title: TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection.
abstract: 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.
authors.affiliation: Division of Virology, Department of Infectious Diseases, and Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Aldridge
authors.forename: Carson E
authors.initials: CE
authors.lastname: Moseley
authors.forename: David A
authors.initials: DA
authors.lastname: Boltz
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Negovetich
authors.forename: Cory
authors.initials: C
authors.lastname: Reynolds
authors.forename: John
authors.initials: J
authors.lastname: Franks
authors.forename: Scott A
authors.initials: SA
authors.lastname: Brown
authors.forename: Peter C
authors.initials: PC
authors.lastname: Doherty
authors.forename: Robert G
authors.initials: RG
authors.lastname: Webster
authors.forename: Paul G
authors.initials: PG
authors.lastname: Thomas
mesh_terms: 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
chemical_list: C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II