A ROLE FOR PERFORIN IN ACTIVATION-INDUCED CELL-DEATH

The granule exocytosis pathway of T cell cytotoxicity is absent in mic e whose perforin gene has been ablated by targeted mutagenesis. The ab ility of activated naive T cells to undergo apoptosis in vitro followi ng reaggregation of the TCR complex with anti-TCR mAbs via a Fas-indep endent pathway was found to be defective in the absence of perforin. P rotection from death was most marked in CD8(+) T cells. In wild-type c ells, perforin was expressed at the same time that apoptosis occurred, and blockade of perforin expression by either incubation with perfori n antisense oligonucleotides or with anti-IL-2 Abs resulted in increas ed viability of activated T cells. The role of perforin was not via pe rforin-dependent fratricidal killing. The results suggest a model in w hich perforin acts internally to cause a form of activation-induced T cell death distinct from that caused by members of the TNFR superfamil y.