title: Restricted aeroallergen access to airway mucosal dendritic cells in vivo limits allergen-specific CD4+ T cell proliferation during the induction of inhalation tolerance.
abstract: Chronic innocuous aeroallergen exposure attenuates CD4(+) T cell-mediated airways hyperresponsiveness in mice; however, the mechanism(s) remain unclear. We examined the role of airway mucosal dendritic cell (AMDC) subsets in this process using a multi-OVA aerosol-induced tolerance model in sensitized BALB/c mice. Aeroallergen capture by both CD11b(lo) and CD11b(hi) AMDC and the delivery of OVA to airway draining lymph nodes by CD8α(-) migratory dendritic cells (DC) were decreased in vivo (but not in vitro) when compared with sensitized but nontolerant mice. This was functionally significant, because in vivo proliferation of OVA-specific CD4(+) T cells was suppressed in airway draining lymph nodes of tolerized mice and could be restored by intranasal transfer of OVA-pulsed and activated exogenous DC, indicating a deficiency in Ag presentation by endogenous DC arriving from the airway mucosa. Bone marrow-derived DC Ag-presenting function was suppressed in multi-OVA tolerized mice, and allergen availability to airway APC populations was limited after multi-OVA exposure, as indicated by reduced OVA and dextran uptake by airway interstitial macrophages, with diffusion rather than localization of OVA across the airway mucosal surface. These data indicate that inhalation tolerance limits aeroallergen capture by AMDC subsets through a mechanism of bone marrow suppression of DC precursor function coupled with reduced Ag availability in vivo at the airway mucosa, resulting in limited Ag delivery to lymph nodes and hypoproliferation of allergen-specific CD4(+) T cells.
authors.affiliation: Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Nedlands, Western Australia, Australia.
authors.forename: Vanessa S
authors.initials: VS
authors.lastname: Fear
authors.forename: Jennifer T
authors.initials: JT
authors.lastname: Burchell
authors.forename: Siew Ping
authors.initials: SP
authors.lastname: Lai
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Wikstrom
authors.forename: Fabian
authors.initials: F
authors.lastname: Blank
authors.forename: Christophe
authors.initials: C
authors.lastname: von Garnier
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Turner
authors.forename: Peter D
authors.initials: PD
authors.lastname: Sly
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Holt
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Strickland
authors.forename: Philip A
authors.initials: PA
authors.lastname: Stumbles
mesh_terms: D000280:Administration, Inhalation; D000485:Allergens / Q000008:administration & dosage* / Q000276:immunology / Q000633:toxicity; D000595:Amino Acid Sequence; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000008:administration & dosage* / Q000276:immunology / Q000633:toxicity; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000276:immunology / Q000633:toxicity; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D000485:Allergens; D018984:Epitopes, T-Lymphocyte; C111390:OVA 323-339; D010446:Peptide Fragments; D010047:Ovalbumin