Dendritic cells are preferentially targeted among hematolymphocytes by Modified Vaccinia Virus Ankara and play a key role in the induction of virus-specific T cell responses in vivo.
Dendritic cells are preferentially targeted among hematolymphocytes by Modified Vaccinia Virus Ankara and play a key role in the induction of virus-specific T cell responses in vivo.
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DOI：
10.1186/1471-2172-9-15
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发表时间：
2008-04-15
期刊：
影响因子：
3
通讯作者：
Feinberg MB
中科院分区：
文献类型：
--
作者：
Liu L;Chavan R;Feinberg MB
改良的安卡拉牛痘（MVA）是一种高度减毒的牛痘病毒（VV）株，其已丢失约15%的VV基因组，沿着在大多数哺乳动物细胞中复制的能力。它在临床前和临床研究中均表现出令人印象深刻的安全性和免疫原性，并且正在积极探索作为许多传染病和恶性肿瘤的有前途的疫苗载体。然而，很少有人知道MVA如何与宿主免疫系统成分，特别是树突状细胞（DC），诱导强烈的免疫反应，尽管它不能在体内复制。使用体外和体内小鼠模型，我们系统地研究了小鼠DCs对MVA感染的易感性，以及感染的免疫后果。我们的数据表明，MVA优先感染专职抗原呈递细胞，特别是DC，在所有的血淋巴细胞亚群。与报道的VV感染后DC成熟和功能的阻断相反，MVA感染的DC在感染后18小时内经历表型成熟并产生先天性细胞因子IFN-α。MVA感染的DC在感染后12小时发生大量凋亡，并且凋亡的DC容易被未感染的DC吞噬。使用MHC I类缺陷型小鼠，我们表明病毒Ag的直接和交叉呈递都可能参与产生病毒特异性CD 8 + T细胞应答。最后，DC耗竭废除了体内T细胞活化。我们提出的第一个在体内的证据表明，在血淋巴细胞，DC是MVA感染的最敏感的目标，DC介导的抗原呈递是必需的MVA特异性免疫反应的诱导。这些结果提供了重要的信息有关的机制，通过该机制，引起强烈的免疫反应MVA编码的抗原，并可能通知努力，以进一步提高免疫原性，这已经很有前途的疫苗载体。
Modified Vaccinia Ankara (MVA) is a highly attenuated strain of vaccinia virus (VV) that has lost approximately 15% of the VV genome, along with the ability to replicate in most mammalian cells. It has demonstrated impressive safety and immunogenicity profile in both preclinical and clinical studies, and is being actively explored as a promising vaccine vector for a number of infectious diseases and malignancies. However, little is known about how MVA interacts with the host immune system constituents, especially dendritic cells (DCs), to induce strong immune responses despite its inability to replicate in vivo. Using in vitro and in vivo murine models, we systematically investigated the susceptibility of murine DCs to MVA infection, and the immunological consequences of the infection. Our data demonstrate that MVA preferentially infects professional antigen presenting cells, especially DCs, among all the subsets of hematolymphoid cells. In contrast to the reported blockage of DC maturation and function upon VV infection, DCs infected by MVA undergo phenotypic maturation and produce innate cytokine IFN-α within 18 h of infection. Substantial apoptosis of MVA-infected DCs occurs after 12 h following infection and the apoptotic DCs are readily phagocytosed by uninfected DCs. Using MHC class I – deficient mice, we showed that both direct and cross-presentation of viral Ags are likely to be involved in generating viral-specific CD8+ T cell responses. Finally, DC depletion abrogated the T cell activation in vivo. We present the first in vivo evidence that among hematolymphoid cells, DCs are the most susceptible targets for MVA infection, and DC-mediated Ag presentation is required for the induction of MVA-specific immune responses. These results provide important information concerning the mechanisms by which strong immune responses are elicited to MVA-encoded antigens and may inform efforts to further improve the immunogenicity of this already promising vaccine vector.
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影响因子：
5.4
作者：
Chavan, R.;Marfatia, K. A.;Feinberg, A. B.
通讯作者：
Feinberg, A. B.
影响因子：
32.4
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Lang, RA
影响因子：
5.4
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Jenne, Lars
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2.8
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Bhardwaj, N
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4.4
作者：
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