S. Kirchhoff et al., TCR-mediated up-regulation of c-FLIPshort correlates with resistance toward CD95-mediated apoptosis by blocking death-inducing signaling complex activity, J IMMUNOL, 165(11), 2000, pp. 6293-6300
To investigate apoptosis resistance upon restimulation in human peripheral
blood T lymphocytes, we used the following in vitro model. This model repre
sents the main features of T cell reactivity: freshly isolated PKA-activate
d T cells cultured in IL-2 for a prolonged period of time develop a CD95 (A
PO-1/Fas) apoptosis-sensitive phenotype, These T cells represent activation
-induced cell death-sensitive T cells during the down phase of an immune re
sponse, A fraction of apoptosis-sensitive activated T cells becomes apoptos
is resistant upon TCR/CD3 restimulation, CD95 apoptosis sensitivity require
s formation of a functional receptor associated death-inducing signaling co
mplex (DISC), i.e., a protein complex of CD95 receptors, the adaptor Pas-as
sociated death domain protein (FADD)/MORT1 and caspase-8 (PADD-like IL-1 be
ta -converting enzyme (FLICE), MACH, Mch5), We identified activation of pro
caspase-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 cel
ls 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 sugg
est that the recruitment of c-FLIPS into the DISC results in reduced DISC a
nd caspase-8 activity.