title: The subcellular location of antigen expressed by adenoviral vectors modifies adaptive immunity but not dependency on cross-presenting dendritic cells.
abstract: Adenoviral (Ad) vaccine vectors can generate protective immunity to various pathogens in animal studies. However, recent failures in clinical vaccine trials have underscored the need for a better understanding of how mucosal immune responses to Ad-encoded vaccine Ags are generated in vivo. In this study, we addressed whether directing Ad-encoded ovalbumin (OVA) to different subcellular compartments influences the generation of OVA-specific acquired immunity and the APCs required following i.n. immunization of mice. We show that both secreted and membrane-anchored OVA activate CD4(+) T cells, induce cytotoxic CD8(+) T lymphocytes (CTLs) and generate serum IgG. Additionally, vaginal IgG is induced when OVA is expressed at these subcellular locations, but only the secreted form generates a significant IgA response in the lungs. On the contrary, intracellular expression of OVA efficiently expands CD8(+) T cells but fails to activate CD4(+) T cells, results in poor CTL activity, and does not generate Abs. Finally, we show that regardless of the subcellular localization of OVA, conventional DCs (cDCs) are required for the activation of T cells. However, the direct transduction of conventional DCs is not essential. These findings have important implications for the improvement of Ad vector design and vaccine-induced mucosal immunity.
authors.affiliation: Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Henning
authors.forename: Tobias
authors.initials: T
authors.lastname: Gustafsson
authors.forename: Carl-Fredrik
authors.initials: CF
authors.lastname: Flach
authors.forename: Yeu-Jiann
authors.initials: YJ
authors.lastname: Hua
authors.forename: Anna
authors.initials: A
authors.lastname: Strömbeck
authors.forename: Jan
authors.initials: J
authors.lastname: Holmgren
authors.forename: Leif
authors.initials: L
authors.lastname: Lindholm
authors.forename: Ulf
authors.initials: U
authors.lastname: Yrlid
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000941:Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D045142:Cross-Priming / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007114:Immunization / Q000379:methods; D007070:Immunoglobulin A / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D000941:Antigens; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D049452:Green Fluorescent Proteins; D010047:Ovalbumin