SLP-76 binding to p56lck: a role for SLP-76 in CD4-induced desensitization of the TCR/CD3 signaling complex.
Nonreceptor protein tyrosine kinases and associated substrates play a pivotal role in Ag receptor stimulation of resting cells and in the initiation of activation-induced cell death (AICD) of preactivated T cells. CD4-associated p56lck has been implicated not only in the activation of primary T cells, but also in the inhibition of T cell responses. We have previously shown that CD4+ T cell clones can be rescued from AICD when surface CD4 is engaged before the TCR stimulus. In this study, we show that prevention of AICD is associated with a CD4-dependent inhibition of TCR-triggered tyrosine phosphorylation of the Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76) and Vav. We provide evidence for a SLP-76 interaction with Src homology 3 domains of p56lck and identify amino acids 185-194 of SLP-76 as relevant docking site. In view of the multiple functions of p56lck and SLP-76/Vav in the initiation of TCR/CD3/CD4 signaling, we propose a model for the CD4-dependent inhibition of TCR signaling and AICD of preactivated T cells. Our data suggest that preformed activation complexes of adapter proteins and enzymes in the vicinity of the CD4/p56lck complex are no longer available for the TCR signal when CD4 receptors are engaged before TCR stimulation.
Sanzenbacher
R
R
Department of Immunology, Paul-Ehrlich-Institute, Langen, Germany.
Kabelitz
D
D
Janssen
O
O
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001665:Binding Sites / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D002999:Clone Cells; D006801:Humans; D007700:Kinetics; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000302:isolation & purification / Q000378:metabolism*; D008954:Models, Biological; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding / Q000276:immunology; D051567:Proto-Oncogene Proteins c-vav; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism; D014443:Tyrosine / Q000037:antagonists & inhibitors / Q000378:metabolism; D018909:src Homology Domains / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015513:Oncogene Proteins; D010750:Phosphoproteins; D051567:Proto-Oncogene Proteins c-vav; D017260:Receptor-CD3 Complex, Antigen, T-Cell; C092947:SLP-76 signal Transducing adaptor proteins; C496618:VAV1 protein, human; D014443:Tyrosine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)