The Journal of Experimental Medicine
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Published online 6 November 2006 doi:10.1084/jem.20060155
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 12, 2649-2660
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ARTICLE

 Reversal of airway hyperresponsiveness by induction of airway mucosal CD4+CD25+ regulatory T cells

Deborah H. Strickland, Philip A. Stumbles, Graeme R. Zosky, Lily S. Subrata, Jenny A. Thomas, Debra J. Turner, Peter D. Sly, and Patrick G. Holt

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

CORRESPONDENCE P.G. Holt: patrick{at}ichr.uwa.edu.au

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.

Abbreviations used: AHR, airways hyperresponsiveness; AMDC, airway mucosal dendritic cell; CPM, counts per minute; DLN, draining lymph node; LPR, late phase reaction; MCh, methacholine; T reg cell, T regulatory cell.

P.A. Stumbles's present address is Division of Health Sciences, Murdoch University, South Street, Murdoch, Western Australia, 6150.


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