Two Distinct Pathways Exist for Down-Regulation of the TCR

Abstract

AbstractTCR down-regulation plays an important role in modulating T cell responses both during T cell development and in mature T cells. Down-regulation 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 ligand- and PKC-induced TCR down-regulation is mediated by two distinct, independent mechanisms. Ligand-induced TCR down-regulation is dependent on the protein tyrosine kinases p56lck and p59fyn but independent of PKC and the CD3γ leucine-based (L-based) internalization motif. In contrast, PKC-induced TCR down-regulation is dependent on the CD3γ L-based internalization motif but independent of p56lck and p59fyn. Finally, our data indicate that in the absence of TCR ligation, TCR expression levels can be finely regulated via the CD3γ L-based motif by the balance between PKC and serine/threonine protein phosphatase activities. Such a TCR ligation-independent regulation of TCR expression levels could probably be important in determining the activation threshold of T cells in their encounter with APC.