T cell activation follows recognition of specific peptide:MHC molecule complexes in the context of proper costimulation. The earliest detectable event in T cell activation, within seconds of TCR ligand recognition, is tyrosine phosphorylation of TCR subunits. This causes a cascade of events leading to up-regulation of gene transcription that will drive T cell proliferation and differentiation. Regulation of TCR-mediated signaling upon T cell commitment is unclear. Here, we report that persistent stimulation of T cells, beyond 10 min, correlated with a reversible decrease in tyrosine phosphorylation of T cell lysates that did not affect T cell commitment to proliferation. Loss of Ag-induced tyrosine phosphorylation was not due to lack of Ag presentation, loss of TCR expression, or T cell death, but, rather, it was associated with a lack of TCR subunit tyrosine phosphorylation. We termed this phenomenon TCR desensitization by analogy to the loss of signaling observed in other receptor systems upon persistent engagement with agonist ligands. TCR desensitization correlated with surface reexpression of TCR without concomitant reexpression of coreceptor molecules. Biochemically, TCR desensitization correlated with increased levels of serine-phosphorylated lck, loss of lck kinase activity, and reversible loss of cytosolic lck. Thus, TCR signaling is regulated by desensitization that may be due to serine phosphorylation of lck causing inactivation and loss of this src kinase. This may have important implications by preventing TCR signaling and activation-induced cell death once the T lymphocyte is committed to proliferate.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.