title: Defective aeroallergen surveillance by airway mucosal dendritic cells as a determinant of risk for persistent airways hyper-responsiveness in experimental asthma.
abstract: A hallmark of atopic asthma is development of chronic airways hyper-responsiveness (AHR) that persists in the face of ongoing exposure to perennial aeroallergens. We investigated underlying mechanisms in sensitized rats focusing on a strain expressing the high-allergen-responder phenotype characteristic of human atopic asthmatics, and find that their high susceptibility to aeroallergen-induced persistent AHR is associated with deficiencies in the immunoregulatory and mucosal trafficking properties of inducible T-regulatory cells (iTregs). Counterintuitively, AHR susceptibility was inversely related to aeroallergen exposure level, high exposures conferring protection. We demonstrate that underlying this AHR-susceptible phenotype is reduced capacity of airway mucosal dendritic cells (AMDCs) for allergen sampling in vivo; this defect is microenvironmentally acquired, as allergen uptake by these cells in vitro is normal. Moreover, intranasal transfer of in vitro aeroallergen-loaded AMDC from naïve animals into AHR-susceptible animals during prolonged aerosol challenge markedly boosts subsequent accumulation of iTregs in the airway mucosa and rapidly resolves their chronic AHR, suggesting that compromised antigen surveillance by AMDC resulting in defective functional programming of iTreg may be causally related to AHR susceptibility.
authors.affiliation: Division of Cell Biology, Telethon Institute for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia. deborahs@ichr.uwa.edu.au
authors.forename: D H
authors.initials: DH
authors.lastname: Strickland
authors.forename: J A
authors.initials: JA
authors.lastname: Thomas
authors.forename: D
authors.initials: D
authors.lastname: Mok
authors.forename: F
authors.initials: F
authors.lastname: Blank
authors.forename: K L
authors.initials: KL
authors.lastname: McKenna
authors.forename: A N
authors.initials: AN
authors.lastname: Larcombe
authors.forename: P D
authors.initials: PD
authors.lastname: Sly
authors.forename: P G
authors.initials: PG
authors.lastname: Holt
mesh_terms: D019264:Adoptive Transfer; D000485:Allergens / Q000276:immunology*; D000818:Animals; D017951:Antigen Presentation; D001249:Asthma / Q000276:immunology* / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D006801:Humans; D007157:Immunologic Surveillance; D056747:Immunomodulation; D010047:Ovalbumin / Q000276:immunology; D051381:Rats; D011914:Rats, Inbred BN; D020545:Respiratory Mucosa / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000485:Allergens; D010047:Ovalbumin