title: PI3Kγ Is Critical for Dendritic Cell-Mediated CD8+ T Cell Priming and Viral Clearance during Influenza Virus Infection.
abstract: Phosphoinositide-3-kinases have been shown to be involved in influenza virus pathogenesis. They are targeted directly by virus proteins and are essential for efficient viral replication in infected lung epithelial cells. However, to date the role of PI3K signaling in influenza infection in vivo has not been thoroughly addressed. Here we show that one of the PI3K subunits, p110γ, is in fact critically required for mediating the host's antiviral response. PI3Kγ deficient animals exhibit a delayed viral clearance and increased morbidity during respiratory infection with influenza virus. We demonstrate that p110γ is required for the generation and maintenance of potent antiviral CD8+ T cell responses through the developmental regulation of pulmonary cross-presenting CD103+ dendritic cells under homeostatic and inflammatory conditions. The defect in lung dendritic cells leads to deficient CD8+ T cell priming, which is associated with higher viral titers and more severe disease course during the infection. We thus identify PI3Kγ as a novel key host protective factor in influenza virus infection and shed light on an unappreciated layer of complexity concerning the role of PI3K signaling in this context.
authors.affiliation: Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Samuel Philip
authors.initials: SP
authors.lastname: Nobs
authors.affiliation: Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Alex Kaspar
authors.initials: AK
authors.lastname: Heer
authors.affiliation: Institute of Biochemistry, ETH Zürich, Zurich, Switzerland.
authors.forename: Jatta
authors.initials: J
authors.lastname: Huotari
authors.affiliation: Institute of Biochemistry, ETH Zürich, Zurich, Switzerland.
authors.forename: Ari
authors.initials: A
authors.lastname: Helenius
authors.affiliation: Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kopf
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D045142:Cross-Priming / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D004847:Epithelial Cells / Q000821:virology; D008168:Lung / Q000276:immunology / Q000821:virology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000821:virology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology
chemical_list: D019869:Phosphatidylinositol 3-Kinases