Calmodulin, a junction between two independent immunosuppressive pathways in Jurkat T cells.
Calmodulin (CaM) antagonists chlorpromazine, trifluoperazine, and N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide HCl inhibit Jurkat T cell activation, as monitored by measuring interleukin-2 synthesis in cells treated by a combination of CD3 monoclonal antibody and phorbol myristate acetate. T cell activation with CD3 monoclonal antibody is accompanied by a decreased synthesis of phosphatidylserine due to the release of Ca2+ from the endoplasmic reticulum. CaM antagonists reverse the phosphatidylserine (PtdSer) inhibition induced by CD3. This increase of PtdSer synthesis was observed in the absence of any modification of CD3-induced Ca2+ movements. Both in intact cells and in an acellular system, the increase of PtdSer synthesis induced by CaM antagonists was abolished in the presence of EGTA, indicating that the base exchange enzyme system responsible for PtdSer synthesis is regulated by CaM provided that Ca2+ is present. By contrast, cyclosporin A that inhibits T cell activation through the interaction of cyclophilin-cyclosporin A complexes with the calmodulin-activated phosphatase, calcineurin, had no effect on PtdSer synthesis. Calmodulin thus appears as a junction leading to at least two independent pathways of regulation of T cell activation, one involving the calcineurin phosphatase and the other the base exchange enzyme system responsible for PtdSer synthesis.
Aussel
C
C
Interaction Cellulaires et Moléculaires en Immunologie, INSERM U 343, Hôpital de l'Archet, Nice, France.
Breittmayer
J P
JP
Pelassy
C
C
Bernard
A
A
D017252:CD3 Complex / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000502:physiology*; D002412:Cations; D002460:Cell Line; D002474:Cell-Free System; D016572:Cyclosporine / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D010718:Phosphatidylserines / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000276:immunology*; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin
D017252:CD3 Complex; D002147:Calmodulin; D002412:Cations; D007376:Interleukin-2; D010718:Phosphatidylserines; D013729:Terpenes; D019284:Thapsigargin; D016572:Cyclosporine