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-media ting cell surface molecule Pas and its ligand, respectively. These mic e develop lymphadenopathy because of an age-related accumulation of no nmalignant CD4(-)CD8(-) T cells in the peripheral lymphoid organs, sug gesting a role for Fas-mediated apoptosis in peripheral T cell homeost asis. However, these accumulating cells are more susceptible to apopto sis ex vivo than peripheral T cells from control mice. To investigate the influence of additional regulatory elements on defects in the Pas- mediated apoptosis pathway, we analyzed the expression of Bcl-2 protei n, a repressor of apoptosis, in T cells of lpr and gld mice. The expre ssion levels of Bcl-2 in peripheral T cells of aged lpr and gld mice w ere significantly reduced when compared with their normal counterparts . Bcl-2 expression decreased with age in peripheral T cells, but not i n 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. Howeve r, all peripheral T cell subsets including CD8(+) cells were susceptib le to glucocorticoid-induced apoptosis, indicating that there is no di rect correlation between the levels of Bcl-2 expression and susceptibi lity to glucocorticoid-induced apoptosis. These studies suggest the pr esence of complex regulatory mechanisms for lymphocyte apoptosis and s urvival.