Regulation of Fas(Apo-1/CD95)- and perforin-mediated lytic pathways of primary cytotoxic T lymphocytes by the protooncogene bcl-2.
Cytotoxic T cells (CTL) induce cell death of their target cells either by the surface interaction between Fas ligand and Fas or by the release of perforin and granzymes. Both lytic pathways induce apoptosis yet it is not known whether identical or distinct apoptotic pathways are activated. The protooncogene bcl-2 is known to protect various hematopoietic cells from apoptosis induced by diverse agents. Here we show that overexpression of the Bcl-2 protein in the murine mastocytoma line P815 or in concanavalin A-activated splenocytes suppresses apoptotic cell death induced by allospecific primary cytotoxic T lymphocytes (CTL) in which only the Fas lytic pathway was functional. Bcl-2 also reduced target cell killing induced by CTL whose lytic activity was dependent on the perforin/granzyme pathway only. These data provide evidence that, in the target cells studied here, both perforin/granzyme and Fas apoptotic pathways are modulated by Bcl-2 and suggest that these two pathways converge at a step prior to Bcl-2 inhibition.
Schröter
M
M
Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Lowin
B
B
Borner
C
C
Tschopp
J
J
D000818:Animals; D001483:Base Sequence; D003602:Cytotoxicity, Immunologic; D012515:Mast-Cell Sarcoma / Q000235:genetics; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2; D011519:Proto-Oncogenes / Q000276:immunology* / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000187:drug effects / Q000494:pharmacology
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D054353:Perforin