CD95L/FasL and its receptor CD95 (APO-1/Fas)

This chapter focuses on CD95L/ FasL, and its receptor CD95. Two groups initiated a screen for a monoclonal antibody that would inhibit the growth of tumor cells by binding to a cell surface antigen. This resulted in the identification of two monoclonal antibodies that induced programmed cell death, or apoptosis, in many tumor cells, anti-APO-1, and CH11. The recognition that is binding of an antibody to cells could trigger a cell death program that was radical at the time, and raised expectations for finding new antitumor drugs. This expectancy was mainly fueled by an experiment in which an injection of anti-APO-1 into nude mice harboring a human tumor resulted in complete regression of the tumor. The molecule was termed Fas or APO-1, and is now known as CD95 or tumor necrosis factor receptor superfamily member 6 (TNFRSF6). The significance of CD95 for the function of the immune system became clear with the recognition that mice carrying the lymphoproliferation (Ipr) mutation have a defect in CD95, which led to the discovery that mutations in CD95 in humans can cause the autoimmune lymphoproliferative syndrome (ALPS). The race was to clone the ligand that bound to CD95, and induced apoptosis. The mature membrane-bound protein contains an extracellular domain, which binds to CD95, a transmembrane domain, and a 77-amino-acid long intracellular domain. Human CD95L shows 76.9% amino acid identity with the mouse protein and mouse CD95L kills human cells and vice versa indicating crossreactivity.