Submitted on December 16, 2007
Accepted on November 12, 2008
Attenuation of allergen-induced Airway Hyperresponsiveness is mediated by airway regulatory T cells
Jennifer T Burchell1, Matthew E Wikstrom2, Phillip A Stumbles3, Peter D. Sly1, and Debra Jane Turner1*
1 Division of Clinical Sciences, Telethon Institute for Child Health Research, Perth, Western Australia, Australia; Centre for Child Health Research, University of Western Australia, Perth, Western Australia, Australia
2 Division of Cell Biology, Telethon Institute for Child Health Research, Perth, Western Australia, Australia; Centre for Child Health Research, University of Western Australia, Perth, Western Australia, Australia
3 Division of Cell Biology, Telethon Institute for Child Health Research, P.O. Box 855, Perth, 6872, Australia; Centre for Child Health Research, University of Western Australia, Perth, Western Australia, Australia; Health Sciences, Murdoch University, Perth, Western Australia, Australia
* To whom correspondence should be addressed. E-mail: debrat{at}ichr.uwa.edu.au.
Understanding the mechanisms involved in respiratory tolerance to inhaled allergens could potentially result in improved therapies for asthma and allergic diseases. Airway hyperresponsiveness (AHR) is a major feature of allergic asthma, thus the aim of the current study was to investigate mechanisms underlying suppression of allergen-induced AHR during chronic allergen exposure. Adult BALB/c mice were systemically sensitised with Ovalbumin (OVA) in adjuvant then challenged with a single, 3 weeks or 6 weeks of OVA-aerosols. Airway and parenchymal responses to inhaled Methacholine (MCh), inflammatory cell counts, cytokines, OVA-specific IgE and IgG1, parenchymal histology and numbers of airway CD4+69+ activated and CD4+25+FoxP3+ regulatory T (Treg) cells were assessed 24 hours after the final aerosol. Single OVA challenge resulted in AHR, eosinophilia, increased serum OVA-specific IgE and Th2 cytokines in bronchoalveolar lavage (BAL) but no difference in numbers of Treg compared to control mice. Three weeks of OVA challenges resulted in suppression of AHR and greater numbers of airway Treg cells and increased TGF
1 compared to control mice, despite the presence of increased eosinophilia, OVA-specific IgE and IgG1, and airway remodelling. Six weeks of OVA challenges restored AHR while airway Treg numbers, TGF1, BAL eosinophilia and Th2 cytokines returned to control levels. Partial in vivo depletion or adoptive transfer of Treg cells restored or inhibited AHR respectively but did not affect TGF1 or Th2 cytokine production. In conclusion, AHR suppression is mediated by airway Treg cells and potentially via a paracrine induction of TGF1 in the airways.
