CD4 ligands inhibit the formation of multifunctional transduction complexes involved in T cell activation.
Ligands binding to the CD4 molecule can inhibit TCR-mediated T cell activation. We have previously reported that transcription factors regulating the expression of the IL-2 gene, NF-AT, NF-kappaB, and AP-1, are targets of this inhibitory effect in an in vitro model using peripheral human CD4+ T cells activated by a CD3 mAb. Two T cell activation pathways involved in the regulation of these transcription factors, calcium flux and the p21ras pathway, were investigated as potential targets. Binding of HIV envelope glycoprotein gp160/gp120 or a CD4 mAb to the CD4+ T cells, prior to TCR/CD3 activation, inhibited the intracellular calcium elevation. This event strongly suggested an inhibition of PLCgamma1 activity. Tyrosine phosphorylation of PLCgamma1, induced by CD3 activation, was not affected, but its association with tyrosine-phosphorylated proteins, including a 62-kDa protein, was disrupted. This PLCgamma1-associated p62 was found to be immunoreactive to p62-Sam68 Abs. The activation-induced phosphorylation of two p21ras effectors, Raf-1 and Erk2, was inhibited by the CD4 ligands, indirectly pointing to inhibition of the p21ras activation pathway. In addition, we demonstrate that TCR activation of normal CD4+ T cells induced the formation of p120GAP and PLCgamma1-containing complexes. These complexes also contain other unidentified proteins. CD4 ligand binding induced a defective formation of these transduction complexes. This may result in inefficient signaling, partially accounting for the inhibitory effects of the CD4 ligands on both p21ras and calcium-activation pathways.
Jabado
N
N
INSERM Unit 429, Necker-Enfants Malades Hospital, Paris, France.
Pallier
A
A
Le Deist
F
F
Bernard
F
F
Fischer
A
A
Hivroz
C
C
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D020690:GTPase-Activating Proteins; D015699:HIV Envelope Protein gp120 / Q000378:metabolism / Q000494:pharmacology*; D019302:HIV Envelope Protein gp160 / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1; D051966:Phospholipase C gamma; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D019908:Proto-Oncogene Proteins c-raf; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020703:ras GTPase-Activating Proteins
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D020690:GTPase-Activating Proteins; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160; D007527:Isoenzymes; D008024:Ligands; D011506:Proteins; D011518:Proto-Oncogene Proteins; D020703:ras GTPase-Activating Proteins; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D002118:Calcium