Resistance of cultured peripheral T cells towards activation-induced cell death involves a lack of recruitment of FLICE (MACH/caspase 8) to the CD95 death-inducing signaling complex.
Phytohemagglutinin-activated peripheral CD95+ T cells (day 1 T cells) are resistant to CD95-mediated apoptosis. After prolonged interleukin-2 treatment, these T cells become CD95-mediated apoptosis-sensitive (day 6 T cells). To elucidate the molecular mechanism of apoptosis resistance, day 1 and day 6 T cells were tested for formation of the CD95 death-inducing signaling complex (DISC). DISC-associated active Fas-associated DD protein (FADD)-like interleukin-1 beta-converting enzyme-like protease (FLICE) also referred to as MACH/caspase 8 was only found in apoptosis-sensitive day 6 T cells. Further-analysis of mRNA and protein expression levels of apoptosis-signaling molecules FADD, receptor interacting protein, hematopoietic cell protein tyrosine phosphatase, Fas-associated phosphatase-1, FLICE, bel-2, bcl-xL, and, bax-alpha showed that only the expression level of bcl-xL correlated with T cell resistance to CD95-mediated apoptosis (day 1 T cells: bcl-xhiL; day 6 T cells: bcl-XloL). In T cells activated in vitro, up-regulation of bcl-xL, has previously been correlated with general apoptosis resistance. However, the experiments presented suggest that resistance to CD95-mediated apoptosis in T cells can also be regulated at the level of recruitment of FLICE to the DISC.
Peter
M E
ME
Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
Kischkel
F C
FC
Scheuerpflug
C G
CG
Medema
J P
JP
Debatin
K M
KM
Krammer
P H
PH
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000276:immunology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D015458:Leukemia, T-Cell; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000096:biosynthesis / Q000502:physiology*
D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases