back to comicT-CellsT-cells are a type of white blood cell that work with macrophages. Unlike macrophages that can attack any invading cell or virus, each T-cell can fight only one type of virus. You might think this means macrophages are stronger than T-cells, but they aren’t. Instead, T-cells are like a special forces unit that fights only one kind of virus that might be attacking your body. More than one kind of T-cell There are two types of T-cells in your body: Helper T-cells and Killer T-cells. Killer T-cells do the work of destroying the infected cells. The Helper T-cells coordinate the attack. Killer T-Cells and Antigens Killer T-cells find and destroy infected cells that have been turned into virus-making factories. To do this they need to tell the difference between the infected cells and healthy cells with the help of special molecules called antigens. Killer T-cells are able to find the cells with viruses and destroy them. Antigens work like identification tags that give your immune system information about your cells and any intruders. Healthy cells have 'self-antigens' on the surface of their membranes. They let T-cells know that they are not intruders. If a cell is infected with a virus, it has pieces of virus antigens on its surface. This is a signal for the Killer T-cell that lets it know this is a cell that must be destroyed. Anatomy of a T-cell T-cells have many identical T-cell receptors that cover their surfaces and can only bind to one shape of antigen. When a T-cell receptor fits with its viral antigen on an infected cell, the Killer T-cell releases cytotoxins to kill that cell. The key to finding infected cells There are 25 million to a billion different T-cells in your body. Each cell has a unique T-cell receptor that can fit with only one kind of antigen, like a lock that can fit with only one shape of key. Antigens and receptors work a lot like a lock and key. Most of these antigens will never get in your body, but the T-cells that patrol your body will recognize them if they do. The T-cell receptor fits with its antigen like a complex key. When the perfectly shaped virus antigen on an infected cell fits into the Killer T-cell receptor, the T-cell releases perforin and cytotoxins. Perforin first makes a pore, or hole, in the membrane of the infected cell. Cytotoxins go directly inside the cell through this pore, destroying it and any viruses inside. This is why Killer T-cells are also called Cytotoxic T-cells. The pieces of destroyed cells and viruses are then cleaned up by macrophages. Helper T-cells The other type of T-cell is the Helper T-cell. These cells don’t make toxins or fight invaders themselves. Instead, they are like team coordinators. They use chemical messages to give instructions to the other immune system cells. These instructions help Killer T-cells and B-cells make a lot more of themselves so they can fight the infection and make sure the fight stays under control. Building a bigger army for a particular invader When a Helper T-cell sends out a chemical message, its matched Killer T-cell is alerted that there is a virus present. After a Killer T-cell finds and destroys an infected cell, this Helper T-cell message tells it to copy itself, making an army of Killer T-cells. Because only T-cells that can fight the invading virus are copied, your body saves energy and is still very good at killing the virus. T-cell screening T-cells are made in the bone marrow, like all red and white blood cells. The name T-cell comes from the organ where they mature, the thymus. The thymus is just above your heart, and is about the size of a deck of playing cards. Most T-cells are made when you’re young, so kids have a bigger thymus than adults. It is also where T-cells are screened to get rid of any that would attack the healthy cells in your body. Getting around the bodyAll white blood cells have two ways to get around the body. One way is through your blood vessels. The other way is through the lymph system. The lymph system has vessels that move milky fluid and white blood cells around the body. Unlike your heart, which pumps your blood, the lymph system uses the movements of your body to push the lymph fluid around. This is one reason why it is good to be active and exercise. Switching transportation systemsMost white blood cells are stored in the lymph system until they are needed to fight an infection. When a virus attacks, they can transfer into the blood vessels so they can quickly attack the viruses. This transfer happens in the lymph nodes, which are located throughout your body. Lots of lymph nodes are in your legs, armpits, and neck. The last time you had a sore throat you probably felt enlarged places on one or both sides of your neck. This is where the T-cells and B-cells multiply and get ready to attack the virus. Other important parts of the lymph system where immune cells grow, multiply, and trap invaders are your bone marrow, thymus, spleen, and tonsils. back to comicA 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 T-cell receptors (TCRs) that can recognize a specific antigen. An antigen is a molecule capable of stimulating an immune response and is often produced by cancer cells, viruses, bacteria or intracellular signals. Antigens inside a cell are bound to class I MHC molecules, and brought to the surface of the cell by the class I MHC molecule, where they can be recognized by the T cell. If the TCR is specific for that antigen, it binds to the complex of the class I MHC molecule and the antigen, and the T cell destroys the cell. 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 affinity between CD8 and the MHC molecule keeps the TC cell and the target cell bound closely together during antigen-specific activation. CD8+ T cells are recognized as TC cells once they become activated and are generally classified as having a pre-defined cytotoxic role within the immune system. However, CD8+ T cells also have the ability to make some cytokines, such as TNF-α and IFN-γ, with antitumour and antimicrobial effects. Development of single positive T cells in the thymus 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 stress and form part of the epithelial barrier[3]). Hematopoietic stem cells in the bone marrow migrate into the thymus, where they undergo V(D)J recombination of their beta-chain TCR DNA to form a developmental form of the TCR protein, known as pre-TCR. If that rearrangement is successful, the cells then rearrange their alpha-chain TCR DNA to create a functional alpha-beta TCR complex. This highly-variable genetic rearrangement product in the TCR genes helps create millions of different T cells with different TCRs, helping the body's immune system respond to virtually any protein of an invader. The vast majority of T cells express alpha-beta TCRs (αβ T cells), but some T cells in epithelial tissues (like the gut) express gamma-delta TCRs (gamma delta T cells), which recognize non-protein antigens. The latter are characterised by their ability to recognise antigens that are not presented. In addition, they can recognise microbial toxic shock proteins and self-cell stress proteins.[4] T γδ cells possess a wide functional plasticity after recognising infected or transformed cells, as they are able to produce cytokines (IFN-γ, TNF-α, IL-17) and chemokines (IP-10, lymphotactin), trigger cytolysis of target cells (perforins, granzymes...), and interact with other cells, such as epithelial cells, monocytes, dendritic cells, neutrophils and B cells. In some infections, such as human cytomegalovirus, there is a clonal expansion of peripheral γδ T cells that have specific TCRs, indicating the adaptive nature of the immune response mediated by these cells.[5] 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:
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. In this immunofluorescence image, a group of killer T cells (outer three) is engaging a cancer cell (centered one). A patch of signaling molecules (pink) that gathers at the site of cell-cell contact indicates that the CTL has identified a target. Lytic granules (red) that contain cytotoxic components then travel along the microtubule cytoskeleton (green) to the contact site and are secreted, thus killing the target. 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 host cells, except for non-nucleated ones, such as erythrocytes. When these cells are infected with a intracellular pathogen, the cells degrade foreign proteins via antigen processing. These result in peptide fragments, some of which are presented by MHC Class I to the T cell antigen receptor (TCR) on CD8+ T cells. 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.
A simple activation of naive CD8+ T cells requires the interaction with professional antigen-presenting cells, mainly with matured dendritic cells. To generate longlasting memory T cells and to allow repetitive stimulation of cytotoxic T cells, dendritic cells have to interact with both, activated CD4+ helper T cells and CD8+ T cells.[9][7] During this process, the CD4+ helper T cells "license" the dendritic cells to give a potent activating signal to the naive CD8+ T cells.[10] 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 interleukin 2 (IL-2), which is a growth and differentiation factor for T cells. This increases the number of cells specific for the target antigen that can then travel throughout the body in search of antigen-positive somatic cells. When exposed to infected/dysfunctional somatic cells, TC cells release the cytotoxins perforin, granzymes, and granulysin. Through the action of perforin, granzymes enter the cytoplasm of the target cell and their serine protease function triggers the caspase cascade, which is a series of cysteine proteases that eventually lead to apoptosis (programmed cell death). This is called a "lethal hit” and allows to observe a wave-like death of the target cells.[13] Due to high lipid order and negatively charged phosphatidylserine present in their plasma membrane, TC cells are resistant to the effects of their perforin and granzyme cytotoxins.[14] 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 FAS ligand (FasL)(Apo1L)(CD95L), which can bind to Fas (Apo1)(CD95) molecules expressed on the target cell. However, this Fas-Fas ligand interaction is thought to be more important to the disposal of unwanted T lymphocytes during their development or to the lytic activity of certain TH cells than it is to the cytolytic activity of TC effector cells. Engagement of Fas with FasL allows for recruitment of the death-induced signaling complex (DISC).[15] The Fas-associated death domain (FADD) translocates with the DISC, allowing recruitment of procaspases 8 and 10.[15] These caspases then activate the effector caspases 3, 6, and 7, leading to cleavage of death substrates such as lamin A, lamin B1, lamin B2, PARP (poly ADP ribose polymerase), and DNA-PKcs (DNA-activated protein kinase). The final result is apoptosis of the cell that expressed Fas. 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.[16] 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.[16] Unlike antibodies, which are effective against both viral and bacterial infections, cytotoxic T cells are mostly effective against viruses.[17] During hepatitis B virus (HBV) infection, cytotoxic T cells kill infected cells and produce antiviral cytokines capable of purging HBV from viable hepatocytes. They also play an important pathogenic role, contributing to nearly all of the liver injury associated with HBV infection.[18] Platelets have been shown to facilitate the accumulation of virus-specific cytotoxic T cells into the infected liver.[19] In some studies with mice, the injection with CXCR5+CD8+T cells show a significative decrease of HBsAg. Also, an increase of CXCL13 levels facilitated the recruitment of intrahepatic CXCR5+CD8+T cells and, these types of cells produced high levels of HBV-specific interferon (IFN)-γ and IL-21, which can help to improve the control of chronic HVB infection.[20] 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 infiltrate of inflammatory cells, mainly CD4+ T lymphocytes, which are the main organiser 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.[21] 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.[22] 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. [23] 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.[24] 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.[24] 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 Type 1 diabetes.[25] Studies in a diabetic mouse model showed that CD4+ cells are responsible for the massive infiltration of mononuclear leukocytes into pancreatic islets. However, CD8+ cells have been shown to play an effector role, responsible for the ultimate destruction of islet beta cells. However, in studies with NOD mice carrying a null mutation at the beta 2-microglobulin (beta 2-mu) locus and thus lacking major histocompatibility complex class I molecules and CD8+ T cells, it was found that they did not develop diabetes.[26] CD8+ T cells may be necessary to resolve chemotherapy-induced peripheral neuropathy (CIPN).[27][28] 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 transplant rejection (cytotoxic T-lymphocytes attack the new organ after detecting it as foreign, due to HLA variation between donor and recipient);[29] in excessive cytokine production in severe SARS-CoV-2 infection (due to an exaggerated lymphocyte response, a large amount of pro-inflammatory cytokines are generated, damaging the subject);[30][31] inflammatory and degenerative diseases of the central nervous system, such as multiple sclerosis (T cells become sensitised to certain proteins, such as myelin, attacking healthy cells and recruiting more immune cells, aggravating the disease).[32]
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