T-cell receptor downregulation by ceramide-induced caspase activation and cleavage of the zeta chain.

Regulation of T-cell receptor (TCR) cell surface expression levels is probably an important mechanism by which T-cell responsiveness is controlled. Previously, two distinct pathways for TCR downregulation have been described. One is dependent on protein kinase C (PKC) and the leucine-based receptor-sorting motif (l-based motif) of the CD3γ chain but independent of tyrosine kinases, whereas the other is dependent on the tyrosine kinase activation but independent of the PKC and the CD3γl-based motif. In this study, we describe a new pathway for TCR downregulation distinct from both the PKC/CD3γl-based motif-dependent and the tyrosine kinase-dependent pathways. This pathway is dependent on ceramide-induced activation of caspases and correlate with caspase-mediated cleavage of the ζ chain. Thus, a 10–15% downregulation of the TCR was induced following the treatment of the T cells with ceramide for 4 h. A close correlation between TCR downregulation, caspase activation, and cleavage of the ζ chain was found. Furthermore, the caspase inhibitors abolished the cleavage of the ζ chain and TCR downregulation in parallel with the inhibition of the caspase activity.