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Cytotoxic T Lymphocyte-mediated Apoptosis of Target Cells

Cytotoxic T Lymphocytes (CTLs), also known as killer T-Cells, are produced during cell-mediated immunity designed to remove body cells displaying "foreign" epitope, such as virus-infected cells, cells containing intracellular bacteria, and cancer cells with mutant surface proteins. CTLs are able to kill these cells by inducing a programmed cell death known as apoptosis....

Cytotoxic T Lymphocyte-mediated Apoptosis of Target Cells

Pathway Summary

Cytotoxic T Lymphocytes (CTLs), also known as killer T-Cells, are produced during cell-mediated immunity designed to remove body cells displaying "foreign" epitope, such as virus-infected cells, cells containing intracellular bacteria, and cancer cells with mutant surface proteins. CTLs are able to kill these cells by inducing a programmed cell death known as apoptosis.CTLs only respond to foreign antigen when it is presented bound to the MHC-I expressed on the surface of all cells. CTLs contain granules composed of proteoglycans to which chemokines are complexed. These granules hold pore-forming proteins called perforins and proteolytic enzymes called granzymes in a protected state. When the TCR and CD8 of CTLs bind to the MHC/Epitope on the surface of the virus-infected cell, it sends a signal through a CD3 molecule which triggers the release of the perforins, granzymes, and chemokines. The perforin molecules polymerize and form pores in the membrane of the infected cell. The pores increase the permeability of the infected cell and activate the apoptotic caspase proteolytic cascade, and also allow other molecules to cross the cell membrane and trigger osmotic lysis of the membrane. The perforin pores also allow granzymes to enter. Certain granzymes, in turn, can then activate the caspase enzymes that lead to apoptosis of the infected cell by destroying the protein structural scaffolding of the cell (the cytoskeleton), degrade the cell's nucleoprotein, and activate enzymes that degrade DNA. In addition, if enough perforin pores form, the cell might not be able to exclude ions and water and may undergo cytolysis. CTLs can also trigger apoptosis of the infected cells through FasL/Fas receptor interactions. Fas recruit the FADD adapter protein to form the death-inducing signaling complex, causing the activation of Caspase8. Caspase8, in turn, activates the downstream caspases, such as Caspase3, -6, -7 culminating in apoptosis. The death signal can also be initiated by the release of mitochondrial CytoC and activation of APAF1 following internal cellular damage. The autolytic activation of Caspase 9 initiates the effector caspase cascade, which activates ICAD (DNA Fragmentation Factor) leading to DNA fragmentation. Many of these interactions found in pro-apoptotic signaling pathways are mediated by one of three related protein-protein interaction motifs: DDs (Death Domains), DEDs (Death Effector Domains) and CARDs. CTLs trigger a second pro-apoptotic pathway through the protease Granzyme-B, which, once released from CTLs, is translocated into the target cell by perforin. This allows Granzyme-B to have access to various cytoplasmic substrates like BID (BH3-Interacting Domain death agonist) that is cleaved to produce tBID (truncated) and the effector caspase cascade is activated.Death by apoptosis does not result in release of cellular contents. Instead, the cell breaks into fragments that are subsequently removed by phagocytes. This reduces inflammation and also prevents the release of viruses that have assembled within the infected cell and their spread into uninfected cells. In addition, the activated enzymes that degrade host DNA can also destroy microbial DNA and thus kill infectious microbes within the cell. Since CTLs are not destroyed in these reactions, they can function over and over again to destroy more virus-infected cells.

Cytotoxic T Lymphocyte-mediated Apoptosis of Target Cells Genes list

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