Age-dependent reduction of Bcl-2 expression in peripheral T cells of lpr and gld mutant mice.
Autoimmune-prone lpr and gld mice carry defects in the apoptosis-mediating cell surface molecule Fas and its ligand, respectively. These mice develop lymphadenopathy because of an age-related accumulation of nonmalignant CD4- CD8- T cells in the peripheral lymphoid organs, suggesting a role for Fas-mediated apoptosis in peripheral T cell homeostasis. However, these accumulating cells are more susceptible to apoptosis ex vivo than peripheral T cells from control mice. To investigate the influence of additional regulatory elements on defects in the Fas-mediated apoptosis pathway, we analyzed the expression of Bcl-2 protein, a repressor of apoptosis, in T cells of lpr and gld mice. The expression levels of Bcl-2 in peripheral T cells of aged lpr and gld mice were significantly reduced when compared with their normal counterparts. Bcl-2 expression decreased with age in peripheral T cells, but not in thymocytes, suggesting that down-regulation of Bcl-2 protein occurs in the periphery. Analysis of T cell subsets indicated that CD4+ and CD4- CD8- T cells expressed significantly reduced levels of Bcl-2, whereas CD8+ cells maintain high levels of Bcl-2 expression. However, all peripheral T cell subsets including CD8+ cells were susceptible to glucocorticoid-induced apoptosis, indicating that there is no direct correlation between the levels of Bcl-2 expression and susceptibility to glucocorticoid-induced apoptosis. These studies suggest the presence of complex regulatory mechanisms for lymphocyte apoptosis and survival.
Tamura
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A
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Yui
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K
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016516:CD4-CD8 Ratio; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005434:Flow Cytometry; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D011518:Proto-Oncogene Proteins / Q000032:analysis* / Q000096:biosynthesis*; D019253:Proto-Oncogene Proteins c-bcl-2; D013601:T-Lymphocytes / Q000737:chemistry*; D013950:Thymus Gland / Q000166:cytology
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D003907:Dexamethasone