bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes.
The vast majority of cortical thymocytes die during T cell development while those that survive this selective process accumulate in the medulla. bcl-2, an inner mitochondrial membrane protein, has been shown to inhibit apoptosis in certain cell lines. In the thymus, bcl-2 is regionally localized to the mature T cells of the medulla. To assess the role of bcl-2 in the programmed death of thymocytes, we generated transgenic mice that redirected bcl-2 expression to cortical thymocytes. bcl-2 protected immature CD4+8+ thymocytes from glucocorticoid, radiation, and anti-CD3-induced apoptosis. Moreover, bcl-2 altered T cell maturation, resulting in increased percentages of CD3hi and CD4-8+ thymocytes. Despite this, clonal deletion of T cells that recognize endogenous superantigens still occurred. This transgenic model indicates that multiple death pathways operate within the thymus that can be distinguished by their dependence on bcl-2.
Sentman
C L
CL
Howard Hughes Medical Institute, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
Shutter
J R
JR
Hockenbery
D
D
Kanagawa
O
O
Korsmeyer
S J
SJ
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D000954:Antigens, Surface / Q000032:analysis; D015153:Blotting, Western; D017252:CD3 Complex; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D016923:Cell Death; D002470:Cell Survival; D003907:Dexamethasone / Q000494:pharmacology; D005434:Flow Cytometry; D013006:Growth Hormone / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2; D011519:Proto-Oncogenes; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015183:Restriction Mapping; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology
D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D003907:Dexamethasone; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases