Ceramide-induced TCR up-regulation

The TCR is a constitutively recycling receptor meaning that a constant frac tion of TCR from the plasma membrane is transported inside the cell at the same time as a constant fraction of TCR from the intracellular pool is tran sported to the plasma membrane, TCR recycling is affected by protein kinase C activity. Thus, an increase in protein kinase C activity affects TCR rec ycling kinetics leading to a new TCR equilibrium with a reduced level of TC R expressed at the T cell surface. Down-regulation of TCR expression compro mises T cell activation. Conversely, TCR up-regulation is expected to incre ase T cell responsiveness. The purpose of this study was to identify and ch aracterize potential pathways for TCR up-regulation, We found that ceramide affected TCR recycling dynamics and induced TCR up-regulation in a concent ration- and time-dependent manner. Experiments applying phosphatase inhibit ors indicated that ceramide-induced TCR up-regulation was most probably med iated by serine/threonine protein phosphatase 2A, Analyses of T cell varian ts demonstrated that TCR up-regulation was dependent on the presence of an intact CD3 gamma L-based motif and thus acted on TCR engaged in the recycli ng pathway. Finally, we showed that TCR up-regulation probably plays a phys iological role by increasing T cell responsiveness. Thus, by affecting the TCR recycling kinetics, T cells have the potential both to up- and down-reg ulate TCR expression and thereby adjust T cell responsiveness.