AICD (activation-induced cell death) isprogrammed cell death caused by the interaction ofFas receptors (Fas, CD95) andFas ligands (FasL, CD95 ligand).[1] AICD is a negative regulator of activatedT lymphocytes that results from repeated stimulation of theirT-cell receptors (TCR) and helps to maintain peripheralimmune tolerance.[2] Alteration of the process may lead toautoimmune diseases.[1] In fact AICD in T cells might be one of the mechanisms of resistance to cancer immunotherapy.[3]
The AICD effector cell is one thatexpresses FasL, andapoptosis is induced in the cell expressing the Fas receptor. Bothactivated T cells andB cells express Fas and undergoclonal deletion by the AICD mechanism.[4][5] Activated T cells that express both Fas and FasL may be killed by themselves or by each other.[1]
The binding of Fas ligand to Fas receptor triggerstrimerization of Fas, whosecytoplasmicdomain is then able to bind thedeath domain of theadaptor proteinFADD (Fas-associated protein with death domain). Procaspase 8 binds to FADD'sdeath effector domain (DED) andproteolytically self-activates ascaspase 8. Fas, FADD, and procaspase 8 together form adeath-inducing signaling complex (DISC). Activated caspase 8 is released into thecytosol, where it activates thecaspase cascade that initiates apoptosis.[6][1]
FasL is primarilyregulated at the transcriptional level. (The other option is regulation of the signal emanating from thedeath receptor itself, controlling sensitivity to the induction of apoptosis.)[4]NFAT activated by TCR stimulation activates FasL transcription, possibly indirectly by upregulatingearly growth response proteins.[1] T cell activation-inducedtranscription of FasL is further regulated byc-Myc–MAXheterodimers, and can be blocked by c-Myc downregulation.[1]Interferon regulatory factorsIRF1 andIRF2 also upregulate FasL transcription by directly binding to the FasLpromoter.[1]
Not much is known about the regulation of Fas and other death receptors. However,overexpression of the proteinCFLAR (caspase and FADD-like apoptosis regulator) inhibits Fas-mediated apoptosis.[7]