It has been documented that caspase-8, a central player in apoptosis, is also crucial for TCR-mediated NF-kappa B activation. However, whether other caspases are also involved this process is unknown. In this report, we showed that in addition to caspase-8, caspase-9 is required for TCR-mediated NF-kappa B activation. Caspase-9 induces activation of PKC-theta, phosphorylation of Bcl10 and NF-kappa B activation in a caspase-3-dependent manner, but it appears that Bcl10 phosphorylation is uncoupled from NF-kappa B activation. Furthermore, caspase-8 lies upstream of caspase-9 during T cell activation. Therefore, TCR ligation elicits a caspase cascade involving caspase-8, caspase-9 and caspase-3 which initiates PKC-theta-dependent pathway leading to NF-kappa B activation and PKC-theta-independent Bcl10 phosphorylation which limits NF-kappa B activity. (C) 2014 Elsevier Inc. All rights reserved.