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 cells causes their apoptosis by a process called TCR-activation-induced cell death (TCR-AICD)1,2,3. TCR-AICD occurs from a late G1 phase cell-cycle check point4 independently of the ‘tumour suppressor’ protein p53 (refs 5, 6). Disruption of the gene for the E2F-1 transcription factor7,8, an inducer of apoptosis9,10,11, causes significant increases in T-cell number and splenomegaly12,13,14,15. Here we show that T cells undergoing TCR-AICD induce the p53-related gene p73, another mediator of apoptosis16, which is hypermethylated in lymphomas17,18. Introducing a dominant-negative E2F-1 protein or a dominant-negative p73 protein into T cells protects them from TCR-mediated apoptosis, whereas dominant-negative E2F-2, E2F-4 or p53 does not. Furthermore, 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-cycle checkpoint that is dependent on both E2F-1 and p73 activities. These observations indicate that, unlike p53, p73 serves to integrate receptor-mediated apoptotic stimuli.