FasL

Fas ligand (FasL), also known as CD95 ligand (CD95L), is a member of the tumor necrosis factor (TNF) cytokine family. It is primarily expressed as a transmembrane protein on activated T cells, natural killer (NK) cells, and other cytotoxic lymphocytes, with additional expression in platelets and various non-lymphoid tissues. A soluble form, generated by proteolytic shedding, can be found in plasma.

FasL binds to its receptor Fas (CD95), triggering the formation of the death-inducing signaling complex (DISC) that includes FADD and caspases, notably caspase-8 or caspase-10. This initiates the caspase cascade and apoptosis of the Fas-expressing target cell. Membrane-bound FasL is generally more potent at inducing cell death than the soluble form, which can have weaker, sometimes non-apoptotic, signaling effects. Depending on cellular context, Fas signaling can also activate inflammatory pathways such as NF-κB and MAP kinases.

Physiologically, FasL participates in immune regulation through activation-induced cell death (AICD) of lymphocytes, helping to maintain peripheral tolerance and terminate immune responses. It contributes to cytotoxic T cell and NK cell–mediated killing of infected or transformed cells and can influence tissue remodeling and immune privilege in certain sites.

Dysregulation of the Fas/FasL axis is linked to pathological conditions. Aberrant FasL expression or signaling has been observed in autoimmune diseases and graft-versus-host disease, while rare mutations in the FASLG gene have been associated with autoimmune and lymphoproliferative disorders. In cancer, FasL expression by tumor cells has been reported and may contribute to immune evasion in some contexts, though its exact role remains debated. Therapeutic approaches targeting this pathway have been explored but face safety and complexity considerations.