TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection.
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.
Aldridge
Jerry R
JR
Division of Virology, Department of Infectious Diseases, and Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Moseley
Carson E
CE
Boltz
David A
DA
Negovetich
Nicholas J
NJ
Reynolds
Cory
C
Franks
John
J
Brown
Scott A
SA
Doherty
Peter C
PC
Webster
Robert G
RG
Thomas
Paul G
PG
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D053124:Influenza A Virus, H5N1 Subtype; D009980:Influenza A virus / Q000276:immunology*; D008171:Lung Diseases / Q000276:immunology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D054390:Receptors, CCR2 / Q000172:deficiency / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II