FAS Ligand, soluble

Fas Ligand (FasL), also known as CD178, CD95L, or TNFSF6, is a 40 kDa type II transmembrane member of the TNF superfamily of proteins. Its ability to induce apoptosis in target cells plays an important role in the development, homeostasis, and function of the immune system. Mature human Fas Ligand consists of a 179 amino acid (aa) extracellular domain (ECD), a 22 aa transmembrane segment, and a 80 aa cytoplasmic domain. Within the ECD, human Fas Ligand shares 81% and 78% aa sequence identity with mouse and rat Fas Ligand, respectively. Both mouse and human Fas Ligand are active on mouse and human cells. Fas Ligand is expressed on the cell surface as a nondisulfidelinked homotrimer on activated CD4+ Th1 cells, CD8+ cytotoxic T cells, and NK cells. Fas Ligand binding to Fas/CD95 on an adjacent cell triggers apoptosis in the Fas expressing cell. Fas Ligand also binds DcR3 which is a soluble decoy receptor that interferes with Fas Ligandinduced apoptosis. Fas Ligand can be released from the cell surface by metalloproteinases as a 26 kDa soluble molecule which remains trimeric. Shed Fas Ligand retains the ability to bind Fas, although its ability to trigger apoptosis is dramatically reduced. In the absence of TGFβ, however, Fas Ligand/Fas interactions instead promote neutrophilmediated inflammatory responses. Fas Ligand itself transmits reverse signals that costimulate the proliferation of freshly antigenstimulated T cells. Fas Ligandinduced apoptosis plays a central role in the development of immune tolerance and the maintance of immune privileged sites. This function is exploited by tumor cells which evade immune surveillance by upregulating Fas Ligand to kill tumor infiltrating lymphocytes. In gld mice, a Fas Ligand point mutation is the cause of severe lympho-proliferation and systemic autoimmunity.