Activation-induced cell death

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AICD (activation-induced cell death) is programmed cell death caused by the interaction of Fas receptors (Fas, CD95) and Fas ligands (FasL, CD95 ligand). [1] 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. [2] Alteration of the process may lead to autoimmune diseases. [1]

Programmed cell death is the death of a cell in any form, mediated by an intracellular program. PCD is carried out in a biological process, which usually confers advantage during an organism's life-cycle. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose; the result is that the digits are separate. PCD serves fundamental functions during both plant and animal tissue development. Apoptosis and autophagy, both are the forms of programmed cell death, but necrosis was long seen as a non-physiological process that occurs as a result of infection or injury.

Fas receptor protein-coding gene in the species Homo sapiens

Fas or FasR, also known as apoptosis antigen 1, 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 was first identified using a monoclonal antibody generated by immunizing mice with the FS-7 cell line. Thus, the name Fas is derived from FS-7-associated surface antigen.

Fas ligand protein-coding gene in the species Homo sapiens

Fas ligand is a type-II transmembrane protein that belongs to the tumor necrosis factor (TNF) family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.

Contents

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 express Fas and undergo clonal deletion by the AICD mechanism. [3] [4] Activated T cells that express both Fas and FasL may be killed by themselves or by each other. [1]

Apoptosis programmed cell death process

Apoptosis is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation, and global mRNA decay. The average adult human loses between 50 and 70 billion cells each day due to apoptosis. For an average human child between the ages of 8 to 14 year old approximately 20 to 30 billion cells die per day.

Clonal deletion is the removal through apoptosis of B cells and T cells that have expressed receptors for self before developing into fully immunocompetent lymphocytes. This prevents recognition and destruction of self host cells, making it a type of negative selection or central tolerance. Central tolerance prevents B and T lymphocytes from reacting to self. Thus, clonal deletion can help protect individuals against autoimmunity. Clonal deletion is thought to be the most common type of negative selection. It is one method of immune tolerance.

Signaling

The binding of Fas ligand to Fas receptor triggers trimerization of Fas, whose cytoplasmic domain is then able to bind the death domain of the adaptor protein FADD (Fas-associated protein with death domain). Procaspase 8 binds to FADD's death effector domain (DED) and proteolytically self-activates as caspase 8. Fas, FADD, and procaspase 8 together form a death-inducing signaling complex (DISC). Activated caspase 8 is released into the cytosol, where it activates the caspase cascade that initiates apoptosis. [5] [1]

Protein trimer

In biochemistry, a protein trimer is a macromolecular complex formed by three, usually non-covalently bound, macromolecules like proteins or nucleic acids. A homo-trimer would be formed by three identical molecules. A hetero-trimer would be formed by three different macromolecules. Type II Collagen is an example of homo-trimeric protein.

Death domain InterPro Domain

The death domain (DD) is a protein interaction module composed of a bundle of six alpha-helices. DD is a subclass of protein motif known as the death fold and is related in sequence and structure to the death effector domain (DED) and the caspase recruitment domain (CARD), which work in similar pathways and show similar interaction properties. DD bind each other forming oligomers. Mammals have numerous and diverse DD-containing proteins. Within these proteins, the DD domains can be found in combination with other domains, including: CARDs, DEDs, ankyrin repeats, caspase-like folds, kinase domains, leucine zippers, leucine-rich repeats (LRR), TIR domains, and ZU5 domains.

Signal transducing adaptor protein

Signal transducing adaptor proteins (STAPs) are proteins that are accessory to main proteins in a signal transduction pathway. Adaptor proteins contain a variety of protein-binding modules that link protein-binding partners together and facilitate the creation of larger signaling complexes. These proteins tend to lack any intrinsic enzymatic activity themselves, instead mediating specific protein–protein interactions that drive the formation of protein complexes. Examples of adaptor proteins include MYD88, Grb2 and SHC1.

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.) [3] NFAT activated by TCR stimulation activates FasL transcription, possibly indirectly by upregulating early growth response proteins. [1] T cell activation-induced transcription of FasL is further regulated by c-Myc–MAX heterodimers, and can be blocked by c-Myc downregulation. [1] Interferon regulatory factors IRF1 and IRF2 also upregulate FasL transcription by directly binding to the FasL promoter. [1]

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 development of cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of interleukin-2 in T cells, as a regulator for T cell immune response, but has since been found to play an important role in regulating many other body systems. NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders.

Early growth response proteins are a family of zinc finger transcription factors.

MAX (gene) protein-coding gene in the species Homo sapiens

MAX is a gene that in humans encodes the MAX transcription factor.

Not much is known about the regulation of Fas and other death receptors. However, overexpression of the protein CFLAR (caspase and FADD-like apoptosis regulator) inhibits Fas-mediated apoptosis. [6]

CFLAR protein-coding gene in the species Homo sapiens

CASP8 and FADD-like apoptosis regulator is a protein that in humans is encoded by the CFLAR gene. Also called c-FLIP.

See also

Immune system A biological system that protects an organism against disease

The immune system is a host defense system comprising many biological structures and processes within an organism that protects against disease. To function properly, an immune system must detect a wide variety of agents, known as pathogens, from viruses to parasitic worms, and distinguish them from the organism's own healthy tissue. In many species, the immune system can be classified into subsystems, such as the innate immune system versus the adaptive immune system, or humoral immunity versus cell-mediated immunity. In humans, the blood–brain barrier, blood–cerebrospinal fluid barrier, and similar fluid–brain barriers separate the peripheral immune system from the neuroimmune system, which protects the brain.

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response in given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens. Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.

Autoimmunity is the system of immune responses of an organism against its own healthy cells and tissues. Any disease that results from such an aberrant immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, sarcoidosis, systemic lupus erythematosus (SLE), Sjögren's syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis (RA), ankylosing spondylitis, polymyositis (PM), dermatomyositis (DM) and multiple sclerosis (MS). Autoimmune diseases are very often treated with steroids.

Related Research Articles

Cytotoxic T cell cell

A cytotoxic T cell is a T lymphocyte that kills cancer cells, cells that are infected, or cells that are damaged in other ways.

Caspase family of cysteine proteases

Caspases are a family of protease enzymes playing essential roles in programmed cell death and inflammation. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 11 or 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

Cell death biological processes that result in permanent cessation of all vital functions of a cell

Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, or may result from such factors as disease, localized injury, or the death of the organism of which the cells are part. Kinds of cell death include the following:

Superantigen

Superantigens (SAgs) are a class of antigens that cause non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs are produced by some pathogenic viruses and bacteria most likely as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response where 0.0001-0.001% of the body’s T-cells are activated, these SAgs are capable of activating up to 20% of the body’s T-cells. Furthermore, Anti-CD3 and Anti-CD28 Antibodies (CD28-SuperMAB) have also shown to be highly potent superantigens.

Death effector domain InterPro Domain

The death-effector domain (DED) is a protein interaction domain found only in eukaryotes that regulates a variety of cellular signalling pathways. The DED domain is found in inactive procaspases and proteins that regulate caspase activation in the apoptosis cascade such as FAS-associating death domain-containing protein (FADD). FADD recruits procaspase 8 and procaspase 10 into a death induced signaling complex (DISC). This recruitment is mediated by a homotypic interaction between the procaspase DED and a second DED that is death effector domain in an adaptor protein that is directly associated with activated TNF receptors. Complex formation allows proteolytic activation of procaspase into the active caspase form which results in the initiation of apoptosis. Structurally the DED domain are a subclass of protein motif known as the death fold and contains 6 alpha helices, that closely resemble the structure of the Death domain(DD)

TRAIL protein-coding gene in the species Homo sapiens

In the field of cell biology, TNF-related apoptosis-inducing ligand (TRAIL), is a protein functioning as a ligand that induces the process of cell death called apoptosis.

CARD domain InterPro Domain

Caspase recruitment domains, or Caspase activation and recruitment domains (CARDs), are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate the formation of larger protein complexes via direct interactions between individual CARDs. CARD domains are found on a strikingly wide range of proteins, including helicases, kinases, mitochondrial proteins, caspases, and other cytoplasmic factors.

Death-inducing signaling complex A protein complex formed by the association of signaling proteins with a death receptor upon ligand binding. The complex includes procaspases and death domain-containing proteins in addition to the ligand-bound receptor, and may control the activatio

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 its ligand (FasL) binding. The DISC is composed of the death receptor, FADD, and caspase 8. It transduces a downstream signal cascade resulting in apoptosis.

FADD protein-coding gene in the species Homo sapiens

Fas-associated protein with death domain (FADD), also called MORT1, is encoded by the FADD gene on the 11q13.3 region of chromosome 11 in humans.

Caspase 8 protein-coding gene in the species Homo sapiens

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 present in birds.

TRADD protein-coding gene in the species Homo sapiens

Tumor necrosis factor receptor type 1-associated DEATH domain protein is a protein that in humans is encoded by the TRADD gene.

Death receptor 4 protein-coding gene in the species Homo sapiens

Death receptor 4 (DR4), also known as TRAIL receptor 1 (TRAILR1) and tumor necrosis factor receptor superfamily member 10A (TNFRSF10A), is a cell surface receptor of the TNF-receptor superfamily that binds TRAIL and mediates apoptosis.

Caspase 10 protein-coding gene in the species Homo sapiens

Caspase-10 is an enzyme that, in humans, is encoded by the CASP10 gene.

Death receptor 5 protein-coding gene in the species Homo sapiens

Death receptor 5 (DR5), also known as TRAIL receptor 2 (TRAILR2) and tumor necrosis factor receptor superfamily member 10B (TNFRSF10B), is a cell surface receptor of the TNF-receptor superfamily that binds TRAIL and mediates apoptosis.

TNFRSF18 protein-coding gene in the species Homo sapiens

Tumor necrosis factor receptor superfamily member 18 (TNFRSF18) also known as activation-inducible TNFR family receptor (AITR) or glucocorticoid-induced TNFR-related protein (GITR) is a protein that in humans is encoded by the TNFRSF18 gene. GITR is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule.

Cytotoxic T lymphocytes (CTLs) are generated by immune activation of cytotoxic T cells (Tc cells). They are generally CD8+, which makes them MHC class I restricted. CTLs are able to eliminate most cells in the body since most nucleated cells express class I MHC molecules. The CTL-mediated immune system can be divided into two phases. In the first phase, functional effector CTLs are generated from naive Tc cells through activation and differentiation. In the second phase, affector CTLs destroy target cells by recognizing the antigen-MHC class I complex.

References

  1. 1 2 3 4 5 6 7 Zhang J, Xu X, Liu Y. (2004), Activation-Induced Cell Death in T Cells and Autoimmunity. Cell Mol Immunol. 1(3):186-92
  2. ↑ Kabelitz D, Janssen O. (1997), Antigen-induced death of T-lymphocytes. Front Biosci. 2:d61-77
  3. 1 2 Green DR, Droin N, Pinkoski M. (2003), Activation-induced cell death in T cells. Immunol Rev. 193:70-81
  4. ↑ Donjerković D, Scott DW. (2000), Activation-induced cell death in B lymphocytes. Cell Res. 10(3):179-92
  5. ↑ Nagata S. (1997), Apoptosis by death factor. Cell. 88(3):355-65
  6. ↑ 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
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