Airway structural cells regulate TLR5-mediated mucosal adjuvant activity.
Antigen-presenting cell (APC) activation is enhanced by vaccine adjuvants. Most vaccines are based on the assumption that adjuvant activity of Toll-like receptor (TLR) agonists depends on direct, functional activation of APCs. Here, we sought to establish whether TLR stimulation in non-hematopoietic cells contributes to flagellin's mucosal adjuvant activity. Nasal administration of flagellin enhanced T-cell-mediated immunity, and systemic and secretory antibody responses to coadministered antigens in a TLR5-dependent manner. Mucosal adjuvant activity was not affected by either abrogation of TLR5 signaling in hematopoietic cells or the presence of flagellin-specific, circulating neutralizing antibodies. We found that flagellin is rapidly degraded in conducting airways, does not translocate into lung parenchyma and stimulates an early immune response, suggesting that TLR5 signaling is regionalized. The flagellin-specific early response of lung was regulated by radioresistant cells expressing TLR5 (particularly the airway epithelial cells). Flagellin stimulated the epithelial production of a small set of mediators that included the chemokine CCL20, which is known to promote APC recruitment in mucosal tissues. Our data suggest that (i) the adjuvant activity of TLR agonists in mucosal vaccination may require TLR stimulation of structural cells and (ii) harnessing the effect of adjuvants on epithelial cells can improve mucosal vaccines.
1] Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, Lille, France [2] Institut National de la Santé et de la Recherche Médicale, Lille, France [3] Centre National de la Recherche Scientifique, Lille, France [4] Univ Lille Nord de France, Lille, France.
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Van Maele
1] Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, Lille, France [2] Institut National de la Santé et de la Recherche Médicale, Lille, France [3] Centre National de la Recherche Scientifique, Lille, France [4] Univ Lille Nord de France, Lille, France.
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Fougeron
1] University of Orléans, Orléans, France [2] CNRS Molecular Immunology and Embryology UMR 6218, Institut de Transgenose, Orléans, France.
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Janot
Imperial College of London, National Heart and Lung Institute, London, UK.
A
A
Didierlaurent
1] Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, Lille, France [2] Institut National de la Santé et de la Recherche Médicale, Lille, France [3] Centre National de la Recherche Scientifique, Lille, France [4] Univ Lille Nord de France, Lille, France.
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Cayet
1] Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, Lille, France [2] Institut National de la Santé et de la Recherche Médicale, Lille, France [3] Centre National de la Recherche Scientifique, Lille, France [4] Univ Lille Nord de France, Lille, France.
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Tabareau
Universidad Nacional de La Plata, Laboratorio de Investigaciones en el Sistema Inmune, Facultad de Ciencias Exactas, La Plata, Argentina.
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Rumbo
1] Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, Lille, France [2] Institut National de la Santé et de la Recherche Médicale, Lille, France [3] Centre National de la Recherche Scientifique, Lille, France [4] Univ Lille Nord de France, Lille, France.
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Corvo-Chamaillard
1] Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, Lille, France [2] Institut National de la Santé et de la Recherche Médicale, Lille, France [3] Centre National de la Recherche Scientifique, Lille, France [4] Univ Lille Nord de France, Lille, France.
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Boulenouar
Jefferiss Trust Research Laboratories, Imperial College, London, UK.
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Jeffs
1] Department of Medical Protein Research, VIB, Ghent, Belgium [2] Department of Biochemistry, Ghent University, Ghent, Belgium.
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Vande Walle
1] Department of Medical Protein Research, VIB, Ghent, Belgium [2] Department of Biochemistry, Ghent University, Ghent, Belgium.
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Lamkanfi
1] Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, Lille, France [2] Institut National de la Santé et de la Recherche Médicale, Lille, France [3] Centre National de la Recherche Scientifique, Lille, France [4] Univ Lille Nord de France, Lille, France.
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Y
Lemoine
1] University of Orléans, Orléans, France [2] CNRS Molecular Immunology and Embryology UMR 6218, Institut de Transgenose, Orléans, France.
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Erard
1] Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, Lille, France [2] Institut National de la Santé et de la Recherche Médicale, Lille, France [3] Centre National de la Recherche Scientifique, Lille, France [4] Univ Lille Nord de France, Lille, France.
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Hot
1] Imperial College of London, National Heart and Lung Institute, London, UK [2] Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, UK.
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Hussell
1] University of Orléans, Orléans, France [2] CNRS Molecular Immunology and Embryology UMR 6218, Institut de Transgenose, Orléans, France.
B
B
Ryffel
Institut des Hautes Études Scientifiques and Centre National de la Recherche Scientifique, Bures-sur-Yvette, France.
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AG
Benecke
1] Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, Lille, France [2] Institut National de la Santé et de la Recherche Médicale, Lille, France [3] Centre National de la Recherche Scientifique, Lille, France [4] Univ Lille Nord de France, Lille, France.
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Sirard
D056704:Adaptive Immunity; D000281:Administration, Intranasal; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D005408:Flagellin / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D018928:Immunity, Mucosal / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D059748:Proteolysis; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000378:metabolism*
D051198:Toll-Like Receptor 5; D005408:Flagellin