Phosphatidylinositol 3-kinase-dependent and -independent cytolytic effector functions.
Two distinct forms of short-term cytolysis have been described for CD8+ CTLs, the perforin/granzyme- and Fas ligand/Fas (CD95 ligand (CD95L)/CD95)-mediated pathways. However, the difference in signal transduction events leading to these cytolytic mechanisms remains unclear. We used wortmannin, an irreversible antagonist of phosphatidylinositol 3-kinase (PI3-K) activity, to investigate the role of PI3-K in influenza-specific CD8+ CTL cytolytic effector function. We found that the addition of wortmannin at concentrations as low as 1 nM significantly inhibited both the Ag/MHC-induced cytolysis of CD95- target cells and serine esterase release. In strong contrast, W did not inhibit the Ag/MHC-induced CD95L expression or the CD95L/CD95-mediated cytolysis of CD95+ targets. A combination of wortmannin and blocking mAb against CD95L inhibited the cytolysis of CD95+ targets, indicating that the wortmannin-independent cytolysis was due to CD95L/CD95 mediated cytolysis. These findings suggest a differential role for PI3-K in mediating cytolysis and, thus far, the earliest difference between perforin/granzyme- and CD95L/CD95-dependent cytolysis. Our data reinforce the idea of a TCR with modular signal transduction pathways that can be triggered or inhibited selectively, resulting in differential effector function.
Fuller
C L
CL
Department of Microbiology, Beirne B. Carter Center for Immunology Research, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Ravichandran
K S
KS
Braciale
V L
VL
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000956:Antigens, Viral / Q000502:physiology; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D009980:Influenza A virus / Q000276:immunology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D000077191:Wortmannin; D019014:fas Receptor / Q000502:physiology
D000730:Androstadienes; D000956:Antigens, Viral; D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077191:Wortmannin; D019014:fas Receptor; C505658:Fasl protein, mouse