Regulation of CD95 ligand expression: a key element in immune regulation?

Peripheral deletion of activated T cells has an important function in the regulation of the extent of an immune response. Upon restimulation through the T cell receptor previously stimulated cells have been shown to die by activation-induced cell death. Recent data indicate that this process is mediated by a CD95 (Fas/APO-1)/CD95 ligand interaction which induces apoptosis of the T cell. CD95 ligand (CD95-L) is absent on unactivated T cells but is readily expressed upon stimulation. Here we discuss evidence that CD95-L expression is induced by T cell receptor-mediated signals and is regulated at different levels. Different inhibitors of activation-induced cell death have been found to directly or indirectly act on the signal transduction pathway leading to CD95-L expression. CD95-L seems not only to be induced in T cells after activation but is also found constitutively expressed in many non-lymphoid tissues. This indicates that CD95-L is not only critically involved in activation-induced T cell death, but may have other functions as well. One such function is in the maintenance of immunological privilege, the protection of some tissues from potentially destructive immune responses. Thus, the regulation of CD95 expression in lymphoid and non-lymphoid cells appears to represent a key element in immune regulation.