Role of Fas and RANKL Signaling in Peripheral Immune Tolerance

The death receptor, Fas, has been well-characterized and is a critical factor in apoptosis in immune cells. Fas also has an important role in maintaining immune tolerance as demonstrated in the autoimmune-prone MRL/lpr mouse strain which carries a defect in Fas-mediated apoptosis of T cells. However, the role of Fas-independent apoptosis remains to be characterized in autoimmune diseases. In dendritic cells (DCs), binding of receptor activator of nuclear factor-κB ligand (RANKL) to RANK perpetuates the survival of mature DCs. However, cross-talk between the RANK/RANKL pathway and Fas-mediated signaling during the function or activation of DCs has not been well-studied. This short communication review describes a mechanism involving interactions between activated DCs and T cells in the autoimmune response of MRL/lpr mice and a novel Fas-independent apoptosis pathway in T cells that maintains peripheral tolerance, and controls autoimmunity in MRL/lpr mice.