A role for perforin in activation-induced cell death.
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.
Spaner
D
D
Department of Medical Biophysics, University of Toronto and Ontario Cancer Institute, Canada. spanerd@srcl.sunnybrook.utoronto.ca
Raju
K
K
Radvanyi
L
L
Lin
Y
Y
Miller
R G
RG
D000818:Animals; D016923:Cell Death; D007376:Interleukin-2 / Q000502:physiology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013601:T-Lymphocytes / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000502:physiology
D007376:Interleukin-2; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D054353:Perforin