Cytotoxic T cells in Apoptosis
Cytotoxic T cells are also known as cytotoxic T lymphocytes (CTLs), killer T cells, T-killer cells and CD8+ T cells. They are specialized immune cells that recognize and respond to foreign or abnormal antigens, inducing apoptosis in the target cell primarily by release of cytotoxic enzymes. By eliminating the target cells, cytotoxic T cells maintain cellular homeostasis and prevent proliferation of potentially dangerous 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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APAF1apoptotic peptidase activating factor 1 BCL2BCL2 apoptosis regulator BIDBH3 interacting domain death agonist CASP3caspase 3 CASP6caspase 6 CASP7caspase 7 CASP8caspase 8 CASP9caspase 9 CD247CD247 molecule CD3DCD3d molecule CD3ECD3e molecule CD3GCD3g molecule CYC1cytochrome c1 CYCScytochrome c, somatic DFFADNA fragmentation factor subunit alpha DFFBDNA fragmentation factor subunit beta FADDFas associated via death domain FASFas cell surface death receptor FASLGFas ligand FCER1GFc fragment of IgE receptor Ig GZMBgranzyme B PRF1perforin 1 TRACT cell receptor alpha constant TRAJ1T cell receptor alpha joining 1 (non-functional) TRAJ10T cell receptor alpha joining 10 TRAJ11T cell receptor alpha joining 11 TRAJ12T cell receptor alpha joining 12 TRAJ13T cell receptor alpha joining 13 TRAJ14T cell receptor alpha joining 14 TRAJ16T cell receptor alpha joining 16 TRAJ17T cell receptor alpha joining 17 TRAJ18T cell receptor alpha joining 18 TRAJ19T cell receptor alpha joining 19 (non-functional) TRAJ2T cell receptor alpha joining 2 (non-functional) TRAJ20T cell receptor alpha joining 20 TRAJ21T cell receptor alpha joining 21 TRAJ22T cell receptor alpha joining 22 TRAJ23T cell receptor alpha joining 23 TRAJ24T cell receptor alpha joining 24 TRAJ25T cell receptor alpha joining 25 (non-functional) TRAJ26T cell receptor alpha joining 26 TRAJ27T cell receptor alpha joining 27 TRAJ28T cell receptor alpha joining 28 TRAJ29T cell receptor alpha joining 29 TRAJ3T cell receptor alpha joining 3 TRAJ30T cell receptor alpha joining 30 TRAJ31T cell receptor alpha joining 31 TRAJ32T cell receptor alpha joining 32 TRAJ33T cell receptor alpha joining 33 TRAJ34T cell receptor alpha joining 34 TRAJ35T cell receptor alpha joining 35 (non-functional) TRAJ36T cell receptor alpha joining 36 TRAJ37T cell receptor alpha joining 37 TRAJ38T cell receptor alpha joining 38 TRAJ39T cell receptor alpha joining 39 TRAJ4T cell receptor alpha joining 4 TRAJ40T cell receptor alpha joining 40 TRAJ41T cell receptor alpha joining 41 TRAJ42T cell receptor alpha joining 42 TRAJ43T cell receptor alpha joining 43 TRAJ44T cell receptor alpha joining 44 TRAJ45T cell receptor alpha joining 45 TRAJ46T cell receptor alpha joining 46 TRAJ47T cell receptor alpha joining 47 TRAJ48T cell receptor alpha joining 48 TRAJ49T cell receptor alpha joining 49 TRAJ5T cell receptor alpha joining 5 TRAJ50T cell receptor alpha joining 50 TRAJ52T cell receptor alpha joining 52 TRAJ53T cell receptor alpha joining 53 TRAJ54T cell receptor alpha joining 54 TRAJ56T cell receptor alpha joining 56 TRAJ57T cell receptor alpha joining 57 TRAJ58T cell receptor alpha joining 58 (non-functional) TRAJ59T cell receptor alpha joining 59 (non-functional) TRAJ6T cell receptor alpha joining 6 TRAJ61T cell receptor alpha joining 61 (non-functional) TRAJ7T cell receptor alpha joining 7 TRAJ9T cell receptor alpha joining 9 TRAV1-1T cell receptor alpha variable 1-1 TRAV1-2T cell receptor alpha variable 1-2 TRAV10T cell receptor alpha variable 10 TRAV11T cell receptor alpha variable 11 (pseudogene) TRAV12-1T cell receptor alpha variable 12-1 TRAV12-2T cell receptor alpha variable 12-2 TRAV12-3T cell receptor alpha variable 12-3 TRAV13-1T cell receptor alpha variable 13-1 TRAV13-2T cell receptor alpha variable 13-2 TRAV14DV4T cell receptor alpha variable 14/delta variable 4 TRAV16T cell receptor alpha variable 16 TRAV17T cell receptor alpha variable 17 TRAV18T cell receptor alpha variable 18 TRAV19T cell receptor alpha variable 19 TRAV2T cell receptor alpha variable 2 TRAV20T cell receptor alpha variable 20 TRAV21T cell receptor alpha variable 21 TRAV22T cell receptor alpha variable 22 TRAV23DV6T cell receptor alpha variable 23/delta variable 6 TRAV24T cell receptor alpha variable 24 TRAV25T cell receptor alpha variable 25 TRAV26-1T cell receptor alpha variable 26-1 TRAV26-2T cell receptor alpha variable 26-2 TRAV27T cell receptor alpha variable 27 TRAV29DV5T cell receptor alpha variable 29/delta variable 5 TRAV3T cell receptor alpha variable 3 TRAV30T cell receptor alpha variable 30 TRAV34T cell receptor alpha variable 34 TRAV36DV7T cell receptor alpha variable 36/delta variable 7 TRAV38-1T cell receptor alpha variable 38-1 TRAV38-2DV8T cell receptor alpha variable 38-2/delta variable 8 TRAV39T cell receptor alpha variable 39 TRAV4T cell receptor alpha variable 4 TRAV40T cell receptor alpha variable 40 TRAV41T cell receptor alpha variable 41 TRAV5T cell receptor alpha variable 5 TRAV6T cell receptor alpha variable 6 TRAV7T cell receptor alpha variable 7 TRAV8-1T cell receptor alpha variable 8-1 TRAV8-2T cell receptor alpha variable 8-2 TRAV8-3T cell receptor alpha variable 8-3 TRAV8-4T cell receptor alpha variable 8-4 TRAV8-6T cell receptor alpha variable 8-6 TRAV8-7T cell receptor alpha variable 8-7 (pseudogene) TRAV9-1T cell receptor alpha variable 9-1 TRAV9-2T cell receptor alpha variable 9-2 TRBC1T cell receptor beta constant 1 TRBC2T cell receptor beta constant 2 TRBD1T cell receptor beta diversity 1 TRBJ1-1T cell receptor beta joining 1-1 TRBJ1-2T cell receptor beta joining 1-2 TRBJ1-3T cell receptor beta joining 1-3 TRBJ1-4T cell receptor beta joining 1-4 TRBJ1-5T cell receptor beta joining 1-5 TRBJ1-6T cell receptor beta joining 1-6 TRBJ2-1T cell receptor beta joining 2-1 TRBJ2-2T cell receptor beta joining 2-2 TRBJ2-2PT cell receptor beta joining 2-2P (non-functional) TRBJ2-3T cell receptor beta joining 2-3 TRBJ2-4T cell receptor beta joining 2-4 TRBJ2-5T cell receptor beta joining 2-5 TRBJ2-6T cell receptor beta joining 2-6 TRBJ2-7T cell receptor beta joining 2-7 TRBV1T cell receptor beta variable 1 (pseudogene) TRBV10-1T cell receptor beta variable 10-1 TRBV10-2T cell receptor beta variable 10-2 TRBV10-3T cell receptor beta variable 10-3 TRBV11-1T cell receptor beta variable 11-1 TRBV11-3T cell receptor beta variable 11-3 TRBV12-1T cell receptor beta variable 12-1 (pseudogene) TRBV12-2T cell receptor beta variable 12-2 (pseudogene) TRBV12-3T cell receptor beta variable 12-3 TRBV12-4T cell receptor beta variable 12-4 TRBV12-5T cell receptor beta variable 12-5 TRBV13T cell receptor beta variable 13 TRBV14T cell receptor beta variable 14 TRBV15T cell receptor beta variable 15 TRBV16T cell receptor beta variable 16 TRBV17T cell receptor beta variable 17 (non-functional) TRBV18T cell receptor beta variable 18 TRBV19T cell receptor beta variable 19 TRBV2T cell receptor beta variable 2 TRBV20-1T cell receptor beta variable 20-1 TRBV23-1T cell receptor beta variable 23-1 (non-functional) TRBV24-1T cell receptor beta variable 24-1 TRBV25-1T cell receptor beta variable 25-1 TRBV26T cell receptor beta variable 26 (pseudogene) TRBV27T cell receptor beta variable 27 TRBV28T cell receptor beta variable 28 TRBV29-1T cell receptor beta variable 29-1 TRBV3-1T cell receptor beta variable 3-1 TRBV30T cell receptor beta variable 30 TRBV4-1T cell receptor beta variable 4-1 TRBV4-2T cell receptor beta variable 4-2 TRBV5-1T cell receptor beta variable 5-1 TRBV5-3T cell receptor beta variable 5-3 (non-functional) TRBV5-4T cell receptor beta variable 5-4 TRBV5-5T cell receptor beta variable 5-5 TRBV5-6T cell receptor beta variable 5-6 TRBV5-7T cell receptor beta variable 5-7 (non-functional) TRBV6-1T cell receptor beta variable 6-1 TRBV6-2T cell receptor beta variable 6-2 TRBV6-4T cell receptor beta variable 6-4 TRBV6-5T cell receptor beta variable 6-5 TRBV6-6T cell receptor beta variable 6-6 TRBV6-7T cell receptor beta variable 6-7 (non-functional) TRBV6-8T cell receptor beta variable 6-8 TRBV7-1T cell receptor beta variable 7-1 (non-functional) TRBV7-2T cell receptor beta variable 7-2 TRBV7-3T cell receptor beta variable 7-3 TRBV7-4T cell receptor beta variable 7-4 TRBV7-6T cell receptor beta variable 7-6 TRBV7-7T cell receptor beta variable 7-7 TRBV7-9T cell receptor beta variable 7-9 TRBV9T cell receptor beta variable 9 TRDCT cell receptor delta constant TRDD1T cell receptor delta diversity 1 TRDD2T cell receptor delta diversity 2 TRDD3T cell receptor delta diversity 3 TRDJ1T cell receptor delta joining 1 TRDJ2T cell receptor delta joining 2 TRDJ3T cell receptor delta joining 3 TRDJ4T cell receptor delta joining 4 TRDV2T cell receptor delta variable 2 TRDV3T cell receptor delta variable 3 TRGC1T cell receptor gamma constant 1 TRGC2T cell receptor gamma constant 2 TRGJ1T cell receptor gamma joining 1 TRGJ2T cell receptor gamma joining 2 TRGJPT cell receptor gamma joining P TRGJP1T cell receptor gamma joining P1 TRGJP2T cell receptor gamma joining P2 TRGV2T cell receptor gamma variable 2 TRGV3T cell receptor gamma variable 3 TRGV4T cell receptor gamma variable 4 TRGV5T cell receptor gamma variable 5 TRGV8T cell receptor gamma variable 8 TRGV9T cell receptor gamma variable 9
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Cytotoxic T cells: Defenders against infections and tumors
Cytotoxic T lymphocytes are powerful effectors of the adaptive immune system, acting as surveyors, detectors and destroyers of infected and abnormal, potentially cancerous cells.
How do cytotoxic T cells function?
Cells infected by a foreign agent such as a virus, or abnormal cells like tumor cells, display fragments of the agent on their cell surface as part of a complex with major histocompatibility complex class-1 (MHC-1). As circulating cytotoxic T cells scan the surface of antigen-presenting cells, they interact with MHC-1 via their CD8 receptor (1). The presence of a recognized foreign or abnormal peptide fragment activates the cytotoxic T lymphocyte, triggering the release of perforin and granzymes that penetrate the target cell membrane and induce apoptosis by activating caspases that breakdown the components of the cell. The cytotoxic T cell can then move on, efficiently identifying and eliminating additional targets cells through a process of serial killing.
Cytotoxic T lymphocytes additionally express FasL (Fas ligand). As they crawl the target cell surface and interact with MHC-1, cytotoxic T cells can also activate the target cell’s Fas death receptor, triggering apoptosis through the extrinsic apoptosis pathway.
To help keep the immune response under control, cytotoxic T cells express regulatory proteins like cytotoxic T-lymphocyte antigen 4 (CTLA-4), which competes with activating signals to reduce T cell activity once the threat has passed.
Cytotoxic T cells vs natural killer cells
Both cytotoxic T lymphocytes and natural killer cells are involved in immune response aimed at destroying infected or abnormal cells, but they differ in their approach. Cytotoxic T cells are part of the adaptive immune system which relies on antigen specificity and requires prior exposure to the pathogen to function effectively. In contrast, natural killer cells are part of the innate immune system that can recognize and kill abnormal or stressed cells without the presence of a recognized antigen. Natural killer cells are critical for early defense, providing time for adaptive immunity to become fully activated (2).
What is the difference between CD8+ T cells and CD4+ T cells?
T cells have traditionally been divided into two groups: cytotoxic T cells and helper T cells. Cytotoxic T cells express the CD8 receptor and are therefore sometimes referred to as CD8 cytotoxic T cells, CD8+ cytotoxic T cells or CD8+ T cells. As described in detail above, these cells directly attack pathogens.
In contrast, T helper cells express the CD4 receptor. Sometimes referred to as CD4+ T cells, this subset of T cells are best known for helping to coordinate the immune response by other cells without attacking pathogens directly. However, recent research has found that a small subset of CD4+ T cells also exhibits cytotoxic capabilities. Known as CD4 cytotoxic T cells, or CD4+ cytotoxic T cells, this subset of T cells has characteristics of both helper and cytotoxic T cells (3).
References
- Raskov H, Orhan A, Christensen JP, Gögenur I. Cytotoxic CD8+ T cells in cancer and cancer immunotherapy. Br J Cancer. 2021;124(2):359–367.
- Hu W, Wang G, Huang D, Sui M, Xu Y. Cancer immunotherapy based on natural killer cells: Current progress and new opportunities. Front Immunol. 2019;10:1205.
- Hoeks C, Duran G, Hellings N, Broux B. When helpers go above and beyond: Development and characterization of cytotoxic CD4+ T cells. Front Immunol. 2022;13:951900.