Killer T cells are involved with triggering apoptosis (programmed cell death) through a variety of pathways.
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What are killer T cells and what do killer T cells do?
Killer T cells, also known as cytotoxic T lymphocytes (CTLs), are produced during cell-mediated immunity and are designed to remove body cells displaying a foreign epitope, such as virus-infected cells, cells containing intracellular bacteria, and cancer cells with mutant surface proteins. The killer T cells are able to kill these cells by inducing a programmed cell death process known as apoptosis (1).
Response of killer T cells
Killer T cells (cytotoxic T lymphocytes), only respond to a foreign antigen when it is presented bound to the MHC-I (Major Histocompatibility Complex Class-I) expressed on the surface of all cells. The killer T cells 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 (T-Cell Receptor Complex) and CD8 of the killer T cell binds 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 impacts of this release are the following:
- 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, also allowing 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 activate the caspase enzymes that lead to apoptosis of the infected cell by destroying the protein structural scaffolding of the cell (the cytoskeleton), degrading the cell's nucleoprotein, and activating 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.
How killer T cells trigger apoptosis
Triggering apoptosis through FasL (Fas Ligand)/Fas receptor interactions
Killer T cells can also trigger apoptosis of infected cells through FasL (Fas Ligand)/Fas receptor interactions (2-3). Fas recruits the FADD (Fas-Associated Death Domain) adapter protein to form a death-inducing signaling complex, causing the activation of Caspase-8. Caspase-8, in turn, activates the downstream caspases, such as Caspase-3, -6, and -7, culminating in apoptosis. The death signal can also be initiated by the release of mitochondrial CytoC (Cytochrome-C) and activation of APAF1 (Apoptotic Protease-Activating Factor-1) 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)
- CARDs (Caspase-Recruitment Domains)
Triggering apoptosis through protease Granzyme B
Killer T cells trigger a second pro-apoptotic pathway through the protease Granzyme-B, which, once released from killer T cells, 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 (4-5).
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 the killer T cells (cytotoxic T lymphocytes) are not destroyed in these reactions, they can function over and over again to destroy more virus-infected cells.
Killer T cell mediated apoptosis pathway
- Janssen EM, Lemmens EE, Gour N, et al. (2010) Distinct roles of cytolytic effector molecules for antigen-restricted killing by CTL in vivo. Immunol Cell Biol 88(7):761-5.
- Chávez-Galán L, Arenas-Del Angel MC, Zenteno E, et al. (2009) Cell death mechanisms induced by cytotoxic lymphocytes. Cell Mol Immunol 6(1):15-25.
- Cullen SP, Brunet M, Martin SJ (2010) Granzymes in cancer and immunity. Cell Death Differ 7(4):616-23.
- Boivin WA, Cooper DM, Hiebert PR, et al. (2009) Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma. Lab Invest 89(11):1195-220.
- Rousalova I, Krepela E (2010) Granzyme B-induced apoptosis in cancer cells and its regulation (review). Int J Oncol 37(6):1361-78.
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