Transmembrane signalling via the T11-dependent pathway of human T cell activation. Evidence for the involvement of 1,2-diacylglycerol and inositol phosphates.
It has previously been shown that some anti-T11 monoclonal antibodies, when used in combination, can activate the human T cell line Jurkat to produce interleukin 2. In this study, we investigate the mechanism by which perturbation of different epitopes of T11 molecules induces activation in Jurkat cells. We show that this activation is initiated by a T11-mediated increase in the concentration of free cytoplasmic calcium ions ([Ca2+]i). The initial increment in [Ca2+]i can occur when extracellular Ca2+ is depleted by EGTA, indicating that Ca2+ from intracellular stores is mobilized. As an early response to extracellular signals provokes a rapid breakdown of a class of lipid known collectively as the phosphoinositides, we measured the levels of phosphatidylinositol bisphosphate (PIP2) which is hydrolyzed to generate inositol triphosphates (IP3), the putative mobilizer of Ca2+ from internal stores and 1,2-diacylglycerol (DAG), the physiological activator of protein kinase C. Monoclonal antibodies directed either against different epitopes of T11 molecules or the T3-Ti antigen receptor complex provoke a rapid breakdown of PIP2, the parental product from which IP3 and DAG derive. In addition antibodies to either the T11 molecules or T3-Ti antigen receptor complex induce marked elevations in IP3, other inositol phosphate compounds and DAG. Taken together, these data indicate that, during T cell activation, due to the perturbation of T11 molecules or T3-Ti antigen receptor complex, membrane phosphoinositides are specifically hydrolyzed. This hydrolysis of phosphoinositides generates two putative second messengers such as IP3 and DAG, which mobilizes Ca2+ from intracellular stores and stimulates protein phosphorylation, respectively.
D000911:Antibodies, Monoclonal / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology*; D001692:Biological Transport; D017252:CD3 Complex; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D004075:Diglycerides / Q000502:physiology*; D004789:Enzyme Activation; D000939:Epitopes / Q000276:immunology; D005989:Glycerides / Q000502:physiology*; D006801:Humans; D007295:Inositol Phosphates / Q000502:physiology*; D007424:Intracellular Fluid / Q000378:metabolism; D008213:Lymphocyte Activation; D008563:Membrane Lipids / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D013403:Sugar Phosphates / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7
C011439:1,2-diacylglycerol; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D017252:CD3 Complex; D004075:Diglycerides; D000939:Epitopes; D005989:Glycerides; D007295:Inositol Phosphates; D008563:Membrane Lipids; D013403:Sugar Phosphates; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D011493:Protein Kinase C; D002118:Calcium