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The Journal of Immunology, 1998, 160: 2655-2664.
Copyright © 1998 by The American Association of Immunologists

A Role for Perforin in Activation-Induced Cell Death1

David Spaner2,*,{dagger}, Kaliannan Raju*, Laszlo Radvanyi*, Yunping Lin* and Richard G. Miller*

* Department of Medical Biophysics, University of Toronto and Ontario Cancer Institute, Toronto, Canada; and {dagger} Division of Cancer Biology, Sunnybrook Research Institute, Sunnybrook Hospital, Toronto, Canada

The granule exocytosis pathway of T cell cytotoxicity is absent in mice whose perforin gene has been ablated by targeted mutagenesis. The ability of activated naive T cells to undergo apoptosis in vitro following reaggregation of the TCR complex with anti-TCR mAbs via a Fas-independent pathway was found to be defective in the absence of perforin. Protection from death was most marked in CD8+ T cells. In wild-type cells, perforin was expressed at the same time that apoptosis occurred, and blockade of perforin expression by either incubation with perforin antisense oligonucleotides or with anti-IL-2 Abs resulted in increased viability of activated T cells. The role of perforin was not via perforin-dependent fratricidal killing. The results suggest a model in which perforin acts internally to cause a form of activation-induced T cell death distinct from that caused by members of the TNFR superfamily.




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