Y. Itoh et al., Serial TCR engagement and down-modulation by peptide : MHC molecule ligands: Relationship to the quality of individual TCR signaling events, J IMMUNOL, 162(4), 1999, pp. 2073-2080
In the present study, we examined the relationships among quantitative aspe
cts of TCR engagement as measured by receptor down-modulation, functional r
esponses, and biochemical signaling events using both mouse and human T cel
l clones, For T cells from both species, ligands that are more potent in in
ducing functional responses promote TCR down-modulation more efficiently th
an weaker ligands, At low ligand density, the number of down-modulated TCR
exceeds the number of available ligands by as much as 80-100:1 in the optim
al human case, confirming the previous description of serial ligand engagem
ent of TCR (Valitutti, et al, 1995, Nature 375:148-151), A previously unapp
reciated relationship involving TCR down-modulation, the pattern of proxima
l TCR signaling., and the extent of serial engagement was revealed by analy
zing different ligands for the same TCR, Functionally, more potent ligands
induce a higher proportion of fully tyrosine phosphorylated zeta-chains and
a greater amount of phosphorylated ZAP-70 than less potent ligands, and th
e number of TCR down-modulated per available ligand is higher with ligands
showing this full agonist-like pattern. The large number of receptors showi
ng partial zeta phosphorylation following exposure to weak ligands indicate
s that the true extent of TCR engagement and signaling, and thus the amount
of sequential engagement, is underestimated by measurement of TCR down-mod
ulation alone, which depends on full receptor activation. These data provid
e new insight into T cell activation by revealing a clear relationship amon
g intrinsic ligand quality, signal amplification by serial engagement, func
tional T cell responses, and observable TCR clearance from the cell surface
.