Differential Activity of Soluble versus Cellular Fas Ligand: Regulation by an Accessory Molecule

Fas ligand induces apoptosis by binding to its receptor Fas. This process has been shown to be important for activation-induced cell death of T lymphocytes, homeostasis of T cell numbers, cytotoxicity, and the maintenance of immunological privilege. Fas ligand is a type II membrane protein that is cleaved by a metalloproteinase to produce an active, soluble molecule. It has been found that a variety of target cells are differentially sensitive to soluble and membrane-associated forms of Fas ligand. However, the explanation for this differential activity has not been determined. One proposed explanation for this differential activity is that membrane-associated Fas ligand is more efficiently aggregated than soluble Fas ligand. Another possibility that we have investigated is that accessory molecules may act to enhance the activity of cellular Fas ligand. We have transfected cells to express membrane-associated Fas ligand and have characterized clones of these transfected cells in terms of Fas ligand and ICAM-1 surface expression. Enhanced activity was associated with enhanced levels of both Fas ligand and ICAM-1. Moreover, inhibition of ICAM-1 modulated the activity of membrane-associated Fas ligand so that its cellular specificity was similar to that of soluble Fas ligand. Thus, ICAM-1 plays a significant role in regulating Fas ligand activity, and this role explains, at least in part, the different functional attributes of the soluble versus the cell-associated molecule.