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* Centre for Asthma and Respiratory Diseases, School of Biomedical Sciences, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Callaghan, Australia;
Division of Molecular Biosciences, John Curtin School of Medical Research, Australian National University, Canberra, Australia; and
Cytokine Receptor Laboratory, Department of Human Immunology, Institute of Medical and Veterinary Science, Hanson Institute, Adelaide, Australia
The eosinophil is a central effector cell in allergic asthma. Differentiation and function of eosinophils are regulated by the CD4 Th2 cytokines IL-3, IL-5, and GM-CSF, which all signal through a common β receptor subunit (βc). Recent therapeutic approaches targeting IL-5 alone have not ablated tissue accumulation of eosinophils and have had limited effects on disease progression, suggesting important roles for IL-3 and GM-CSF. By using a mouse model of allergic airways inflammation, we show that allergen-induced expansion and accumulation of eosinophils in the lung are abolished in βc-deficient (βc–/–) mice. Moreover, βc deficiency resulted in inhibition of hallmark features of asthma, including airways hypersensitivity, mucus hypersecretion, and production of Ag-specific IgE. Surprisingly, we also identified a critical role for this receptor in regulating type 2 immunity. Th2 cells in the lung of allergen-challenged βc–/– mice were limited in their ability to proliferate, produce cytokines, and migrate to effector sites, which was attributed to reduced numbers of myeloid dendritic cells in the lung compartment. Thus, the βc plays a critical role in allergen-induced eosinophil expansion and infiltration and is pivotal in regulating molecules that promote both early and late phases of allergic inflammation, representing a novel target for therapy.
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 grants from the National Institutes of Health (R01-AI50744-02 to A.F.L.) and the National Health and Medical Research Council of Australia.
2 Address correspondence and reprint requests to Dr. Paul S. Foster, Centre for Asthma and Respiratory Diseases, 5th Floor, David Maddison Building, Corner of King and Watt Streets, Newcastle, New South Wales, 2300, Australia. E-mail address: Paul.Foster{at}newcastle.edu.au
3 Abbreviations used in this paper: AHR, airway hyperreactivity; AM, alveolar macrophage; βc, common β receptor chain; βIL-3, IL-3 β receptor chain; BALF, bronchoalveolar lavage fluid; DC, dendritic cell; mDC, myeloid DC; MSC, mucus-secreting cell; PBLN, peribronchial lymph node; pDC, plasmacytoid DC; WT, wild type.
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