Ligation of CD28, which is present on the majority of CD4+T cells, promotes proliferation and immune responses. However, expression of CD28 declines with aging, and apoptosis may contribute to this decline. We have investigated the molecular mechanism underlying the decrease in CD28 expression in Jurkat T cells cultured with FasL. FasL blocks expression of CD28 at the transcriptional level. This correlates with activation of caspase cascades: active caspase-3 can be detected and inhibitors of caspase-3 and caspase-8 increase CD28 promoter activity and CD28 expression. These findings are consistent with the hypothesis that apoptosis plays a key role in the age-related decline of CD28 expression and hence in immunosenescence.