CD95(APO-1/FAS) Signalling and Diseases

P.H. Krammer

Tumorimmunology Program, German Cancer Research Center, Heidelberg, Germany

CD95, a member of the tumor necrosis factor (TNF) receptor superfamily induces apoptosis upon receptor oligomerization. The receptor and its ligand are important for apoptosis of peripheral T cells, for downregulation of an immune response and most likely, at least in part, also for peripheral T cell tolerance. In Aids, apoptosis mediated by this system might contribute to the depletion of T helper lymphocytes. Likewise, in diseases in which liver cells are destroyed the CD95 system might play a major role.

In a search to identify the intracellular signalling pathway of CD95 several molecules coupling to oligomerized CD95 were immunoprecipitated from apoptosis-sensitive human leukemic T cell and lymphoblastoid B cell lines. The following binding molecules were only associated with aggregated and not with monomeric CD95: phosphorylated FADD (MORT1) and caspase 8. Thus, caspase 8 was identified as the most CD95 receptor proximal protease which starts the cascade of protease reactions important for CD95-mediated apoptosis. Association of FADD and caspase 8 with CD95 was not observed with C-terminally truncated non-signalling CD95. FADD and FLICE did also not associate with a CD95 cytoplasmic tail carrying the lprcg amino acid replacement. FADD and caspase 8 form a death-inducing signalling complex (DISC) with the CD95 receptor and are, thus, the first CD95 associating proteins of a signalling cascade mediating apoptosis.The function of the DISC is discussed in detail, particularly with respect to its role in sensitivity and resistance to apoptosis.

The CD95 death system plays a role in destruction of liver tissue. In hepatitis cytotoxic T lymphocytes might use the CD95 system to kill infected hepatocytes. In M. Wilson copper overload leads to upregulation of the CD95 ligand that may finally contribute to acute liver failure. In HCC from patients treated with chemotherapeutic drugs the CD95 receptor and ligand are upregulated and may contribute to apoptosis of the tumor or, dependent on the drug sensitivity of the tumor, to the status of the tumor as an immunoprivileged site.