2 DISTINCT PATHWAYS EXIST FOR DOWN-REGULATION OF THE TCR

TCR down-regulation plays an important role in modulating T cell respo nses bath during T cell development an in mature T cells, Down-regulat ion of the TCR is induced by engagement of the TCR by specific ligands and/or by activation of protein kinase C (PKC), We report here that l igand- and PKC-induced TCR down-regulation is mediated by trio distinc t, independent mechanisms. Ligand-induced TCR down-regulation is depen dent on the protein tyrosine kinases p56(lck) and p59(fyn) but indepen dent of PKC and the CD3(gamma) leucine-based (L-based) internalization motif. In contrast, PKC-induced TCR down-regulation is dependent on t he CD3(gamma) L-based internalization motif but independent of p56(lck ) and p59(fyn). Finally, our data indicate that in the absence of TCR ligation, TCR expression levels can be finely regulated via the CD3(ga mma) L-based motif by the balance between PKC and serine/threonine pro tein phosphatase activities. Such a TCR ligation-independent regulatio n of TCR expression levels could probably be important ire determining the activation threshold of T cells in their encounter with APC.