TCR-mediated up-regulation of c-FLIPshort correlates with resistance toward CD95-mediated apoptosis by blocking death-inducing signaling complex activity

• Verfasst von: Kirchhoff, Sabine [VerfasserIn]
• Verfasst von: Krammer, Peter H. [VerfasserIn]
• Titel: TCR-mediated up-regulation of c-FLIPshort correlates with resistance toward CD95-mediated apoptosis by blocking death-inducing signaling complex activity
• Verf.angabe: Sabine Kirchhoff, Wolfgang W. Müller, Andreas Krueger, Ingo Schmitz, and Peter H. Krammer
• E-Jahr: 2000
• Jahr: December 1, 2000
• Umfang: 8 S.
• Teil: volume:165
• Teil: year:2000
• Teil: number:11
• Teil: pages:6293-6300
• Teil: extent:8
• Fussnoten: Gesehen am 26.04.2021 ; Im Titel ist der Ausdruck "short" tiefgestellt
• Titel Quelle: Enthalten in: The journal of immunology
• Ort Quelle: Bethesda, Md. : Soc., 1916
• Jahr Quelle: 2000
• Band/Heft Quelle: 165(2000), 11, Seite 6293-6300
• ISSN Quelle: 1550-6606
• DOI: doi:10.4049/jimmunol.165.11.6293
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1755927908

Abstract

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-1β-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.