CD38 is functionally dependent on the TCR/CD3 complex in human T cells.
One of the functions of surface CD38 is the induction of phosphorylation of discrete cytoplasmic substrates and mobilization of cytoplasmic calcium (Ca2+). The present work addresses the issue of whether the signaling mediated via CD38 operates through an independent pathway or, alternatively, is linked to the TCR/CD3 signaling machinery. We studied the signals elicited through CD38 by the specific agonistic IB4 monoclonal antibody (mAb) by monitoring the levels of cytoplasmic Ca2+ and the induced phenotypic and functional variations in T cell growth. IB4 mAb presented the unique ability to increase cytoplasmic Ca2+ levels, which correlated with the phosphorylation of the PLC-gamma1. These effects were blocked by phorbol 12-myristate 13-acetate (PMA) and were dependent on the presence of a functional TCR/CD3 surface complex, no effects being recorded on mutant Jurkat cells lacking part of the CD3 structures. CD38 signaling appeared to share with TCR/CD3 the ability to induce apoptotic cell death in Jurkat T cells, an event paralleled by specific up-regulation of the Fas molecule and inhibited by cyclosporin A. CD28, a costimulatory molecule, is synergized by increasing CD38-induced apoptotic cell death. The results indicate the existence of a strong functional interdependence between CD38 and TCR/CD3.
Morra
M
M
Department of Genetics, Biology and Medical Chemistry, and Postgraduate School of Clinical Pathology, University of Torino Medical School, Italy.
Zubiaur
M
M
Terhorst
C
C
Sancho
J
J
Malavasi
F
F
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD / Q000502:physiology*; D000943:Antigens, Differentiation / Q000502:physiology*; D017209:Apoptosis; D018106:CD28 Antigens / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002999:Clone Cells; D016572:Cyclosporine / Q000494:pharmacology; D014644:Genetic Variation; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D019169:Jurkat Cells; D007700:Kinetics; D008562:Membrane Glycoproteins; D009244:NAD+ Nucleosidase / Q000502:physiology*; D051966:Phospholipase C gamma; D010766:Phosphorylation; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism; D019014:fas Receptor / Q000502:physiology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D019014:fas Receptor; D016572:Cyclosporine; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium