ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

The apoptosis-inducing Fas ligand ( FasL) is a type II transmembrane protein that is involved in the downregulation of immune reactions by activation- induced cell death ( AICD) as well as in T cell- mediated cytotoxicity. Proteolytic cleavage leads to the generation of membrane- bound N- terminal fragments and a soluble FasL ( sFasL) ectodomain. sFasL can be detected in the serum of patients with dysregulated inflammatory diseases and is discussed to affect Fas- FasL- mediated apoptosis. Using pharmacological approaches in 293T cells, in vitro cleavage assays as well as loss and gain of function studies in murine embryonic fibroblasts ( MEFs), we demonstrate that the disintegrin and metalloprotease ADAM10 is critically involved in the shedding of FasL. In primary human T cells, FasL shedding is significantly reduced after inhibition of ADAM10. The resulting elevated FasL surface expression is associated with increased killing capacity and an increase of T cells undergoing AICD. Overall, our findings suggest that ADAM10 represents an important molecular modulator of FasL- mediated cell death.