TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection

JR Aldridge Jr, CE Moseley, DA Boltz… - Proceedings of the …, 2009 - National Acad Sciences
JR Aldridge Jr, CE Moseley, DA Boltz, NJ Negovetich, C Reynolds, J Franks, SA Brown…
Proceedings of the National Academy of Sciences, 2009National Acad Sciences
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 …
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-γ 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.
National Acad Sciences