gp120 ligation of CD4 induces p56lck activation and TCR desensitization independent of TCR tyrosine phosphorylation.
HIV gp120 binding to CD4 suppresses TCR function. The molecular mechanism of this anergizing effect is incompletely understood. Studies reported here reveal that CD4 ligation initiates p56lck activation and renders human peripheral T cells and HPB-ALL cells hyporesponsive to Ag receptor stimulation, as indicated by the failure of TCR binding ligands to induce either protein tyrosine phosphorylation or elevation of intracellular-free calcium concentration. To approach the possibility that p56lck-mediated tyrosine phosphorylation of specific sites within TCR zeta-chain might be involved in the gp120-induced TCR signaling defect, we tested the kinase's ability to phosphorylate various zeta peptides. Kinetics analyses indicate that peptides derived from the in vitro autophosphorylation site of p56lck Y394 and two sites within zeta, Y84, and Y152, are equally effective substrates for p56lck, whereas p56fyn prefers a substrate peptide derived from a different site within zeta, Y142. Although these data are consistent with the possibility that gp120-mediated signal disruption of TCR could be due to p56lck phosphorylation of Y84 and Y152 residues within zeta, further experiments revealed that gp120 does not induce detectable zeta tyrosine phosphorylation under conditions in which it disrupts TCR signaling. These data indicate that gp120 can induce uncoupling of TCR from the earliest events in signal transduction and that this effect can be mediated by a mechanism other than tyrosine phosphorylation of TCR zeta-chain.
Goldman
F
F
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206.
Jensen
W A
WA
Johnson
G L
GL
Heasley
L
L
Cambier
J C
JC
D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D008565:Membrane Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D019000:Phosphotyrosine; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C494957:FYN protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn