T‐Cell Receptor Downregulation by Ceramide‐Induced Caspase Activation and Cleavage of the ζ Chain

Publisher Website
Google Scholar
Abstract
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.