title: Indirect Toll-like receptor 5-mediated activation of conventional dendritic cells promotes the mucosal adjuvant activity of flagellin in the respiratory tract.
abstract: The Toll-like receptor 5 (TLR5) agonist flagellin is an effective adjuvant for vaccination. Recently, we demonstrated that the adaptive responses stimulated by intranasal administration of flagellin and antigen were linked to TLR5 signaling in the lung epithelium. The present study sought to identify the antigen presenting cells involved in this adjuvant activity. We first found that the lung dendritic cells captured antigen very efficiently in a process independent of TLR5. However, TLR5-mediated signaling specifically enhanced the maturation of lung dendritic cells. Afterward, the number of antigen-bound and activated conventional dendritic cells (both CD11b(+) and CD103(+)) increased in the mediastinal lymph nodes in contrast to monocyte-derived dendritic cells. These data suggested that flagellin-activated lung conventional dendritic cells migrate to the draining lymph nodes. The lymph node dendritic cells, in particular CD11b(+) cells, were essential for induction of CD4 T-cell response. Lastly, neutrophils and monocytes were recruited into the lungs by flagellin administration but did not contribute to the adjuvant activity. The functional activation of conventional dendritic cells was independent of direct TLR5 signaling, thereby supporting the contribution of maturation signals produced by flagellin-stimulated airway epithelium. In conclusion, our results demonstrated that indirect TLR5-dependent stimulation of airway conventional dendritic cells is essential to flagellin's mucosal adjuvant activity.
authors.affiliation: Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, F-59019 Lille, France; Institut National de la Santé et de la Recherche Médicale, U1019, F-59019 Lille, France; Centre National de la Recherche Scientifique, UMR 8204, F-59019 Lille, France; Université de Lille, F-59000 Lille, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Fougeron
authors.affiliation: Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, F-59019 Lille, France; Institut National de la Santé et de la Recherche Médicale, U1019, F-59019 Lille, France; Centre National de la Recherche Scientifique, UMR 8204, F-59019 Lille, France; Université de Lille, F-59000 Lille, France.
authors.forename: Laurye
authors.initials: L
authors.lastname: Van Maele
authors.affiliation: Institute of Microbiology, Eidgenössische Technische Hochschule Zürich, CH-8093 Zürich, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Songhet
authors.affiliation: Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, F-59019 Lille, France; Institut National de la Santé et de la Recherche Médicale, U1019, F-59019 Lille, France; Centre National de la Recherche Scientifique, UMR 8204, F-59019 Lille, France; Université de Lille, F-59000 Lille, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Cayet
authors.affiliation: Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, F-59019 Lille, France; Institut National de la Santé et de la Recherche Médicale, U1019, F-59019 Lille, France; Centre National de la Recherche Scientifique, UMR 8204, F-59019 Lille, France; Université de Lille, F-59000 Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Hot
authors.affiliation: Department of Molecular Cell Biology, VU Medical Center, NL-1007 Amsterdam, The Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.affiliation: Max Planck Institute for Infection Biology, D-10117 Berlin, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Mollenkopf
authors.affiliation: Institute of Microbiology, Eidgenössische Technische Hochschule Zürich, CH-8093 Zürich, Switzerland.
authors.forename: Wolf-Dietrich
authors.initials: WD
authors.lastname: Hardt
authors.affiliation: Institut des Hautes Études Scientifiques and Centre National de la Recherche Scientifique, F-91440 Bures-sur-Yvette, France.
authors.forename: Arndt G
authors.initials: AG
authors.lastname: Benecke
authors.affiliation: Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, F-59019 Lille, France; Institut National de la Santé et de la Recherche Médicale, U1019, F-59019 Lille, France; Centre National de la Recherche Scientifique, UMR 8204, F-59019 Lille, France; Université de Lille, F-59000 Lille, France. Electronic address: jean-claude.sirard@inserm.fr.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Sirard
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism*; D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D005408:Flagellin / Q000378:metabolism*; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D020545:Respiratory Mucosa / Q000276:immunology*; D012137:Respiratory System / Q000276:immunology*; D051198:Toll-Like Receptor 5 / Q000819:agonists*
chemical_list: D000276:Adjuvants, Immunologic; D051198:Toll-Like Receptor 5; D005408:Flagellin
keywords: Dendritic cell; Innate immunity; Interleukin 1; Mucosal immunity; Toll-like receptor