，基于VSV的加强免疫对结核病的保护作用增强较差。这种较差的保护作用与肺中差异印记的先天吞噬细胞有关，特别是 CD11c(+) CD11b(+/-) 细胞。我们确定 1 型干扰素 (IFN) 反应增强是触发机制。因此，增加的 IFN-β 会严重削弱受感染吞噬细胞中白细胞介素 12 的反应，进而损害其一氧化氮的产生和抗分枝杆菌活性。我们的研究表明，疫苗载体可能会在免疫粘膜部位差异性地印记先天细胞，这可能会影响免疫保护结果，而与 T 细胞免疫无关，并且在疫苗研究中确定 T 细胞和先天细胞免疫非常重要。
Homologous and heterologous parenteral prime-mucosal boost immunizations have shown great promise in combating mucosal infections such as tuberculosis and AIDS. However, their immune mechanisms remain poorly defined. In particular, it is still unclear whether T-cell and innate immunity may be independently affected by these immunization modalities and how it impacts immune protective outcome. Using two virus-based tuberculosis vaccines (adenovirus (Ad) and vesicular stomatitis virus (VSV) vectors), we found that while both homologous (Ad/Ad) and heterologous (Ad/VSV) respiratory mucosal boost immunizations elicited similar T-cell responses in the lung, they led to drastically different immune protective outcomes. Compared with Ad-based boosting, VSV-based boosting resulted in poorly enhanced protection against tuberculosis. Such inferior protection was associated with differentially imprinted innate phagocytes, particularly the CD11c(+) CD11b(+/-) cells, in the lung. We identified heightened type 1 interferon (IFN) responses to be the triggering mechanism. Thus, increased IFN-beta severely blunted interleukin-12 responses in infected phagocytes, which in turn impaired their nitric oxide production and antimycobacterial activities. Our study reveals that vaccine vectors may differentially imprint innate cells at the mucosal site of immunization, which can impact immune-protective outcome, independent of T-cell immunity, and it is of importance to determine both T-cell and innate cell immunity in vaccine studies.