AICD (activation-induced cell death) is

programmed cell death Programmed cell death (PCD; sometimes referred to as cellular suicide) is the death of a cell (biology), cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers ...

caused by the interaction of

Fas receptor The Fas receptor, also known as Fas, FasR, apoptosis antigen 1 (APO-1 or APT), cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6), is a protein that in humans is encoded by the ''FAS'' gene. Fas ...

s (Fas, CD95) and Fas ligands (FasL, CD95 ligand).Zhang J, Xu X, Liu Y. (2004), Activation-Induced Cell Death in T Cells and Autoimmunity. Cell Mol Immunol. 1(3):186-92 AICD is a negative regulator of activated T lymphocytes that results from repeated stimulation of their T-cell receptors (TCR) and helps to maintain peripheral immune tolerance. Alteration of the process may lead to

autoimmune disease An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly ...

s. The AICD effector cell is one that expresses FasL, and apoptosis is induced in the cell expressing the Fas receptor. Both activated T cells and

B cells B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

express Fas and undergo clonal deletion by the AICD mechanism.Green DR, Droin N, Pinkoski M. (2003), Activation-induced cell death in T cells. Immunol Rev. 193:70-81 Activated T cells that express both Fas and FasL may be killed by themselves or by each other.

Signaling

The binding of Fas ligand to Fas receptor triggers trimerization of Fas, whose cytoplasmic domain is then able to bind the

death domain Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...

of the adaptor protein

FADD FAS-associated death domain protein, also called MORT1, is encoded by the ''FADD'' gene on the 11q13.3 region of chromosome 11 in humans. FADD is an adaptor protein that bridges members of the tumor necrosis factor receptor superfamily, such ...

(Fas-associated protein with death domain). Procaspase 8 binds to FADD's death effector domain (DED) and proteolytically self-activates as

caspase 8 Caspase-8 is a caspase protein, encoded by the ''CASP8'' gene. It most likely acts upon caspase-3. ''CASP8'' orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also prese ...

. Fas, FADD, and procaspase 8 together form a

death-inducing signaling complex The death-inducing signaling complex or DISC is a multi-protein complex formed by members of the death receptor family of apoptosis-inducing cellular receptors. A typical example is FasR, which forms the DISC upon trimerization as a result of ...

(DISC). Activated caspase 8 is released into the cytosol, where it activates the

caspase Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cyst ...

cascade that initiates apoptosis.

Regulation of Fas-FasL and AICD

FasL is primarily regulated at the transcriptional level. (The other option is regulation of the signal emanating from the death receptor itself, controlling sensitivity to the induction of apoptosis.)

NFAT Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the developme ...

activated by TCR stimulation activates FasL transcription, possibly indirectly by upregulating early growth response proteins. T cell activation-induced transcription of FasL is further regulated by

c-Myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' ( MYC), ''l-myc'' ( MYCL), and ''n-myc'' ( MYCN). ''c-myc'' (also sometimes re ...

–

MAX Max or MAX may refer to: Animals * Max (dog) (1983–2013), at one time purported to be the world's oldest living dog * Max (English Springer Spaniel), the first pet dog to win the PDSA Order of Merit (animal equivalent of OBE) * Max (gorilla) ...

heterodimers, and can be blocked by c-Myc downregulation. Interferon regulatory factors

IRF1 Interferon regulatory factor 1 is a protein that in humans is encoded by the ''IRF1'' gene. Function Interferon regulatory factor 1 was the first member of the interferon regulatory transcription factor (IRF) family identified. Initially descr ...

and

IRF2 Interferon regulatory factor 2 is a protein that in humans is encoded by the ''IRF2'' gene. Function IRF2 encodes interferon regulatory factor 2, a member of the interferon regulatory transcription factor (IRF) family. IRF2 competitively inhib ...

also upregulate FasL transcription by directly binding to the FasL promoter. Not much is known about the regulation of Fas and other death receptors. However, overexpression of the protein

CFLAR CASP8 and FADD-like apoptosis regulator is a protein that in humans is encoded by the ''CFLAR'' gene. Also called c-FLIP (FLICE Caspase-8 is a caspase protein, encoded by the ''CASP8'' gene. It most likely acts upon caspase-3. ''CASP8'' ortholo ...

(caspase and FADD-like apoptosis regulator) inhibits Fas-mediated apoptosis.Scaffidi C, Schmitz I, Krammer PH, Peter ME. (1999é, The role of c-FLIP in modulation of CD95-induced apoptosis. J Biol Chem 274:1541–1548

References

Cell biology

Signaling

Regulation of Fas-FasL and AICD

See also

References