Cytotoxic T cell
Encyclopedia
A cytotoxic T cell belongs to a sub-group of T lymphocyte
s (a type of white blood cell
) that are capable of inducing the death of infected
somatic
or tumor
cells; they kill cells that are infected with virus
es (or other pathogens), or are otherwise damaged or dysfunctional. Most cytotoxic T cells express T-cell receptors (TCRs) that can recognize a specific antigen
ic peptide
bound to Class I MHC
molecules, present on all nucleated cells, and a glycoprotein
called CD8
, which is attracted to non-variable portions of the Class I MHC molecule. 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.
Hematopoietic stem cells in the bone marrow
migrate into the thymus
, where they undergo VDJ 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 (γδ T cells), which recognize non-protein antigens.
T cells with functionally stable TCRs express both the CD4
and CD8
co-receptor
s 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.
cells. When these cells are infected with a virus
(or another 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.
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.
Once activated, the TC cell undergoes clonal expansion with the help of a cytokine called Interleukin-2 (IL-2) that 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 cell
s.
, granzymes, and granulysin
. Perforin forms pores (aqueous channels) in the target cell's plasma membrane allowing granzymes, types of serine proteases that cleave at aspartate residues in the substrate, to enter the target cell, which then activate a series of cysteine proteases, the caspase
cascade, that eventually lead to apoptosis
(programed cell death). A second way to induce apoptosis is via cell-surface interactions 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). The Fas-associated death domain (FADD) translocates with the DISC, allowing recruitment of procaspases 8 and 10. 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 DNAPK (DNA-activated protein kinase). The final result is apoptosis of the cell that expressed Fas.
: depletion of knee joint cartilage
macromolecules such as glycosaminoglycans by CTLs and macrophage
s has been observed in a rat model of the disease.
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s (a type of white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
) that are capable of inducing the death of infected
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
somatic
Somatic
The term somatic means 'of the body',, relating to the body. In medicine, somatic illness is bodily, not mental, illness. The term is often used in biology to refer to the cells of the body in contrast to the germ line cells which usually give rise to the gametes...
or tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
cells; they kill cells that are infected with virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es (or other pathogens), or are otherwise damaged or dysfunctional. Most cytotoxic T cells express T-cell receptors (TCRs) that can recognize a specific antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
ic peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
bound to Class I MHC
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
molecules, present on all nucleated cells, and a glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
called CD8
CD8
CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene...
, which is attracted to non-variable portions of the Class I MHC molecule. 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.
Development
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
migrate into the thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
, where they undergo VDJ recombination of their beta-chain TCR
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
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
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
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 (γδ T cells), which recognize non-protein antigens.
T cells with functionally stable TCRs express both the CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
and CD8
CD8
CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene...
co-receptor
Co-receptor
A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate biological processes, such as entry of a pathogen into a host cell.-Co-receptor Properties:...
s 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 too weakly to MHC-presented self antigens undergo apoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
because of their inability to recognize MHC-protein complexes. - negative selection, in which those double-positive T cells that bind too strongly to MHCMajor histocompatibility complexMajor histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
-presented self antigenAntigenAn antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s undergo apoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
because their propensity (an often intense natural inclination or preference) to become autoreactive could lead to autoimmunityAutoimmunityAutoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
.
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
With an exception of some cell types, such as non-nucleated cells (including erythrocytes), Class I MHC is expressed by all hostHost (biology)
In biology, a host is an organism that harbors a parasite, or a mutual or commensal symbiont, typically providing nourishment and shelter. In botany, a host plant is one that supplies food resources and substrate for certain insects or other fauna...
cells. When these cells are infected with a virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
(or another intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
), the cells degrade foreign proteins via antigen processing
Antigen processing
Antigen processing is a biological process that prepares antigens for presentation to special cells of the immune system called T lymphocytes. This process involves two distinct pathways for processing of antigens from an organism's own proteins or intracellular pathogens , or from phagocytosed...
. These result in peptide fragments, some of which are presented by MHC Class I to the T cell antigen receptor
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
(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
Antigen-presenting cell
An antigen-presenting cell or accessory cell is a cell that displays foreign antigen complexes with major histocompatibility complex on their surfaces. T-cells may recognize these complexes using their T-cell receptors...
(APC). For instance, consider the two signal model for TC cell activation.
| Signal | T cell | APC | Description >- | first signal |
TCR T cell receptor The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules... |
peptide-bound MHC class I MHC class I MHC class I molecules are one of two primary classes of major histocompatibility complex molecules and are found on every nucleated cell of the body... molecule |
CD8 CD8 CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene... coreceptor and the class I MHC molecule to stabilize this signal. >- | second signal |
CD28 CD28 CD28 is one of the molecules expressed on T cells that provide co-stimulatory signals, which are required for T cell activation. CD28 is the receptor for CD80 and CD86 . When activated by Toll-like receptor ligands, the CD80 expression is upregulated in antigen presenting cells... molecule on the T cell |
either CD80 CD80 Cluster of Differentiation 80 is a protein found on activated B cells and monocytes that provides a costimulatory signal necessary for T cell activation and survival... or CD86 CD86 Cluster of Differentiation 86 is a protein expressed on antigen-presenting cells that provides costimulatory signals necessary for T cell activation and survival... (also called B7-1 and B7-2) |
CD80 and CD86 are known as costimulators Co-stimulation During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.- Co-stimulation T cells require :... for T cell activation. This second signal can be assisted (or replaced) by stimulating the TC cell with cytokines released from helper T cells. |
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.
Once activated, the TC cell undergoes clonal expansion with the help of a cytokine called Interleukin-2 (IL-2) that 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 cell
Somatic cell
A somatic cell is any biological cell forming the body of an organism; that is, in a multicellular organism, any cell other than a gamete, germ cell, gametocyte or undifferentiated stem cell...
s.
Effector functions
When exposed to infected/dysfunctional somatic cells, TC cells release the cytotoxins perforinPerforin
Perforin-1 is a protein that in humans is encoded by the PRF1 gene.- Function :Perforin is a cytolytic protein found in the granules of CD8 T-cells and NK cells. Upon degranulation, perforin inserts itself into the target cell's plasma membrane, forming a pore. The lytic membrane-inserting part...
, granzymes, and granulysin
Granulysin
Granulysin is a substance released by cytotoxic T cells when they are attached to infected body cells. It functions to create holes in the target cell membrane and destroy it...
. Perforin forms pores (aqueous channels) in the target cell's plasma membrane allowing granzymes, types of serine proteases that cleave at aspartate residues in the substrate, to enter the target cell, which then activate a series of cysteine proteases, the caspase
Caspase
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....
cascade, that eventually lead to apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
(programed cell death). A second way to induce apoptosis is via cell-surface interactions between the TC and the infected cell. When a TC is activated it starts to express the surface protein FAS ligand
FAS ligand
Fas ligand is a type-II transmembrane protein that belongs to the tumor necrosis factor family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.- Structure :Fas ligand or...
(FasL)(Apo1L)(CD95L), which can bind to Fas
Fas
Fas can mean the following:* Fas receptor, an important cell surface receptor protein of the TNF receptor family known also as CD95, that induces apoptosis on binding Fas ligand.* Fes, Morocco, the third largest city in Morocco, as an alternate spelling...
(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). The Fas-associated death domain (FADD) translocates with the DISC, allowing recruitment of procaspases 8 and 10. 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 DNAPK (DNA-activated protein kinase). The final result is apoptosis of the cell that expressed Fas.
Role in disease pathogenesis
During hepatitis B virus (HBV) infection cytotoxic T cells play an important pathogenetic role. They contribute to nearly all of the liver injury associated with HBV infection and, by killing infected cells and by producing antiviral cytokines capable of purging HBV from viable hepatocytes, cytotoxic T cells also eliminate the virus. Recently platelets have been shown to facilitate the accumulation of virus-specific cytotoxic T cells into the infected liver. Recently CTLs have been implicated in the progression of arthritisArthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
: depletion of knee joint cartilage
Cartilage
Cartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...
macromolecules such as glycosaminoglycans by CTLs and macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s has been observed in a rat model of the disease.
External links
- T-cell Group - Cardiff University
- Malaria (Flash Animation)