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

Am J Physiol Lung Cell Mol Physiol. 2006 Nov;291(5):L862-70. doi: 10.1152/ajplung.00516.2005. Epub 2006 Jun 16.

Abstract

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 gammadelta 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 IFNgamma 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-13Ralpha2 was reduced in bim(-/-) mice compared with WT mice at 4 days. Furthermore, treatment of bronchiolar explant cultures with increasing IFNgamma levels reduced immunostaining for IL-13Ralpha2. Collectively, these studies suggest that, during prolonged exposure to allergen, Bim plays no role in the resolution of GCM, but increased IFNgamma levels in bim(-/-) mice may be responsible for reduced expression of IL-13Ralpha2 and enhanced GCM despite similar levels of IL-13 in bim(+/+) and bim(-/-) mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allergens / immunology
  • Allergens / pharmacology
  • Animals
  • Apoptosis / immunology*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / immunology*
  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Goblet Cells / immunology
  • Goblet Cells / pathology*
  • Interferon-gamma / metabolism
  • Interleukin-13 Receptor alpha2 Subunit / metabolism
  • Lung / immunology*
  • Lung / pathology*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Membrane Proteins / metabolism
  • Metaplasia / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Ovalbumin / immunology
  • Ovalbumin / pharmacology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology*
  • Proto-Oncogene Proteins / metabolism
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism
  • Th1 Cells / immunology
  • Th1 Cells / pathology
  • Th2 Cells / immunology
  • Th2 Cells / pathology

Substances

  • Allergens
  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Interleukin-13 Receptor alpha2 Subunit
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Receptors, Antigen, T-Cell, gamma-delta
  • Interferon-gamma
  • Ovalbumin