A cytotoxic T cell is a T lymphocyte that kills cancer cells, cells that are infected,
or cells that are damaged in other ways.
Most cytotoxic T cells express T-cell receptors that can recognize a specific antigen.
An antigen is a molecule capable of stimulating an immune response, and is often produced
by cancer cells or viruses.
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.
Development
The immune system must recognize millions of potential antigens.
There are fewer than 30,000 genes in the human body, so it's 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.
TCRs have two parts, usually an alpha and a beta chain.
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, but some T cells in epithelial tissues
express gamma-delta TCRs, which recognize non-protein antigens.
T cells with functionally stable TCRs express both the CD4 and CD8 co-receptors and are
therefore termed "double-positive" T cells.
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 apoptosis because of
their inability to recognize MHC-protein complexes.
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, depending on whether their TCR recognizes an MHC class I-presented antigen or an MHC
class II-presented antigen.
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, Class I MHC is expressed by all host cells.
When these cells are infected with a virus, 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 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.
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 the cytokine Interleukin-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.
Effector functions 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.
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(Apo1L)(CD95L),
which can bind to Fas(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.
The Fas-associated death domain 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, and DNAPK.
The final result is apoptosis of the cell that expressed Fas.
Role in disease pathogenesis
During hepatitis B virus 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, cytotoxic T cells have been implicated in the progression of arthritis: depletion
of knee joint cartilage macromolecules such as glycosaminoglycans by cytotoxic T cells
and macrophages has been observed in a rat model of the disease.
See also Active Hexose Correlated Compound
References
External links T-cell Group - Cardiff University
Malaria