Resistance of short term activated T cells to CD95-mediated apoptosis correlates with de novo protein synthesis of c-FLIPshort.
In the early phase of an immune response, T cells are activated and acquire effector functions. Whereas these short term activated T cells are resistant to CD95-mediated apoptosis, activated T cells in prolonged culture are readily sensitive, leading to activation-induced cell death and termination of the immune response. The translation inhibitor, cycloheximide, partially overcomes the apoptosis resistance of short term activated primary human T cells. Using this model we show in this study that sensitization of T cells to apoptosis occurs upstream of mitochondria. Neither death-inducing signaling complex formation nor expression of Bcl-2 proteins is altered in sensitized T cells. Although the caspase-8 inhibitor c-FLIP(long) was only slightly down-regulated in sensitized T cells, c-FLIP(short) became almost undetectable. This correlated with caspase-8 activation and apoptosis. These data suggest that c-FLIP(short), rather than c-FLIP(long), confers resistance of T cells to CD95-mediated apoptosis in the context of immune responses.
Schmitz
Ingo
I
Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
Weyd
Heiko
H
Krueger
Andreas
A
Baumann
Sven
S
Fas
Stefanie C
SC
Krammer
Peter H
PH
Kirchhoff
Sabine
S
D017209:Apoptosis / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D053418:Death Domain Receptor Signaling Adaptor Proteins; D015536:Down-Regulation / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008564:Membrane Potentials / Q000187:drug effects / Q000276:immunology; D008928:Mitochondria / Q000187:drug effects / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D019014:fas Receptor / Q000502:physiology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D003513:Cycloheximide; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases