Interaction with XIAP prevents full caspase‐3/‐7 activation in proliferating human T lymphocytes

Caspases are essential mediators of cytokine release and apoptosis. Additionally, caspase activity is required for the proliferation of naive T lymphocytes. It remained unclear how proliferating cells are able to cope with the pro‐apoptotic activity especially of effector caspases‐3 and ‐7. Possible reasons might include limited subcellular localization of active caspases or inhibition by endogenous caspase inhibitors. Here, we compared the activation of various caspases in proliferating human T cells with that in apoptotic cells. We show that cleaved caspases‐3/‐7 appear to be widely distributed in apoptotic cells while they are largely confined to the cytoplasm in proliferating cells. Additionally, in proliferating T cells caspase‐3 remains incompletely cleaved, while in apoptotic cells fully mature caspase‐3 is generated. We provide evidence that during T cell proliferation the intracellular caspase inhibitor X‐linked inhibitor‐of‐apoptosis protein (XIAP) interacts with caspases‐3/‐7, thereby blocking their full activation, substrate cleavage, and cell death. The lack of substrate cleavage might also lead to the observed limited subcellular distribution of caspases‐3/‐7. After induction of apoptosis, second mitochondria‐derived activator of caspases/direct inhibitor of apoptosis‐binding protein with low isoelectric point (Smac/DIABLO) is released from mitochondria, resulting in the abrogation of the inhibitory effect of XIAP, full activation of caspases‐3/‐7, and apoptosis.