A membrane-bound Fas decoy receptor expressed by human thymocytes

Human thymocytes at several stages of maturation express Fas, yet resist ap optosis induction through its ligation, A proximal step in apoptotic signal ing through Fas is implicated in this resistance, as these cells undergo no rmal levels of apoptosis induction after exposure to tumor necrosis factor- cu, We studied the Fas receptors expressed in human thymocytes to search fo r mechanisms of receptor-mediated inhibition of Fas signaling in these cell s. We describe here a unique, membrane-bound form of Fas receptor that cont ained a complete extracellular domain of Fas but that lacked a death domain due to alternative splicing of exon 7. This Fas decoy receptor (FDR) was s hown to have nearly wild-type ability to bind native human Fas ligand and w as expressed predominantly at the plasma membrane. Unlike soluble forms of Fas receptor, FDR dominantly inhibited apoptosis induction by Fas ligand in transfected human embryonic kidney cells. Titration ofFDR in Fas-expressin g cells suggests that FDR may operate through the formation of mixed recept or complexes. FDR also dominantly inhibited Fas-induced apoptosis in Jurkat T cells. In mixing experiments with wild-type Fas, FDR was capable of inhi biting death signaling at molar ratios less than 0.5, and this relative lev el of FDR: wild type message was observed in at least some thymocytes teste d. The data suggest that Fas signal pathways in primary human cells may be regulated by expression of a membrane-bound decoy receptor, analogous to th e regulation of tumor necrosis factor-related apoptosis inducing ligand (TR AIL)-induced apoptosis by decoy receptors.