Stimulation of a T helper cell class 2 clone with immobilized anti-T cell receptor antibody activates a Ca2+ and protein kinase C-independent lethal signaling pathway.
Stimulation of an IL-2-dependent variant of the Th2 clone D10.G4.1 with antibodies (Ab) specific for CD3 epsilon or the TCR-alpha beta caused either activation of the clone to secrete the autocrine lymphokine IL-4, or lethal activation in which the cells secreted high quantities of IL-4 but then died within 2 days. High densities of immobilized Ab delivered a lethal signal, whereas soluble forms of Ab and low densities of immobilized Ab caused productive activation in which cell viability was maintained. Lethal activation was not prevented by accessory cells, IL-1, or IL-2, or by co-cross-linkage of CD4 and TCR. The lethal signal was not mediated via a soluble effector from the activated cells. Lethal signaling was insensitive to cyclosporin A or dexamethasone. Studies with activators of protein kinase C (PKC), and PKC inhibitors, indicated that direct activation of PKC was not sufficient for lethal signaling. Nor could direct activation of PKC prevent the lethal signal. The lethal signal was not caused by Ca2+ mobilization mediated by Ca2+ ionophore and there was no evidence of apoptosis. The combination of a PKC activator and Ca2+ ionophore was not lethal, thereby showing that together these events are not sufficient. That these signal pathways were not necessary for lethal activation was evidenced by their inability to lower the density of immobilized anti-CD3 required to cause cell death. In this model, ligation of the TCR specifically activates a Ca2+/PKC-independent lethal signal transduction pathway.
Cherwinski
H M
HM
Department of Molecular Immunology, Syntex Research, Palo Alto, CA 94304.
Semenuk
G T
GT
Ransom
J T
JT
D000818:Animals; D015704:CD4 Antigens / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival; D002999:Clone Cells; D016572:Cyclosporine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D011493:Protein Kinase C / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D015704:CD4 Antigens; D007375:Interleukin-1; D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4; D003907:Dexamethasone; D016572:Cyclosporine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium