Regulation of the serine-base exchange enzyme system by CD4: effects of monoclonal antibodies, jacalin, interleukin 16 and the HIV membrane protein gp120.
Phosphatidylserine (PtdSer) is synthesized by an exchange of the polar head group of phospholipids for a serine residue. The enzyme responsible for this reaction, the serine-base exchange enzyme system (serine-BEES) is inhibited during lymphocyte activation. We show here that triggering the CD4 cell surface molecule in several CD4+ T-cell lines regulates the serine-BEES activity, thus resulting in marked changes in PtdSer synthesis. CD4 ligands able to generate an activating signal in T-cells such as the lectin jacalin, down-regulate the synthesis of PtdSer. In contrast, monoclonal antibodies (mAbs) directed against the CD4 molecule, such as IOT4 and IOT4a, which have previously been described as generating an inhibitory signal to T-cells, induced an up-regulation of the serine-BEES and impaired CD3-induced inhibition of PtdSer synthesis. Similarly, the HIV-gp120 envelope glycoprotein, in both soluble and cross-linked forms, induces an increase in PtdSer synthesis. The protein tyrosine kinase p56lck participates in the regulation of serine-BEES activity because the effect of CD4 mAbs was additive to that of amino-hydroxyflavone, an inhibitor of p56lck. Also, CD4 mAbs were inactive in J Cam 1.6 cells or when the CD3 signals were bypassed by using thapsigargin. These results demonstrate that the CD4 surface molecule can transmit both activating and inhibiting intracellular signals depending on the CD4 ligand used. We suggest that PtdSer synthesis would be one of the intracellular signals that could explain the opposite effects of different CD4 ligands on T-cells.
Dumaurier
M J
MJ
INSERM U343, Hôpital de l'Archet, BP 79, 06202 Nice Cedex 03, France.
Pelassy
C
C
Breittmayer
J P
JP
Aussel
C
C
D000911:Antibodies, Monoclonal / Q000276:immunology; D017252:CD3 Complex / Q000502:physiology; D015704:CD4 Antigens / Q000276:immunology / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D019833:Genistein / Q000031:analogs & derivatives; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D006801:Humans; D019410:Interleukin-16 / Q000494:pharmacology*; D019169:Jurkat Cells; D007700:Kinetics; D037102:Lectins / Q000494:pharmacology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors; D019884:Nitrogenous Group Transferases / Q000378:metabolism*; D010718:Phosphatidylserines / Q000096:biosynthesis*; D010743:Phospholipids / Q000378:metabolism; D037121:Plant Lectins; D011994:Recombinant Proteins / Q000494:pharmacology; D012694:Serine / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D015704:CD4 Antigens; D004791:Enzyme Inhibitors; D005419:Flavonoids; D015699:HIV Envelope Protein gp120; D019410:Interleukin-16; D037102:Lectins; D010718:Phosphatidylserines; D010743:Phospholipids; D037121:Plant Lectins; D011994:Recombinant Proteins; C043696:jacalin; C067397:4'-amino-6-hydroxyflavone; D012694:Serine; D019284:Thapsigargin; D019833:Genistein; D019884:Nitrogenous Group Transferases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); C022370:phospholipid serine base exchange enzyme