title: Inhaled house dust programs pulmonary dendritic cells to promote type 2 T-cell responses by an indirect mechanism.
abstract: The induction of allergen-specific T helper 2 (Th2) cells by lung dendritic cells (DCs) is a critical step in allergic asthma development. Airway delivery of purified allergens or microbial products can promote Th2 priming by lung DCs, but how environmentally relevant quantities and combinations of these factors affect lung DC function is unclear. Here, we investigated the ability of house dust extract (HDE), which contains a mixture of environmental adjuvants, to prime Th2 responses against an innocuous inhaled antigen. Inhalational exposure to HDE conditioned lung conventional DCs, but not monocyte-derived DCs, to induce antigen-specific Th2 differentiation. Conditioning of DCs by HDE was independent of Toll-like receptor 4 signaling, indicating that environmental endotoxin is dispensable for programming DCs to induce Th2 responses. DCs directly treated with HDE underwent maturation but were poor stimulators of Th2 differentiation. In contrast, DCs treated with bronchoalveolar lavage fluid (BALF) from HDE-exposed mice induced robust Th2 differentiation. DC conditioning by BALF was independent of the proallergic cytokines IL-25, IL-33, and thymic stromal lymphopoietin. BALF treatment of DCs resulted in upregulation of CD80 but low expression of CD40, CD86, and IL-12p40, which was associated with Th2 induction. These findings support a model whereby environmental adjuvants in house dust indirectly program DCs to prime Th2 responses by triggering the release of endogenous soluble factor(s) by airway cells. Identifying these factors could lead to novel therapeutic targets for allergic asthma.
authors.affiliation: Immunity, Inflammation and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina; Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina tmoran@email.unc.edu.
authors.forename: Timothy P
authors.identifier: http://orcid.org/0000-0002-6832-9772
authors.initials: TP
authors.lastname: Moran
authors.affiliation: Immunity, Inflammation and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina;
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakano
authors.affiliation: Immunity, Inflammation and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina;
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Whitehead
authors.affiliation: Immunity, Inflammation and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina;
authors.forename: Seddon Y
authors.initials: SY
authors.lastname: Thomas
authors.affiliation: Immunity, Inflammation and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina;
authors.forename: Donald N
authors.initials: DN
authors.lastname: Cook
authors.affiliation: Immunity, Inflammation and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina;
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakano
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001249:Asthma / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D004391:Dust / Q000276:immunology*; D007378:Interleukins / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D004391:Dust; D007378:Interleukins
keywords: T helper 2 responses; allergic asthma; dendritic cells; environmental allergens; house dust