F. Goldman et al., GP120 LIGATION OF CD4 INDUCES P56(LCK) ACTIVATION AND TCR DESENSITIZATION INDEPENDENT OF TCR TYROSINE PHOSPHORYLATION, The Journal of immunology, 153(7), 1994, pp. 2905-2917
HIV gp120 binding to CD4 suppresses TCR function. The molecular mechan
ism of this anergizing effect is incompletely understood. Studies repo
rted here reveal that CD4 ligation initiates p56(lck) activation and r
enders human peripheral T cells and HPB-ALL cells hyporesponsive to Ag
receptor stimulation, as indicated by the failure of TCR binding liga
nds to induce either protein tyrosine phosphorylation or elevation of
intracellular-free calcium concentration. To approach the possibility
that p56(lck)-mediated tyrosine phosphorylation of specific sites with
in TCR zeta-chain might be involved in the gp120-induced TCR signaling
defect, we tested the kinase's ability to phosphorylate various zeta
peptides. Kinetic analyses indicate that peptides derived from the in
vitro autophosphorylation site of p56(lck) Y394 and two sites within z
eta, Y84, and Y152, are equally effective substrates for p56(lck), whe
reas p59(fyn) prefers a substrate peptide derived from a different sit
e within zeta, Y142. Although these data are consistent with the possi
bility that gp120-mediated signal disruption of TCR could be due to p5
6(lck) phosphorylation of Y84 and Y152 residues within zeta, further e
xperiments revealed that gp120 does not induce detectable zeta tyrosin
e 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 med
iated by a mechanism other than tyrosine phosphorylation of TCR zeta-c
hain.