'T cells' belong to a group of
white blood cellWhite blood cells , or leukocytes , are cells of the immune system 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...
s known as lymphocytes, and play a central role in
cell-mediated immunityCell-mediated immunity is an immune response that does not involve antibodies or complement but rather involves the activation of macrophages, natural killer cells , antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen...
. They can be distinguished from other lymphocyte types, such as
B cellB cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of Antigen Presenting Cells and eventually develop into memory B cells after activation by antigen interaction...
s and
natural killer cellNatural killer cells are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses...
s by the presence of a special receptor on their cell surface called
T cell receptorThe T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is, in general, responsible for recognizing antigens bound to major histocompatibility complex molecules....
s (TCR). The abbreviation
T, in
T cell, stands for
thymusIn human anatomy, the thymus is an organ located in the upper anterior portion of the chest cavity just behind the sternum. The main function of the thymus is to provide an area for T lymphocyte maturation, and is vital in protecting against autoimmunity....
, since this is the principal organ responsible for the T cell's maturation. Several different subsets of T cells have been discovered, each with a distinct function.
Helper
T cells which express the
CD4CD4 is a glycoprotein expressed on the surface of T helper cells, regulatory T 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...
protein on their surface are called T helper cells because they assist other leukocytes (e.g. macrophages, B cells, cytotoxic T cells) in immunological processes. There is also a sub-population of CD4 cells which suppress the activity of B cells via the production of gamma interferon and equally a sub-population of CD4 cells may suppress cell mediated immune responses via the production IL-4 and IL-10. Helper T cells are presented peptide
antigenAn antigen is a substance that prompts the generation of antibodies and can cause an immune response. "Self" antigens are usually tolerated by the immune system; whereas "Non-self" antigens are identified as intruders and attacked by the immune system...
s associated with
MHC class IIMHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....
on the surface of Antigen Presenting Cells (APCs). Once activated, they divide rapidly and secrete small proteins called
cytokineCytokines are any of a number of substances that are secreted by specific cells of the immune system which carry signals locally between cells, and thus have an effect on other cells. They are a category of signaling molecules that are used extensively in cellular communication. They are proteins,...
s that regulate or assist in the immune response. Depending on the size, cytokine signals received, these cells differentiate into T
H1, T
H2,
TH3Th3 cells have different cytokine requirements for their growth from CD25+ CD4+ Treg cells. The survival of CD25+ CD4+ Treg cells is dependent upon IL-2 , while in vitro differentiation of Th3 cells is enhanced by TGF-β, IL-4, and IL-10....
, T
H17,
TFHFollicular B helper T cells , are antigen-experienced CD4+ T cells found in the B cell follicles of secondary lymphoid organs such as lymph nodes, spleens and Peyer's patches, and are identified by their constitutive expression of the B cell follicle homming receptor CXCR5...
, or one of other subsets, which secrete different cytokines.
Cytotoxic
Cytotoxic T cellA cytotoxic T cell belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or dysfunctional...
s (T
C cells, or CTLs) destroy virally infected cells and tumor cells, and are also implicated in
transplantOrgan transplant is the moving of an organ from one body to another , for the purpose of replacing the recipient's damaged or failing organ with a working one from the donor site. Organ donors can be living or deceased...
rejection. These cells are also known as CD8
+ T cells (associated with MHC class I), since they express the
CD8CD8 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...
glycoprotein at their surface. Through IL-10, adenosine and other molecules secreted by T regulatory CD4+CD25+FoxP3+ cells, the CD8+ cells can be inactivated to an anergic state, which prevent autoimmune diseases such as
experimental autoimmune encephalomyelitisExperimental autoimmune encephalomyelitis, sometimes Experimental Allergic Encephalomyelitis is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system...
.
Memory
Memory T cells are a subset of
antigenAn antigen is a substance that prompts the generation of antibodies and can cause an immune response. "Self" antigens are usually tolerated by the immune system; whereas "Non-self" antigens are identified as intruders and attacked by the immune system...
-specific T cells that persist long-term after an infection has resolved. They quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen, thus providing the immune system with "memory" against past infections. Memory T cells comprise two subtypes: central memory T cells (T
CM cells) and effector memory T cells (T
EM cells). Memory cells may be either CD4+ or CD8+.
Regulatory
Regulatory T cellRegulatory T cells are a specialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self-antigens. The existence of a dedicated population of suppressive T cells was the subject of significant...
s (T
reg cells), formerly known as
suppressor T cells, are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Two major classes of CD4+ regulatory T cells have been described, including the naturally occurring T
reg cells and the adaptive T
reg cells. Naturally occurring T
reg cells (also known as CD4
+CD25
+FoxP3
+ T
reg cells) arise in the
thymusIn human anatomy, the thymus is an organ located in the upper anterior portion of the chest cavity just behind the sternum. The main function of the thymus is to provide an area for T lymphocyte maturation, and is vital in protecting against autoimmunity....
, whereas the adaptive T
reg cells (also known as Tr1 cells or Th3 cells) may originate during a normal immune response. Naturally occurring T
reg cells can be distinguished from other T cells by the presence of an intracellular molecule called
FoxP3FOXP3 is a gene involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as the master regulator in the development and function of regulatory T cells....
. Mutations of the
FOXP3 gene can prevent regulatory T cell development, causing the fatal
autoimmune diseaseAutoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. This may be restricted to certain organs or involve a particular tissue in different places Autoimmune...
IPEX.
Natural killer
Natural killer T cellNatural killer T cells are a heterogeneous group of T cells that share properties of both T cells and natural killer cells. Many of these cells recognize the non-polymorphic CD1d molecule, an antigen-presenting molecule that binds self- and foreign lipids and glycolipids...
s (NKT cells) are a special kind of lymphocyte that bridges the
adaptive immune systemThe adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic challenges. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older...
with the
innate immune systemThe innate immune system comprises the cells and mechanisms that defend the host from infection by other organisms, in a non-specific manner. This means that the cells of the innate system recognize and respond to pathogens in a generic way, but unlike the adaptive immune system, it does not confer...
. Unlike conventional T cells that recognize peptide antigen presented by
major histocompatibility complexThe major histocompatibility complex is a large genomic region or gene family found in most vertebrates. It is the most gene-dense region of the mammalian genome and plays an important role in the immune system and autoimmunity. The diversity of MHC is important in the immune diversity in the...
(MHC) molecules, NKT cells recognize glycolipid antigen presented by a molecule called CD1d. Once activated, these cells can perform functions ascribed to both T
h and T
c cells (i.e., cytokine production and release of cytolytic/cell killing molecules). They are also able to recognize and eliminate some tumor cells and cells infected with herpes viruses.
γδ
γδ T cells (
gammaGamma uppercase Γ, lowercase γ; ) is the third letter of the Greek alphabet. In the system of Greek numerals it has a value of 3. It was derived from the Phoenician letter Gimel . Letters that arose from Gamma include the Roman C and G and the Cyrillic letters Ge Г and Ghe Ґ.In Modern Greek, it...
deltaDelta is the fourth letter of the Greek alphabet. In the system of Greek numerals it has a value of 4. It was derived from the Phoenician letter Dalet...
T cell'T cells' 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 lymphocyte types, such as B cells and natural killer cells by the presence of a special receptor on their cell surface called T cell receptors...
s) represent a small subset of T cells that possess a distinct
T cell receptorThe T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is, in general, responsible for recognizing antigens bound to major histocompatibility complex molecules....
(TCR) on their surface. A majority of T cells have a
TCRThe T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is, in general, responsible for recognizing antigens bound to major histocompatibility complex molecules....
composed of two
glycoproteinGlycoproteins are proteins that contain oligosaccharide chains covalently attached to their 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...
chains called α- and β- TCR chains. However, in γδ T cells, the TCR is made up of one γ-chain and one δ-chain. This group of T cells is much less common (5% of total T cells) than the αβ T cells, but are found at their highest abundance in the gut mucosa, within a population of lymphocytes known as
intraepithelial lymphocyteIntraepithelial lymphocytes are lymphocytes found in the epithelial layer of mammalian mucosal linings, such as the gastrointestinal tract and reproductive tract. However, unlike other T cells, IEL's do not need priming. Upon encountering antigens, they immediately release cytokines and cause...
s (IELs). The antigenic molecules that activate γδ T cells are still widely unknown. However, γδ T cells are not MHC restricted and seem to be able to recognise whole proteins rather than requiring peptides to be presented by MHC molecules on antigen presenting cells. Some recognize MHC class IB molecules though. Human Vγ9/Vδ2 T cells, which constitute the major γδ T cell population in peripheral blood, are unique in that they specifically and rapidly respond to a small non-peptidic microbial metabolite, HMB-PP, an
isopentenyl pyrophosphateIsopentenyl pyrophosphate is an intermediate in the classical, HMG-CoA reductase pathway used by organisms in the biosynthesis of terpenes and terpenoids. IPP is formed from acetyl-CoA via mevalonic acid...
precursor.
Development in the thymus
See ThymocyteThymocytes are lymphocytes which develop in the thymus. They can develop into T cells or natural killer cells.The processes of beta-selection, positive selection and negative selection shape the population thymocytes into a peripheral pool of T cells that are able to respond to foreign pathogens...
for review of thymic selection
All T cells originate from
hematopoietic stem cellsHematopoietic stem cells are multipotent stem cells that give rise to all the blood cell types including myeloid , and lymphoid lineages...
in the
bone marrowBone marrow is the flexible tissue found in the hollow interior of bones. In adults, marrow in large bones produces new blood cells. It constitutes 4% of total body weight, i.e...
. Hematopoietic progenitors derived from
hematopoietic stem cellsHematopoietic stem cells are multipotent stem cells that give rise to all the blood cell types including myeloid , and lymphoid lineages...
populate the
thymusIn human anatomy, the thymus is an organ located in the upper anterior portion of the chest cavity just behind the sternum. The main function of the thymus is to provide an area for T lymphocyte maturation, and is vital in protecting against autoimmunity....
and expand by cell division to generate a large population of immature thymocytes. The earliest thymocytes express neither CD4 nor CD8, and are therefore classed as
double-negative (CD4
-CD8
-) cells. As they progress through their development they become
double-positive thymocytes (CD4
+CD8
+), and finally mature to
single-positive (CD4
+CD8
- or CD4
-CD8
+) thymocytes that are then released from the
thymusIn human anatomy, the thymus is an organ located in the upper anterior portion of the chest cavity just behind the sternum. The main function of the thymus is to provide an area for T lymphocyte maturation, and is vital in protecting against autoimmunity....
to peripheral tissues.
About 98% of thymocytes die during the development processes in the thymus by failing either
positive selection or
negative selection, whereas the other 2% survive and leave the thymus to become mature immunocompetent T cells.
The thymus contributes more naive T cells at younger ages. As the thymus shrinks by about 3% a year throughout middle age, there is a corresponding fall in the thymic production of naive T cells, leaving peripheral T cell expansion to play a greater role in protecting older subjects.
Positive selection
Positive selection "selects for" T-cells capable of interacting with MHC. Double-positive
thymocyteThymocytes are lymphocytes which develop in the thymus. They can develop into T cells or natural killer cells.The processes of beta-selection, positive selection and negative selection shape the population thymocytes into a peripheral pool of T cells that are able to respond to foreign pathogens...
s (CD4+/CD8+) move deep into the thymic
cortexIn anatomy and zoology the cortex is the outermost layer of an organ. Organs with well-defined cortical layers include kidneys, adrenal glands, ovaries, the thymus, and portions of the brain, including the cerebral cortex, the most well-known of all cortices.The cerebral cortex is the thin gray...
where they are presented with self-
antigenAn antigen is a substance that prompts the generation of antibodies and can cause an immune response. "Self" antigens are usually tolerated by the immune system; whereas "Non-self" antigens are identified as intruders and attacked by the immune system...
s (i.e., antigens that are derived from molecules belonging to the host of the T cell) complexed with
MHCThe major histocompatibility complex is a large genomic region or gene family found in most vertebrates. It is the most gene-dense region of the mammalian genome and plays an important role in the immune system and autoimmunity. The diversity of MHC is important in the immune diversity in the...
molecules on the surface of cortical epithelial cells. Only those thymocytes that bind the MHC/antigen complex with adequate affinity will receive a vital "survival signal." Developing thymocytes that do not have adequate affinity cannot serve useful functions in the body (i.e. the cells must be able to interact with MHC and peptide complexes in order to affect immune responses). Because of this, the thymocytes with low affinity die by
apoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death; in more specific terms, a series of biochemical events that lead to a variety of...
and are engulfed by
macrophageMacrophages are white blood cells within tissues, produced by the division of monocytes. Human macrophages are about in diameter...
s.
A thymocyte's fate is also determined during positive selection. Double-positive cells (CD4+/CD8+) that are positively selected on MHC class II molecules will eventually become CD4+ cells, while cells positively selected on MHC class I molecules mature into CD8+ cells. A T cell becomes a CD4+ cell by downregulating expression of its CD8 cell surface receptors. If the cell does not lose its signal through the ITAM pathway, it will continue downregulating CD8 and become a CD4+, single positive cell. But if there is signal drop, the cell stops downregulating CD8 and switches over to downregulating CD4 molecules instead, eventually becoming a CD8+, single positive cell.
This process does not remove thymocytes that may cause
autoimmunityAutoimmunity 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...
. The potentially autoimmune cells are removed by the process of
negative selection (discussed below).
Negative selection
Negative selection removes thymocytes that are capable of strongly binding with "self" peptides presented by MHC. Thymocytes that survive positive selection migrate towards the boundary of the thymic cortex and thymic medulla. While in the medulla, they are again presented with self-antigen in complex with MHC molecules on
antigen-presenting cellAn antigen-presenting cell or accessory cell is a cell that displays foreign antigen complex with major histocompatibility complex on its surface...
s (APCs) such as
dendritic cellDendritic cells are immune cells that form part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system, thus functioning as antigen-presenting cells....
s and
macrophageMacrophages are white blood cells within tissues, produced by the division of monocytes. Human macrophages are about in diameter...
s. Thymocytes that interact too strongly with the antigen receive an
apoptoticApoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death; in more specific terms, a series of biochemical events that lead to a variety of...
signal that leads to cell death. The vast majority of all thymocytes end up dying during this process. The remaining cells exit the thymus as mature naive T cells. This process is an important component of immunological tolerance and serves to prevent the formation of self-reactive T cells that are capable of generating
autoimmune diseaseAutoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. This may be restricted to certain organs or involve a particular tissue in different places Autoimmune...
s in the host.
Maturation paradox
Positive and negative selection should theoretically kill all developing T cells. The first stage of selection kills all T cells that do not interact with self-MHC, while the second stage selection kills all cells that do. This poses the question: How do we have immunity at all? Currently, two models attempt to explain this:
- Differential Avidity Hypothesis
The differential avidity hypothesis is one of two models that attempt to explain how humans have immunity despite such aggressive selection to kill developing T cells during their maturation process...
- the strength of the signal dictates the fate of the T cell.
- Differential Signaling Hypothesis
The differential signaling hypothesis is one of two models that attempt to explain how humans have immunity despite such aggressive selection to kill developing T cells during their maturation process. The other model is the differential avidity hypothesis.The differential signaling hypothesis...
- the signals that are transduced differ at each stage.
Activation
Although the specific mechanisms of activation vary slightly between different types of T cells, the "two-signal model" in CD4+ T cells holds true for most. Activation of CD4+ T cells occurs through the engagement of both the
T cell receptorThe T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is, in general, responsible for recognizing antigens bound to major histocompatibility complex molecules....
and
CD28CD28 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 B7.1 and B7.2 . When activated by Toll-like receptor ligands, the B7.1 expression is upregulated in antigen presenting cells...
on the T cell by the
Major histocompatibility complexThe major histocompatibility complex is a large genomic region or gene family found in most vertebrates. It is the most gene-dense region of the mammalian genome and plays an important role in the immune system and autoimmunity. The diversity of MHC is important in the immune diversity in the...
peptidePeptides are short polymers formed from the linking, in a defined order, of α-amino acids. The link between one amino acid residue and the next is called an amide bond or a peptide bond....
and
B7B7 is a type of peripheral membrane protein found on activated antigen presenting cells that, when paired with either a CD28 or CD152 surface protein on a T cell, can produce a costimulatory signal to enhance or decrease the activity of a MHC-TCR signal between the APC and the T cell,...
family members on the
APCAn antigen-presenting cell or accessory cell is a cell that displays foreign antigen complex with major histocompatibility complex on its surface...
, respectively. Both are required for production of an effective immune response; in the absence of CD28
co-stimulationDuring 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 :...
, T cell receptor signalling alone results in
anergyAnergy is a term in immunobiology that describes a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune system is unable to mount a normal...
. The signalling pathways downstream from both
CD28CD28 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 B7.1 and B7.2 . When activated by Toll-like receptor ligands, the B7.1 expression is upregulated in antigen presenting cells...
and the T cell receptor involve many proteins.
The first signal is provided by binding of the T cell receptor to a short peptide presented by the major histocompatibility complex (MHC) on another cell. This ensures that only a T cell with a TCR specific to that peptide is activated. The partner cell is usually a professional antigen presenting cell (APC), usually a
dendritic cellDendritic cells are immune cells that form part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system, thus functioning as antigen-presenting cells....
in the case of
naïveA naive T cell or Th0 cell is a T cell that has differentiated in bone marrow, and successfully undergone the positive and negative processes of central selection in the thymus...
responses, although B cells and macrophages can be important APCs. The peptides presented to
CD8CD8 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...
+ T cells by MHC class I molecules are 8-9 amino acids in length; the peptides presented to
CD4CD4 is a glycoprotein expressed on the surface of T helper cells, regulatory T 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...
+ cells by
MHCThe major histocompatibility complex is a large genomic region or gene family found in most vertebrates. It is the most gene-dense region of the mammalian genome and plays an important role in the immune system and autoimmunity. The diversity of MHC is important in the immune diversity in the...
class II molecules are longer, as the ends of the binding cleft of the MHC class II molecule are open.
The second signal comes from co-stimulation, in which surface receptors on the APC are induced by a relatively small number of stimuli, usually products of pathogens, but sometimes breakdown products of cells, such as
necroticNecrosis is the premature death of cells and living tissue. Necrosis is caused by external factors, such as infection, toxins , or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
-bodies or heat-shock proteins. The only co-stimulatory receptor expressed constitutively by naïve T cells is
CD28CD28 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 B7.1 and B7.2 . When activated by Toll-like receptor ligands, the B7.1 expression is upregulated in antigen presenting cells...
, so co-stimulation for these cells comes from the
CD80The protein CD80 is a molecule found on activated B cells and monocytes which provides a costimulatory signal necessary for T cell activation and survival. It is also known as B7.1....
and
CD86The protein CD86 is a molecule expressed on antigen-presenting cells that provide costimulatory signals necessary for T cell activation and survival. It is the ligand for two proteins at the cell surface of T cells, CD28 antigen and CTLA-4 . CD86 is also known as B7.2...
proteins, which together constitute the
B7B7 is a type of peripheral membrane protein found on activated antigen presenting cells that, when paired with either a CD28 or CD152 surface protein on a T cell, can produce a costimulatory signal to enhance or decrease the activity of a MHC-TCR signal between the APC and the T cell,...
protein, (B7.1 and B7.2 respectively) on the APC. Other receptors are expressed upon activation of the T cell, such as OX40 and
ICOSInducible T-cell costimulator is a protein that in humans is encoded by the ICOS gene.CD278 or ICOS is a CD28-superfamily costimulatory molecule that is expressed on activated T cells...
, but these largely depend upon
CD28CD28 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 B7.1 and B7.2 . When activated by Toll-like receptor ligands, the B7.1 expression is upregulated in antigen presenting cells...
for their expression. The second signal licenses the T cell to respond to an antigen. Without it, the T cell becomes
anergicAnergy is a term in immunobiology that describes a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune system is unable to mount a normal...
, and it becomes more difficult for it to activate in future. This mechanism prevents inappropriate responses to self, as self-peptides will not usually be presented with suitable co-stimulation.
The
T cell receptorThe T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is, in general, responsible for recognizing antigens bound to major histocompatibility complex molecules....
exists as a complex of several proteins. The actual T cell receptor is composed of two separate peptide chains, which are produced from the independent T cell receptor alpha and beta (TCRα and TCRβ) genes. The other proteins in the complex are the CD3 proteins: CD3εγ and CD3εδ heterodimers and, most important, a CD3ζ homodimer, which has a total of six
ITAMAn immunoreceptor tyrosine-based activation motif is a conserved sequence of four amino acids that is repeated twice in the cytoplasmic tails of certain cell surface proteins of the immune system....
motifs. The ITAM motifs on the CD3ζ can be phosphorylated by
LckLck is a protein that is found inside specialized cells of the immune system called lymphocytes. Lck is a tyrosine kinase, which phosphorylates tyrosine residues of certain proteins involved in the intracellular signaling pathways of these lymphocytes...
and in turn recruit
ZAP-70ZAP-70 is an abbreviation for Zeta-chain-associated protein kinase 70 . The protein is a member in the protein-tyrosine kinase family...
. Lck and/or ZAP-70 can also phosphorylate the tyrosines on many other molecules, not least
CD28CD28 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 B7.1 and B7.2 . When activated by Toll-like receptor ligands, the B7.1 expression is upregulated in antigen presenting cells...
, ,
LATLinker of Activated T cells also known as LAT is a protein which in humans is encoded by the LAT gene. Alternative splicing results in multiple transcript variants encoding different isoforms.- Function :...
and SLP-76, which allows the aggregation of signalling complexes around these proteins.
Phosphorylated
LATLinker of Activated T cells also known as LAT is a protein which in humans is encoded by the LAT gene. Alternative splicing results in multiple transcript variants encoding different isoforms.- Function :...
recruits SLP-76 to the membrane, where it can then bring in PLCγ,
VAV1Proto-oncogene vav is a protein that in humans is encoded by the VAV1 gene.-Interactions:VAV1 has been shown to interact with Ku70, PLCG1, Lymphocyte cytosolic protein 2, Janus kinase 2, SIAH2, S100B, Abl gene, ARHGDIB, SHB, PIK3R1, PRKCQ, Grb2, MAPK1, Syk, Linker of activated T cells, Cbl gene and...
,
ItkItk is a framework for building mega-widgets using the [incr Tcl] object system. Mega-widgets are high-level widgets like a file browser or a tab notebook that act like ordinary Tk widgets but are constructed using Tk widgets as component parts, without having to write C code. In effect, a...
and potentially PI3K. Both PLCγ and PI3K act on PI(4,5)P2 on the inner leaflet of the membrane to create the active intermediaries diacylglycerol (
DAGA diglyceride, or a diacylglycerol , is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages....
), inositol-1,4,5-trisphosphate (
IP3Inositol trisphosphate or inositol 1,4,5-trisphosphate , together with diacylglycerol, is a secondary messenger molecule used in signal transduction and Lipid signaling in biological cells...
), and phosphatidlyinositol-3,4,5-trisphosphate (PIP3). DAG binds and activates some PKCs, most important, in T cells PKCθ, a process important for activating the transcription factors NF-κB and AP-1.
IP3Inositol trisphosphate or inositol 1,4,5-trisphosphate , together with diacylglycerol, is a secondary messenger molecule used in signal transduction and Lipid signaling in biological cells...
is released from the membrane by PLCγ and diffuses rapidly to activate receptors on the
ERThe endoplasmic reticulum is an eukaryotic organelle that forms an interconnected network of tubules, vesicles, and cisternae within cells. The lacey membranes of the endoplasmic reticulum were first seen by Keith R. Porter, Albert Claude, and Ernest F...
, which induce the release of
calciumCalcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft grey alkaline earth metal, and is the fifth most abundant element by mass in the Earth's crust...
. The released calcium then activates
calcineurinCalcineurin is a protein phosphatase also known as protein phosphatase 3, PPP3CA, and formerly known as protein phosphatase 2B . It activates the T cells of the immune system and can be blocked by drugs. Calcineurin activates NFATc , a transcription factor by dephosphorylating it...
, and
calcineurinCalcineurin is a protein phosphatase also known as protein phosphatase 3, PPP3CA, and formerly known as protein phosphatase 2B . It activates the T cells of the immune system and can be blocked by drugs. Calcineurin activates NFATc , a transcription factor by dephosphorylating it...
activates
NFATNuclear factor of activated T-cells is a general name applied to a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system...
, which then translocates to the nucleus. NFAT is a
transcription factorIn the field of molecular biology, a transcription factor is a protein that binds to specific DNA sequences and thereby controls the transfer of genetic information from DNA to mRNA...
, which activates the transcription of a pleiotropic set of genes, most notable,
IL-2Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self...
, a cytokine that promotes long term proliferation of activated T cells.
External links