Cytotoxic T cell
A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.[1]
Most cytotoxic T cells express
In order for the TCR to bind to the class I MHC molecule, the former must be accompanied by a glycoprotein called CD8, which binds to the constant portion of the class I MHC molecule. Therefore, these T cells are called CD8+ T cells.
The
Development
The immune system must recognize millions of potential antigens. There are fewer than 30,000 genes in the human body, so it is impossible to have one gene for every antigen. Instead, the DNA in millions of white blood cells in the bone marrow is shuffled to create cells with unique receptors, each of which can bind to a different antigen. Some receptors bind to tissues in the human body itself, so to prevent the body from attacking itself, those self-reactive white blood cells are destroyed during further development in the thymus, in which iodine is necessary for its development and activity.[2]
TCRs have two parts, usually an alpha and a beta chain. (Some TCRs have a gamma and a delta chain. They are inherent to act against
T cells with functionally stable TCRs express both the CD4 and CD8 co-receptors and are therefore termed "double-positive" (DP) T cells (CD4+CD8+). The double-positive T cells are exposed to a wide variety of self-antigens in the thymus and undergo two selection criteria:
- positive selection, in which those double-positive T cells that bind to foreign antigen in the presence of self MHC. They will differentiate into either CD4+ or CD8+ depending on which MHC is associated with the antigen presented (MHC1 for CD8, MHC2 for CD4). In this case, the cells would have been presented antigen in the context of MHC1. Positive selection means selecting those TCRs capable of recognizing self MHC molecules.
- negative selection, in which those double-positive T cells that bind too strongly to MHC-presented self antigens undergo apoptosis because they could otherwise become autoreactive, leading to autoimmunity.
Only those T cells that bind to the MHC-self-antigen complexes weakly are positively selected. Those cells that survive positive and negative selection differentiate into single-positive T cells (either CD4+ or CD8+), depending on whether their TCR recognizes an MHC class I-presented antigen (CD8) or an MHC class II-presented antigen (CD4). It is the CD8+ T-cells that will mature and go on to become cytotoxic T cells following their activation with a class I-restricted antigen.
Activation
This section may be confusing or unclear to readers. (August 2023) |
T cells go through different stages, depending on the number of times they have been in contact with the antigen. In the first place, naïve T-lymphocytes are those cells that have not yet encountered an antigen in the thymus. Then, T-lymphocytes become memory T cells. This type of T cells are those that have been in contact with the antigen at least once but have returned subsequently to a quiescent or inactive state, ready to respond again to the antigen against which they were stimulated. Finally, when the specific immune response is triggered, these naive and memory T cells are activated, giving rise to effector T cells that have the capacity to kill pathogens or tumor cells.[6][7]
The threshold for activation of these cells is very high, and the process can occur via two pathways: thymus-independent (by infected APCs) or thymus-dependent (by CD4+ T cells). In the thymus-independent pathway, because the APC is infected, it is highly activated and expresses a large number of co-receptors for coactivation. If APCs are not infected, CD4 cells need to be involved: either to activate the APC by co-stimulation (more common) or to directly activate the Tc cell by secreting IL-2.
If activation occurs, the lymphocyte polarizes its granules towards the site of the synapse and releases them, producing a "lethal hit". At this point, it separates from the target cell, and can move on to another, and another. The target cell dies in about 6 hours, usually by apoptosis.[8]
Class I MHC is expressed by all
The activation of cytotoxic T cells is dependent on several simultaneous interactions between molecules expressed on the surface of the T cell and molecules on the surface of the antigen-presenting cell (APC). For instance, consider the two signal model for TC cell activation.
Signal | T cell | APC | Description |
First Signal | TCR |
peptide-bound MHC class I molecule | There is a second interaction between the CD8 coreceptor and the class I MHC molecule to stabilize this signal. |
Second Signal | CD28 molecule on the T cell | either CD80 or CD86 (also called B7-1 and B7-2) | CD80 and CD86 are known as costimulators for T cell activation. This second signal can be assisted (or replaced) by stimulating the TC cell with cytokines released from T helper cells. |
A simple activation of naive CD8+ T cells requires the interaction with professional antigen-presenting cells, mainly with matured
Furthermore, maturation of CD8+ T cells is mediated by CD40 signalling.[11] Once the naïve CD8+ T cell is bound to the infected cell, the infected cell is triggered to release CD40.[11] This CD40 release, with the aid of helper T cells, will trigger differentiation of the naïve CD8+ T cells to mature CD8+ T cells.[11]
While in most cases activation is dependent on TCR recognition of antigen, alternative pathways for activation have been described. For example, cytotoxic T cells have been shown to become activated when targeted by other CD8 T cells leading to tolerization of the latter.[12]
Once activated, the TC cell undergoes clonal expansion with the help of the cytokine
Effector functions
When exposed to infected/dysfunctional somatic cells, TC cells release the cytotoxins
A second way to induce apoptosis is via cell-surface interaction between the TC and the infected cell. When a TC is activated it starts to express the surface protein
The transcription factor Eomesodermin is suggested to play a key role in CD8+ T cell function, acting as a regulatory gene in the adaptive immune response.[17] Studies investigating the effect of loss-of-function Eomesodermin found that a decrease in expression of this transcription factor resulted in decreased amount of perforin produced by CD8+ T cells.[17]
Role in disease pathogenesis
Unlike antibodies, which are effective against both viral and bacterial infections, cytotoxic T cells are mostly effective against viruses.[18]
During
Cytotoxic T cells have been implicated in the progression of arthritis. The main involvement of rheumatoid arthritis is its joint involvement. The synovial membrane is characterised by hyperplasia, increased vascularity and infiltration of inflammatory cells; mainly CD4+ T lymphocytes, which are the main organisers of cell-mediated immune responses. In different studies, rheumatoid arthritis is strongly linked to major histocompatibility complex (MHC) class II antigens. The only cells in the body that express MHC class II antigens are constitutive antigen-presenting cells. This strongly suggests that rheumatoid arthritis is caused by unidentified arthritogenic antigens. The antigen could be any exogenous antigen, such as viral proteins, or an endogenous protein.[22] Recently, a number of possible endogenous antigens have been identified, for example, human cartilage glycoprotein 39, heavy chain binding protein and citrullinated protein. Activated CD4+ T lymphocytes stimulate monocytes, macrophages and synovial fibroblasts to elaborate the cytokines interleukin-1, interleukin-6 and tumour necrosis factor alpha (TNFa), and to secrete metalloproteinases. The first three of which are key in driving inflammation in rheumatoid arthritis. These activated lymphocytes also stimulate B cells to produce immunoglobulins, including rheumatoid factor.[23] Their pathogenic role is unknown, but may be due to complement activation through immune complex formation. Moreover, several animal studies suggest that cytotoxic T cells may have a predominantly proinflammatory effect in the disease. It is also studied that the production of cytokines by the CD8+ cells may accelerate the progresses of the arthritis disease.[24]
CD8+ T cells have been found to play a role in HIV infection. HIV over time has developed many strategies to evade the host cell immune system. For example, HIV has adopted very high mutation rates to allow them to escape recognition by CD8+ T cells.[25] They are also able to down-regulate expression of surface MHC Class I proteins of cells that they infect, in order to further evade destruction by CD8+ T cells.[25] If CD8+ T cells cannot find, recognize and bind to infected cells, the virus will not be destroyed and will continue to grow.
Furthermore, CD8+ T cells may be involved in
CD8+ T cells may be necessary to resolve chemotherapy-induced peripheral neuropathy (CIPN).[28][29] Mice without CD8+ T cells show prolonged CIPN compared to normal mice and injection of educated CD8+ T cells resolve or prevent CIPN.
Cytotoxic T-lymphocytes have been implicated in the development of various diseases and disorders, for example in
See also
References
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Helper T cells/CD4+ •express CD4 glycoproteins on their cell surface, which activate in the presence of peptide antigens on the surface of invading pathogens; •respond immediately to protect the immune system; •secrete different cytokine proteins according to the immune response.
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External links
- Media related to Cytotoxic T cells at Wikimedia Commons
- T-cell Group – Cardiff University