INACTIVATION OF LCK AND LOSS OF TCR-MEDIATED SIGNALING UPON PERSISTENT ENGAGEMENT WITH COMPLEXES OF PEPTIDE-MHC MOLECULES

T cell activation follows recognition of specific peptide:MHC molecule complexes in the context of proper costimulation. The earliest detect able event in T cell activation, within seconds of TCR ligand recognit ion, is tyrosine phosphorylation of TCR subunits. This causes a cascad e of events leading to up-regulation of gene transcription that will d rive T cell proliferation and differentiation. Regulation of TCR-media ted signaling upon T cell commitment is unclear. Here, we report that persistent stimulation of T cells, beyond 10 min, correlated with a re versible decrease in tyrosine phosphorylation of T cell lysates that d id not affect T cell commitment to proliferation. Loss of Ag-induced t yrosine phosphorylation was not due to lack of Ag presentation, loss o f TCR expression, or T cell death, but, rather, it was associated with a lack of TCR subunit tyrosine phosphorylation. We termed this phenom enon TCR desensitization by analogy to the loss of signaling observed in other receptor systems upon persistent engagement with agonist liga nds. TCR desensitization correlated with surface reexpression of TCR w ithout concomitant reexpression of coreceptor molecules. Biochemically , TCR desensitization correlated with increased levels of serine-phosp horylated lck, loss of lck kinase activity, and reversible loss of cyt osolic lck. Thus, TCR signaling is regulated by desensitization that m ay be due to serine phosphorylation of lck causing inactivation and lo ss of this src kinase. This may have important implications by prevent ing TCR signaling and activation-induced cell death once the T lymphoc yte is committed to proliferate.