Fas ligand
Summary
Fas ligand (FasL, CD95L) is a type II transmembrane protein of the TNF family that binds Fas (CD95) death receptor to trigger extrinsic apoptosis. It is critical for immune homeostasis, killing of virus-infected/tumor cells by cytotoxic T cells and NK cells, and maintenance of immune privilege in sites like the eye and testis.
Detail
Fas ligand engages Fas (CD95) on target cells, causing receptor trimerization and recruitment of FADD (Fas-associated death domain) adaptor protein, which activates caspase-8. This initiates the extrinsic (death receptor) apoptotic pathway, leading to activation of downstream executioner caspases (caspase-3, -6, -7) and programmed cell death. FasL is expressed on activated cytotoxic T lymphocytes (CD8+), NK cells, and cells in immune-privileged sites (eye, testis) to induce apoptosis in infiltrating lymphocytes, helping prevent excessive immune responses ('immune privilege').
Clinical significance: Mutations in Fas or FasL cause autoimmune lymphoproliferative syndrome (ALPS), characterized by failure of lymphocyte apoptosis, resulting in lymphadenopathy, splenomegaly, autoimmune cytopenias, and increased risk of lymphoma. FasL is also implicated in activation-induced cell death (AICD), important for peripheral tolerance by eliminating autoreactive T cells after clonal expansion. Cancer cells and virus-infected cells sometimes exploit dysregulated Fas/FasL signaling to evade immune destruction. This pathway is contrasted with the intrinsic (mitochondrial) apoptotic pathway, which involves Bcl-2 family proteins and cytochrome c release, activating caspase-9.
Sources
- First Aid for the USMLE Step 1
- Robbins and Cotran Pathologic Basis of Disease
- Janeway's Immunobiology
- Kuby Immunology
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