TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection
TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection
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DOI：
10.1073/pnas.0900655106
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发表时间：
2009-03-31
影响因子：
11.1
通讯作者：
Thomas, Paul G.
中科院分区：
文献类型：
--
作者：
Aldridge, Jerry R., Jr.;Moseley, Carson E.;Thomas, Paul G.
高致病性甲型流感病毒的呼吸道感染的特征在于细胞因子和趋化因子的大量产生以及先天性炎性细胞的增强募集。在这里，我们表明，用强毒甲型流感病毒（包括目前流行的H5 N1毒株）攻击小鼠，会导致特定树突状细胞亚群（tipDCs）在肺炎气道中的选择性积累增加。这些tipDC是流感特异性CD 8（+）T细胞在感染肺中进一步增殖所必需的，因为阻断它们在CCR 2（-/-）小鼠中的募集会减少CD 8（+）效应子的数量，并最终损害病毒清除。然而，通过使用过氧化物酶体增殖物激活受体-γ激动剂吡格列酮治疗，减少而不是完全消除tipDC的运输，可以缓和过度tipDC募集的潜在致命后果，而不会废除CD 8（+）T细胞扩增或损害病毒控制。因此，以这种方式瞄准tipDC为面对灾难性大流行时的治疗干预提供了可能性。
Respiratory infection with highly pathogenic influenza A viruses is characterized by the exuberant production of cytokines and chemokines and the enhanced recruitment of innate inflammatory cells. Here, we show that challenging mice with virulent influenza A viruses, including currently circulating H5N1 strains, causes the increased selective accumulation of a particular dendritic cell subset, the tipDCs, in the pneumonic airways. These tipDCs are required for the further proliferation of influenza-specific CD8(+) T cells in the infected lung, because blocking their recruitment in CCR2(-/-) mice decreases the numbers of CD8(+) effectors and ultimately compromises virus clearance. However, diminution rather than total elimination of tipDC trafficking by treatment with the peroxisome proliferator-activated receptor-gamma agonist pioglitazone moderates the potentially lethal consequences of excessive tipDC recruitment without abrogating CD8(+) T cell expansion or compromising virus control. Targeting the tipDCs in this way thus offers possibilities for therapeutic intervention in the face of a catastrophic pandemic.