title: Ceramide-induced TCR up-regulation.
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.
authors.affiliation: Institute of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Menné
authors.forename: J P
authors.initials: JP
authors.lastname: Lauritsen
authors.forename: J
authors.initials: J
authors.lastname: Dietrich
authors.forename: J
authors.initials: J
authors.lastname: Kastrup
authors.forename: A M
authors.initials: AM
authors.lastname: Wegener
authors.forename: N
authors.initials: N
authors.lastname: Odum
authors.forename: C
authors.initials: C
authors.lastname: Geisler
mesh_terms: D020816:Amino Acid Motifs / Q000187:drug effects / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005089:Exocytosis / Q000187:drug effects / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D007930:Leucine / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008565:Membrane Proteins / Q000502:physiology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D054648:Protein Phosphatase 2; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects* / Q000276:immunology*
chemical_list: D008565:Membrane Proteins; C064769:N-acetylsphingosine; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D007930:Leucine; D013110:Sphingosine