Membrane-bound Fas ligand only is essential for Fas-induced apoptosis

FasL's non-apoptotic functions The transmembrane protein known as FasL (Fas ligand) is a member of the tumour necrosis factor family with an important role in immune regulation. The binding of FasL with its receptor induces apoptosis, but it has not been clear how important cell death is in FasL's cellular functions. Experiments using gene-targeted mice that either lack secreted FasL but express normal levels of membrane-bound FasL or, that lack membrane-bound FasL but can still produce secreted FasL, show that soluble FasL promotes autoimmunity and tumorigenesis through mechanisms that do not involve apoptosis. Fas ligand (FasL) and its receptor Fas are critical for the shutdown of chronic immune responses and prevention of autoimmunity. FasL function is regulated by deposition in the plasma membrane and metalloprotease-mediated shedding, but it is unclear what the respective roles of these secreted and membrane-bound forms are. Gene-targeted mice that selectively lack either secreted FasL or membrane-bound FasL are now generated, shedding light on this problem. Fas ligand (FasL), an apoptosis-inducing member of the TNF cytokine family, and its receptor Fas are critical for the shutdown of chronic immune responses 1 , 2 , 3 and prevention of autoimmunity 4 , 5 . Accordingly, mutations in their genes cause severe lymphadenopathy and autoimmune disease in mice 6 , 7 and humans 8 , 9 . FasL function is regulated by deposition in the plasma membrane and metalloprotease-mediated shedding 10 , 11 . Here we generated gene-targeted mice that selectively lack either secreted FasL (sFasL) or membrane-bound FasL (mFasL) to resolve which of these forms is required for cell killing and to explore their hypothesized non-apoptotic activities. Mice lacking sFasL ( FasL Δs/Δs ) appeared normal and their T cells readily killed target cells, whereas T cells lacking mFasL ( FasL Δm/Δm ) could not kill cells through Fas activation. FasL Δm/Δm mice developed lymphadenopathy and hyper-gammaglobulinaemia, similar to FasL gld/gld mice, which express a mutant form of FasL that cannot bind Fas, but surprisingly, FasL Δm/Δm mice (on a C57BL/6 background) succumbed to systemic lupus erythematosus (SLE)-like autoimmune kidney destruction and histiocytic sarcoma, diseases that occur only rarely and much later in FasL gld/gld mice. These results demonstrate that mFasL is essential for cytotoxic activity and constitutes the guardian against lymphadenopathy, autoimmunity and cancer, where