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The subcellular location of antigen expressed by adenoviral vectors modifies adaptive immunity but not dependency on cross-presenting dendritic cells.

Journal article
Authors Petra Henning
Tobias Gustafsson
Carl-Fredrik Flach
Yeu-Jiann Hua
Anna Strömbeck
Jan Holmgren
Leif Lindholm
Ulf Yrlid
Published in European journal of immunology
Volume 41
Issue 8
Pages 2185-96
ISSN 1521-4141
Publication year 2011
Published at Institute of Biomedicine, Department of Microbiology and Immunology
Pages 2185-96
Language en
Links dx.doi.org/10.1002/eji.201041009
Keywords Adaptive Immunity, immunology, Adenoviridae, genetics, immunology, Animals, Antigens, genetics, immunology, metabolism, Cell Line, Cell Line, Tumor, Cross-Priming, immunology, Dendritic Cells, immunology, metabolism, Female, Flow Cytometry, Genetic Vectors, genetics, immunology, Green Fluorescent Proteins, genetics, immunology, metabolism, HEK293 Cells, Humans, Immunization, methods, Immunoglobulin A, immunology, metabolism, Immunoglobulin G, blood, immunology, Lung, immunology, metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Ovalbumin, genetics, immunology, metabolism, T-Lymphocytes, immunology, metabolism, T-Lymphocytes, Cytotoxic, immunology, metabolism, Transduction, Genetic
Subject categories Microbiology in the medical area, Immunology in the medical area, Immunobiology

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.

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