Granzyme A initiates an alternative pathway for granule-mediated apoptosis

Granzyme (gzm) B-deficient cytotoxic lymphocytes (CTL) have a severe defect in the rapid induction of target cell apoptosis that is almost completely corrected by prolonged incubation of the CTL effecters and their targets. W e show in this report that perforin-dependent, gzmB-independent cytotoxicit y is caused by gzmA (or tightly linked genes). CTL deficient for gzmA and g zmB retain normal perforin function, but these CTL have a cytotoxic defect in vivo that is as severe as perforin-deficient CTL. Collectively, these re sults suggest that perforin provides target cell access and/or trafficking signals for the gzms, and that the gzms themselves deliver the lethal hits. The gzmA pathway appears to function independently from gzmB and may there fore provide a critical "back-up" system when gzmB is inhibited in the targ et cell.