Inhibition of thymocyte apoptosis and negative antigenic selection in bcl-2 transgenic mice.
The bcl-2 gene, which is overexpressed in human follicular B-cell lymphomas, has been found to extend cellular lifespan through inhibition of apoptosis, or programmed cell death. However, the physiological role of the Bcl-2 protein in lymphocyte development is unclear. We have established a transgenic mouse line that expresses high levels of the Bcl-2 protein in both cortical and medullary thymocytes, disrupting the normal pattern of expression of this gene. We found that in these mice, immature thymocytes became resistant to apoptosis mediated by corticosteroids and calcium ionophores. Untreated thymocytes also exhibited a survival advantage in suspension cultures compared with controls. In addition, overexpression of bcl-2 enabled a proportion of thymocytes and peripheral T cells to escape the process of clonal deletion, which normally eliminates self-reactive T cells during thymocyte maturation. These findings implicate the Bcl-2 protein in regulating the lifespan of maturing thymocytes and in the antigenic-selection process.
Siegel
R M
RM
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104.
Katsumata
M
M
Miyashita
T
T
Louie
D C
DC
Greene
M I
MI
Reed
J C
JC
D000818:Animals; D000941:Antigens / Q000276:immunology*; D016923:Cell Death; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D003433:Crosses, Genetic; D003907:Dexamethasone / Q000494:pharmacology; D004742:Enhancer Elements, Genetic; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D016130:Immunophenotyping; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D011519:Proto-Oncogenes; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*
D000941:Antigens; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D003907:Dexamethasone