title: Reversal of airway hyperresponsiveness by induction of airway mucosal CD4+CD25+ regulatory T cells.
abstract: An important feature of atopic asthma is the T cell-driven late phase reaction involving transient bronchoconstriction followed by development of airways hyperresponsiveness (AHR). Using a unique rat asthma model we recently showed that the onset and duration of the aeroallergen-induced airway mucosal T cell activation response in sensitized rats is determined by the kinetics of functional maturation of resident airway mucosal dendritic cells (AMDCs) mediated by cognate interactions with CD4+ T helper memory cells. The study below extends these investigations to chronic aeroallergen exposure. We demonstrate that prevention of ensuing cycles of T cell activation and resultant AHR during chronic exposure of sensitized rats to allergen aerosols is mediated by CD4+CD25+Foxp3+LAG3+ CTLA+CD45RC+ T cells which appear in the airway mucosa and regional lymph nodes within 24 h of initiation of exposure, and inhibit subsequent Th-mediated upregulation of AMDC functions. These cells exhibit potent regulatory T (T reg) cell activity in both in vivo and ex vivo assay systems. The maintenance of protective T reg activity is absolutely dependent on continuing allergen stimulation, as interruption of exposure leads to waning of T reg activity and reemergence of sensitivity to aeroallergen exposure manifesting as AMDC/T cell upregulation and resurgence of T helper 2 cytokine expression, airways eosinophilia, and AHR.
authors.affiliation: Telethon Institute for Child Health Research, and Centre for Child Health Research, Faculty of Medicine and Dentistry, The University of Western Australia, Perth, Western Australia 6008.
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Strickland
authors.forename: Philip A
authors.initials: PA
authors.lastname: Stumbles
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Zosky
authors.forename: Lily S
authors.initials: LS
authors.lastname: Subrata
authors.forename: Jenny A
authors.initials: JA
authors.lastname: Thomas
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
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005260:Female; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051381:Rats; D020545:Respiratory Mucosa / Q000276:immunology* / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*