A common E2F-1 and p73 pathway mediates cell death induced by TCR activation

Strong stimulation of the T-cell receptor (TCR) on cycling peripheral T cel ls causes their apoptosis by a process called TCR-activation-induced cell d eath (TCR-AICD)(1-3). TCR-AICD occurs from a late G1 phase cell-cycle check point(4) independently of the 'tumour suppressor' protein p53 (refs 5, 6). Disruption of the gene for the E2F-1 transcription factor(7,8), an inducer of apoptosis(9-11), causes significant increases in T-cell number and sple nomegaly(12-15). Here we show that T cells undergoing TCR-AICD induce the p 53-related gene p73, another mediator of apoptosis(16), which is hypermethy lated in lymphomas(17,18). Introducing a dominant-negative E2F-1 protein or a dominant-negative p73 protein into T cells protects them from TCR-mediat ed apoptosis, whereas dominant-negative E2F-2, E2F-4 or p53 does not. Furth ermore, E2F-1-null or p73-null primary T cells do not undergo TCR-mediated apoptosis either. We conclude that TCR-AICD occurs from a late G1 cell-cycl e checkpoint that is dependent on both E2F-1 and p73 activities. These obse rvations indicate that, unlike p53, p73 serves to integrate receptor-mediat ed apoptotic stimuli.