title: Trif-dependent induction of Th17 immunity by lung dendritic cells.
abstract: Allergic asthma is thought to stem largely from maladaptive T helper 2 (Th2) responses to inhaled allergens, which in turn lead to airway eosinophilia and airway hyperresponsiveness (AHR). However, many individuals with asthma have airway inflammation that is predominantly neutrophilic and resistant to treatment with inhaled glucocorticoids. An improved understanding of the molecular basis of this form of asthma might lead to improved strategies for its treatment. Here, we identify novel roles of the adaptor protein, TRIF (TIR-domain-containing adapter-inducing interferon-β), in neutrophilic responses to inhaled allergens. In different mouse models of asthma, Trif-deficient animals had marked reductions in interleukin (IL)-17, airway neutrophils, and AHR compared with wild-type (WT) mice, whereas airway eosinophils were generally similar in these two strains. Compared with lung dendritic cells (DCs) from WT mice, lung DCs from Trif-deficient mice displayed impaired lipopolysaccharide (LPS)-induced migration to regional lymph nodes, lower levels of the costimulatory molecule, CD40, and produced smaller amounts of the T helper 17 (Th17)-promoting cytokines, IL-6, and IL-1β. When cultured with allergen-specific, naive T cells, Trif-deficient lung DCs stimulated robust Th2 cell differentiation but very weak Th1 and Th17 cell differentiation. Together, these findings reveal a TRIF-CD40-Th17 axis in the development of IL-17-associated neutrophilic asthma.
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Hsia
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Whitehead
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: S Y
authors.initials: SY
authors.lastname: Thomas
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: K
authors.initials: K
authors.lastname: Nakano
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Gowdy
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Aloor
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: H
authors.initials: H
authors.lastname: Nakano
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: D N
authors.initials: DN
authors.lastname: Cook
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology; D001249:Asthma / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000502:physiology*; D004195:Disease Models, Animal; D004804:Eosinophils / Q000502:physiology*; D006801:Humans; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology*; D052638:Particulate Matter / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D058408:Th1-Th2 Balance; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D039741:Antigens, Dermatophagoides; D019013:CD40 Antigens; D016207:Cytokines; D052638:Particulate Matter; C476286:Ticam1 protein, mouse