TY - JOUR

T1 - Ceramide-induced TCR up-regulation

AU - Menné, C

AU - Lauritsen, Jens Peter Holst

AU - Dietrich, J

AU - Kastrup, J

AU - Wegener, A M

AU - Odum, Niels

AU - Geisler, C

N1 - Keywords: Amino Acid Motifs; Down-Regulation; Enzyme Activation; Exocytosis; Humans; Jurkat Cells; Kinetics; Leucine; Leukocytes, Mononuclear; Lymphocyte Activation; Membrane Proteins; Phorbol 12,13-Dibutyrate; Phosphoprotein Phosphatases; Protein Kinase C; Protein Phosphatase 2; Receptor-CD3 Complex, Antigen, T-Cell; Receptors, Antigen, T-Cell; Sphingosine; T-Lymphocytes; Up-Regulation

PY - 2000

Y1 - 2000

N2 - The TCR is a constitutively recycling receptor meaning that a constant fraction 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 transported to the plasma membrane. TCR recycling is affected by protein kinase C activity. Thus, an increase in protein kinase C activity affects TCR recycling kinetics leading to a new TCR equilibrium with a reduced level of TCR expressed at the T cell surface. Down-regulation of TCR expression compromises T cell activation. Conversely, TCR up-regulation is expected to increase T cell responsiveness. The purpose of this study was to identify and characterize potential pathways for TCR up-regulation. We found that ceramide affected TCR recycling dynamics and induced TCR up-regulation in a concentration- and time-dependent manner. Experiments applying phosphatase inhibitors indicated that ceramide-induced TCR up-regulation was most probably mediated by serine/threonine protein phosphatase 2A. Analyses of T cell variants demonstrated that TCR up-regulation was dependent on the presence of an intact CD3gamma L-based motif and thus acted on TCR engaged in the recycling pathway. Finally, we showed that TCR up-regulation probably plays a physiological role by increasing T cell responsiveness. Thus, by affecting the TCR recycling kinetics, T cells have the potential both to up- and down-regulate TCR expression and thereby adjust T cell responsiveness.

AB - The TCR is a constitutively recycling receptor meaning that a constant fraction 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 transported to the plasma membrane. TCR recycling is affected by protein kinase C activity. Thus, an increase in protein kinase C activity affects TCR recycling kinetics leading to a new TCR equilibrium with a reduced level of TCR expressed at the T cell surface. Down-regulation of TCR expression compromises T cell activation. Conversely, TCR up-regulation is expected to increase T cell responsiveness. The purpose of this study was to identify and characterize potential pathways for TCR up-regulation. We found that ceramide affected TCR recycling dynamics and induced TCR up-regulation in a concentration- and time-dependent manner. Experiments applying phosphatase inhibitors indicated that ceramide-induced TCR up-regulation was most probably mediated by serine/threonine protein phosphatase 2A. Analyses of T cell variants demonstrated that TCR up-regulation was dependent on the presence of an intact CD3gamma L-based motif and thus acted on TCR engaged in the recycling pathway. Finally, we showed that TCR up-regulation probably plays a physiological role by increasing T cell responsiveness. Thus, by affecting the TCR recycling kinetics, T cells have the potential both to up- and down-regulate TCR expression and thereby adjust T cell responsiveness.

M3 - Journal article

C2 - 10975817

VL - 165

SP - 3065

EP - 3072

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 6

ER -