The Fas ligand as a cell death factor and signal transducer

Fas ligand (FasL, CD95L) is the key death factor of receptor‐triggered programmed cell death in immune cells. FasL/Fas‐dependent apoptosis plays a pivotal role in activation‐induced cell death, termination of immune responses, elimination of autoreactive cells, cytotoxic effector function of T and NK cells and the establishment of immune privilege. Dysregulation of FasL‐expression has severe impact on the maintenance of immune homeostasis and defense and is often associated with pathophysiology. Moreover, it was recently shown that FasL serves as a costimulatory receptor during T cell activation. However, it is still not known whether FasL‐ligation induces a ‘direct’ signal or whether the regulation of activation signals is a more ‘indirect’ result of alterations in intracellular protein‐protein‐interactions. In the latter scenario, the proline rich domain of FasL was shown to be required for a directed transport and localization of FasL. Over the past years, potential FasL‐associating molecules were identified which mostly bind via Src homology 3 or WW domains to the proline rich domain of FasL. This review summarizes facts and hypotheses about these FasL‐interacting proteins. It reflects their potential role in reverse signal transduction and FasL biology in T lymphocytes and other cell types.