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Am J Physiol Lung Cell Mol Physiol (June 16, 2006). doi:10.1152/ajplung.00516.2005
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Submitted on December 7, 2005
Accepted on May 25, 2006

Loss of Pro-apoptotic Bim Promotes Accumulation of Pulmonary T Lymphocytes and Enhances Allergen-Induced Goblet Cell Metaplasia

Joseph Pierce1, Jules Rir-Sima-Ah2, Isaac Estrada2, Julie Wilder3, Andrea Strasser4, and Yohannes Tesfaigzi5*

1 Lovelace Respiratory Research Institute, Alburqueque, New Mexico, United States
2 Asthma and Immunology, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States
3 Lovelace Respiratory Research Institute, Alburquerque, New Mexico, United States
4 The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
5 Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States; The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

* To whom correspondence should be addressed. E-mail: ytesfaig{at}lrri.org.

Immunological tolerance during prolonged exposure to allergen is accompanied by a shift in the lymphocyte content and a reduction of goblet cell metaplasia (GCM). Bim initiates negative selection of autoreactive T and B cells and shut-down of T cell immune responses in vivo. The present study investigated whether Bim plays a role in the resolution of GCM during prolonged exposure to allergen. Loss of Bim increased T lymphocyte numbers in the bronchoalveolar lavage at 4 and 15 d of allergen exposure. The numbers of pulmonary CD4+8-, CD4-8+, and {gamma}{delta} T cells were significantly higher in naive and allergen-challenged bim-/- mice compared to wt littermates. When activated, pulmonary bim-/- T cells produced increased levels of IFN{gamma} compared to bim+/+ T cells. No differences were noted in the total numbers of epithelial cells per mm of basal lamina between bim+/+ and bim-/- mice and the rate of resolution over 15-d exposure was similar in both groups of mice. However, GCM was significantly enhanced and expression of IL-13R{alpha}2 was reduced in bim-/- mice compared to wt mice at 4 d. Furthermore, treatment of bronchiolar explant cultures with increasing IFN{gamma} levels reduced immunostaining for IL-13R{alpha}2. Collectively, these studies suggest that during prolonged exposure to allergen, Bim plays no role in the resolution of GCM but increased IFN{gamma} levels in bim-/- mice may be responsible for reduced expression of IL-13R{alpha}2 and enhanced GCM despite similar levels of IL-13 in bim+/+ and bim-/- mice.




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