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Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany
To investigate apoptosis resistance upon restimulation in human
peripheral blood T lymphocytes, we used the following in vitro model.
This model represents the main features of T cell reactivity: freshly
isolated PHA-activated T cells cultured in IL-2 for a prolonged period
of time develop a CD95 (APO-1/Fas) apoptosis-sensitive phenotype. These
T cells represent activation-induced cell death-sensitive T cells
during the down phase of an immune response. A fraction of
apoptosis-sensitive activated T cells becomes apoptosis resistant upon
TCR/CD3 restimulation. CD95 apoptosis sensitivity requires formation of
a functional receptor associated death-inducing signaling complex
(DISC), i.e., a protein complex of CD95 receptors, the adaptor
Fas-associated death domain protein (FADD)/MORT1 and caspase-8
(FADD-like IL-1
-converting enzyme (FLICE), MACH, Mch5). We
identified activation of procaspase-8 at the DISC as the main target
for the protective activity of TCR/CD3 restimulation. We found that
procaspase-8 cleavage is reduced in T cells after TCR/CD3
restimulation. In addition, we detected up-regulation of
c-FLIPS (the short splice variant of the cellular FLICE
inhibitory protein) and strongly enhanced recruitment of
c-FLIPS into the DISC. These data suggest that the
recruitment of c-FLIPS into the DISC results in reduced
DISC and caspase-8 activity.
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