Lymphopenia Associated with Highly Virulent H5N1 Virus Infection Due to Plasmacytoid Dendritic Cell-Mediated Apoptosis of T Cells
Lymphopenia Associated with Highly Virulent H5N1 Virus Infection Due to Plasmacytoid Dendritic Cell-Mediated Apoptosis of T Cells
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DOI：
10.4049/jimmunol.1302992
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发表时间：
2014-06-15
影响因子：
4.4
通讯作者：
Subbarao, Kanta
中科院分区：
文献类型：
--
作者：
Boonnak, Kobporn;Vogel, Leatrice;Subbarao, Kanta
尽管淋巴细胞减少症是人类严重感染高致病性H5 N1和新出现的H7 N9流感病毒的标志，但致命H5 N1病毒导致哺乳动物宿主淋巴细胞减少症的机制仍然知之甚少。由于流感特异性T细胞反应在肺引流淋巴结（LN）中启动，淋巴细胞随后流向肺或外周循环，因此我们在小鼠模型中比较了致死性A/HK/483/97或非致死性A/HK/486/97（H5 N1）病毒感染后肺引流淋巴结中的免疫反应。我们发现，致死性H5 N1病毒感染小鼠可增强浆细胞样树突状细胞（pDC）上Fas配体（FasL）的表达，通过Fas-FasL介导的途径导致流感特异性CD 8（+）T细胞凋亡，但非致死性H5 N1病毒感染小鼠则无此作用。我们还发现，pDC，而不是其他DC亚群，优先积累在致命的H5 N1病毒感染的小鼠的肺引流LN中，并且pDC上的FasL表达的诱导与肺引流LN中高水平的IL-12 p40单体/同源二聚体相关。我们的数据表明，与致命的H5 N1病毒感染相关的淋巴细胞减少症的机制之一涉及pDC的有害作用。
Although lymphopenia is a hallmark of severe infection with highly pathogenic H5N1 and the newly emerged H7N9 influenza viruses in humans, the mechanism(s) by which lethal H5N1 viruses cause lymphopenia in mammalian hosts remains poorly understood. Because influenza-specific T cell responses are initiated in the lung draining lymph nodes (LNs), and lymphocytes subsequently traffic to the lungs or peripheral circulation, we compared the immune responses in the lung draining LNs postinfection with a lethal A/HK/483/97 or nonlethal A/HK/486/97 (H5N1) virus in a mouse model. We found that lethal H5N1, but not nonlethal H5N1, virus infection in mice enhances Fas ligand (FasL) expression on plasmacytoid dendritic cells (pDCs), resulting in apoptosis of influenza-specific CD8(+) T cells via a Fas-FasL-mediated pathway. We also found that pDCs, but not other DC subsets, preferentially accumulate in the lung draining LNs of lethal H5N1 virus-infected mice, and that the induction of FasL expression on pDCs correlates with high levels of IL-12p40 monomer/homodimer in the lung draining LNs. Our data suggest that one of the mechanisms of lymphopenia associated with lethal H5N1 virus infection involves a deleterious role for pDCs.