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Resolution of Der p1-Induced Allergic Airway Inflammation Is Dependent on CD4⁺CD25⁺Foxp3⁺ Regulatory Cells¹

^* Immunobiology Group, Medical Research Council Centre for Inflammation Research, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, United Kingdom

Allergic airway inflammation (AAI) is characterized by airway hyperreactivity, eosinophilia, goblet cell hyperplasia, and elevated serum IgE, however, it is unclear what mediates natural resolution after cessation of allergen exposure. This is important because the outcome of subsequent allergen challenge may depend on the concurrent inflammatory milieu of the lung. Using a murine AAI model, we demonstrate that after exposure to a defined natural protein allergen, Der p1, the response in lungs and draining mediastinal lymph nodes (dMLN) peaks between 4 and 6 days then declines until resolution by 21 days. Der p1-specific serum IgE follows the same pattern while IgG1 continues to increase. Resolution of AAI is mediated by CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs), which appear in lungs and dMLN following airway challenge. Treg depletion exacerbated lung eosinophilia, increased dMLN IL-5 and IL-13 but not IL-10 secretion, and increased allergic Ab responses. Most convincingly, transfer of CD4⁺CD25⁺Foxp3⁺ T cells from Ag naive mice (natural Tregs) abolished AAI, decreased dMLN IL-5 and IL-13 secretion, increased dMLN IL-10 secretion, abolished IgE, and decreased IgG1 Abs. Blocking IL-10 receptor function in vivo did not block the anti-inflammatory function of transferred natural Tregs but did restore dMLN IL-5 and IL-13 secretion. Thus natural Tregs can control AAI in an IL-10 independent manner.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the European Community, the Medical Research Council, and the Norman Salvesen Emphysema Research Trust.

² Current address: Institute of Immunology and Infection Research, Kings’ Buildings, University of Edinburgh, West Mains Road, Edinburgh, Scotland.

³ Current address: Centre for Biophotonics, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow, U.K.

⁴ Address correspondence and reprint requests to Dr. Sarah Howie, Immunobiology Group, Medical Research Council Centre for Inflammation Research, University of Edinburgh, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ Scotland. E-mail address: s.e.m.howie{at}ed.ac.uk

⁵ Abbreviations used in this paper: AAI, allergic airway inflammation; dMLN, draining mediastinal lymph node; i.t., intratracheal; Treg, regulatory T cell; BAL, bronchoalveolar lavage.

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