International Immunology Advance Access originally published online on July 6, 2005
International Immunology 2005 17(8):993-1007; doi:10.1093/intimm/dxh281
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Asthmatic changes in mice lacking T-bet are mediated by IL-13
1 Laboratory of Cellular and Molecular Immunology of the Lung and 2 Pathology Department, University of Mainz, Mainz, Germany
3 Department of Immunology and Infections Diseases, Harvard School of Public Health and 4 Department of Medicine, Harvard Medical School, Boston, MA, USA
Correspondence to: L. H. Glimcher; E-mail: lglimche{at}hsph.harvard.edu or S. Finotto; E-mail: finotto{at}mail.uni-mainz.de
Mice with a targeted deletion of the T-bet gene exhibit spontaneous airway hyperresponsiveness (AHR), airway inflammation, enhanced recovery of Th2 cytokines from bronchoalveolar lavage fluid, sub-epithelial collagen deposition and myofibroblast transformation. Here we analyze the mechanisms responsible for the chronic airway remodeling observed in these mice. CD4+ T cells isolated from the lung of T-bet-deficient mice were spontaneously activated CD44highCD69high memory T cells, with a typical Th2 cytokine profile. Neutralization of IL-13 but not IL-4 resulted in amelioration of AHR in airways of mice lacking T-bet. IL-13 blockade also led to reduced eosinophilia and decreased vimentin, transforming growth factor beta (TGF-ß) and alpha smooth muscle actin (
SMA) levels. T-bet–/– lung fibroblasts proliferated very rapidly and released increased amounts of TGF-ß. Interestingly, neutralization of TGF-ß ameliorated aspects of the chronic airway remodeling phenotype but did not reduce AHR. These data highlight a T-bet-directed function for IL-13 in controlling lung remodeling that is both dependent on and independent of its interaction with TGF-ß in the asthmatic airway.
Keywords: airway remodeling, asthma, cytokines, T-bet, TGF-ß
Transmitting editor: A. Singer
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