Ceramide-induced TCR up-regulation

J Immunol. 2000 Sep 15;165(6):3065-72. doi: 10.4049/jimmunol.165.6.3065.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs / drug effects
  • Amino Acid Motifs / immunology
  • Down-Regulation / drug effects
  • Down-Regulation / immunology
  • Enzyme Activation / drug effects
  • Enzyme Activation / immunology
  • Exocytosis / drug effects
  • Exocytosis / immunology
  • Humans
  • Jurkat Cells
  • Kinetics
  • Leucine / physiology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Lymphocyte Activation / drug effects
  • Membrane Proteins / physiology
  • Phorbol 12,13-Dibutyrate / pharmacology
  • Phosphoprotein Phosphatases / metabolism
  • Phosphoprotein Phosphatases / physiology
  • Protein Kinase C / physiology
  • Protein Phosphatase 2
  • Receptor-CD3 Complex, Antigen, T-Cell / physiology
  • Receptors, Antigen, T-Cell / antagonists & inhibitors
  • Receptors, Antigen, T-Cell / biosynthesis*
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Antigen, T-Cell / physiology
  • Sphingosine / analogs & derivatives*
  • Sphingosine / pharmacology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Up-Regulation / drug effects*
  • Up-Regulation / immunology*

Substances

  • Membrane Proteins
  • N-acetylsphingosine
  • Receptor-CD3 Complex, Antigen, T-Cell
  • Receptors, Antigen, T-Cell
  • antigen T cell receptor, zeta chain
  • Phorbol 12,13-Dibutyrate
  • Protein Kinase C
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2
  • Leucine
  • Sphingosine