Fas

Fas (CD95/APO-1) is a member of the TNF receptor superfamily expressed on many cell types, including activated lymphocytes. Binding of Fas to Fas ligand (FasL, expressed on cytotoxic T cells and NK cells) induces receptor trimerization and recruitment of the adaptor protein FADD, which activates caspase-8 (initiator caspase). Caspase-8 then activates downstream effector caspases (caspase-3, -6, -7), leading to apoptosis via the extrinsic pathway—distinct from the intrinsic (mitochondrial) pathway regulated by Bcl-2 family proteins and cytochrome c release. This mechanism is important for: (1) activation-induced cell death (AICD), which eliminates autoreactive or excess activated T and B lymphocytes to maintain peripheral tolerance and terminate immune responses; (2) cytotoxic T lymphocyte (CTL) and NK cell-mediated killing of virus-infected or tumor cells (alongside the perforin/granzyme pathway); and (3) immune privilege in sites like the eye and testis, where FasL expression on local cells induces apoptosis of infiltrating Fas-bearing lymphocytes. Defects in the Fas-FasL pathway (e.g., mutations in FAS gene) cause Autoimmune Lymphoproliferative Syndrome (ALPS), characterized by chronic lymphadenopathy, splenomegaly, autoimmune cytopenias, and increased susceptibility to lymphoma due to failure of lymphocyte apoptosis. This concept is frequently tested in relation to apoptosis pathways (extrinsic vs intrinsic), autoimmune disease mechanisms, and cancer immune evasion (tumors downregulating Fas or upregulating FasL to evade immune destruction, sometimes killing Fas-expressing lymphocytes—the 'Fas counterattack').