T-cell receptor downregulation by ceramide-induced caspase activation and cleavage of the zeta chain.
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 CD3 gamma chain but independent of tyrosine kinases, whereas the other is dependent on the tyrosine kinase activation but independent of the PKC and the CD3 gamma L-based motif. In this study, we describe a new pathway for TCR downregulation distinct from both the PKC/CD3 gamma L-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 zeta 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 zeta chain was found. Furthermore, the caspase inhibitors abolished the cleavage of the zeta chain and TCR downregulation in parallel with the inhibition of the caspase activity.
Menné
C
C
Institute of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark.
Lauritsen
J P
JP
Dietrich
J
J
Kastrup
J
J
Wegener
A K
AK
Andersen
P S
PS
Odum
N
N
Geisler
C
C
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D020169:Caspases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000201:enzymology; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009842:Oligopeptides / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014162:Transfection
D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D008565:Membrane Proteins; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; C064769:N-acetylsphingosine; D009842:Oligopeptides; D011948:Receptors, Antigen, T-Cell; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011993:Recombinant Fusion Proteins; C054979:antigen T cell receptor, zeta chain; C120992:benzyloxycarbonyl aspartyl-glutamyl-valyl-aspartyl-chloromethyl ketone; D011505:Protein-Tyrosine Kinases; D020169:Caspases; D013110:Sphingosine