title: Harnessing alveolar macrophages for sustained mucosal T-cell recall confers long-term protection to mice against lethal influenza challenge without clinical disease.
abstract: Vaccines that induce T cells, which recognize conserved viral proteins, could confer universal protection against seasonal and pandemic influenza strains. An effective vaccine should generate sufficient mucosal T cells to ensure rapid viral control before clinical disease. However, T cells may also cause lung injury in influenza, so this approach carries inherent risks. Here we describe intranasal immunization of mice with a lentiviral vector expressing influenza nucleoprotein (NP), together with an NFκB activator, which transduces over 75% of alveolar macrophages (AM). This strategy recalls and expands NP-specific CD8+ T cells in the lung and airway of mice that have been immunized subcutaneously, or previously exposed to influenza. Granzyme B-high, lung-resident T-cell populations persist for at least 4 months and can control a lethal influenza challenge without harmful cytokine responses, weight loss, or lung injury. These data demonstrate that AM can be harnessed as effective antigen-presenting cells for influenza vaccination.
authors.affiliation: Division of Infection and Immunity and MRC Centre for Medical Molecular Virology, University College London, London, UK.
authors.forename: D C
authors.initials: DC
authors.lastname: Macdonald
authors.affiliation: Division of Infection and Immunity and MRC Centre for Medical Molecular Virology, University College London, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Singh
authors.affiliation: Division of Medicine, University College London, London, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Whelan
authors.affiliation: Division of Infection and Immunity and MRC Centre for Medical Molecular Virology, University College London, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Escors
authors.affiliation: Division of Infection and Immunity and MRC Centre for Medical Molecular Virology, University College London, London, UK.
authors.forename: F
authors.initials: F
authors.lastname: Arce
authors.affiliation: Division of Medicine, University College London, London, UK.
authors.forename: S E
authors.initials: SE
authors.lastname: Bottoms
authors.affiliation: Division of Virology, Imperial College London, St Mary's Campus, London, UK.
authors.forename: W S
authors.initials: WS
authors.lastname: Barclay
authors.affiliation: Division of Infection and Immunity and MRC Centre for Medical Molecular Virology, University College London, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Maini
authors.affiliation: Division of Infection and Immunity and MRC Centre for Medical Molecular Virology, University College London, London, UK.
authors.forename: M K
authors.initials: MK
authors.lastname: Collins
authors.affiliation: Division of Medicine, University College London, London, UK.
authors.forename: W M C
authors.initials: WM
authors.lastname: Rosenberg
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003429:Cross Reactions / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007114:Immunization; D007117:Immunization, Secondary; D007156:Immunologic Memory; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology*; D016086:Lentivirus / Q000235:genetics; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic; D019076:Transgenes; D014779:Virus Replication / Q000276:immunology
chemical_list: D016207:Cytokines; D018984:Epitopes, T-Lymphocyte