Activation-induced T cell death occurs at G1A phase of the cell cycle

Peripheral negative selection of cycling T cells after TCR engagement and d eletion of activated T cells after an immune response occur by an apoptotic process termed activation-induced cell death (AICD). The cross-linking of TCR-CD3 complex with anti-CD3 monoclonal antibody led to significant apopto tic cell death in peripheral blood T cells. To further define cell cycle re striction points for triggering AICD in T cells, we evaluated the associati on between cell cycle progression and death signal transduction. Simultaneo us DNA/RNA quantification analysis revealed that T cells entering G1A phase of the cell cycle may acquire sensitivity to AICD. The activation of caspa se-3 was induced when T cells entered G1A phase. Up-regulation of cyclin-de pendent kinases (Cdk4 and Cdk6) and cyclin D3 was initiated in TOP-stimulat ed T cells entering G1A phase and expression of these markers steadily incr eased as T cells progressed from G1A into G1B phase. Interestingly, caspase -3 inhibitors could inhibit the up-regulation of these G1 cell cycle regula tors and induce G0/G1A arrest as well as the inhibition of AICD. On the bas is of these results, AICD signals are most likely transduced into TCR-stimu lated T cells entering G1A phase. T cells that fail to progress from G1A in to G1B phase undergo AICD.