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Loss of pro-apoptotic Bim promotes accumulation of pulmonary T lymphocytes and enhances allergen-induced goblet cell metaplasia

¹Lovelace Respiratory Research Institute, Albuquerque, New Mexico; and ²The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

Submitted 7 December 2005 ; accepted in final form 25 May 2006

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 days of allergen exposure. The numbers of pulmonary CD4⁺8^–, CD4^–8⁺, and T cells were significantly higher in naive and allergen-challenged bim^–/– mice compared with wild-type (WT) littermates. When activated, pulmonary bim^–/– T cells produced increased levels of IFN compared with bim^+/+ T cells. No differences were noted in the total numbers of epithelial cells per millimeter of basal lamina between bim^+/+ and bim^–/– mice, and the rate of resolution over 15 days of exposure was similar in both groups of mice. However, GCM was significantly enhanced and expression of IL-13R2 was reduced in bim^–/– mice compared with WT mice at 4 days. Furthermore, treatment of bronchiolar explant cultures with increasing IFN levels reduced immunostaining for IL-13R2. Collectively, these studies suggest that, during prolonged exposure to allergen, Bim plays no role in the resolution of GCM, but increased IFN levels in bim^–/– mice may be responsible for reduced expression of IL-13R2 and enhanced GCM despite similar levels of IL-13 in bim^+/+ and bim^–/– mice.

asthma; interferon- and tolerance; apoptosis; IL-13R2; mucous cell metaplasia

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