CD28
Encyclopedia
CD28 is one of the molecule
s expressed on T cells that provide co-stimulatory
signals, which are required for T cell
activation. CD28 is the receptor for CD80
(B7.1) and CD86
(B7.2). When activated by Toll-like receptor
ligands, the CD80 expression is upregulated in antigen presenting cells (APCs). The CD86 expression on antigen presenting cells is constitutive. CD28 is the only B7 receptor constitutively expressed on naive T cell
s.
Stimulation through CD28 in addition to the TCR
can provide a potent co-stimulatory signal to T cells for the production of various interleukin
s (IL-2
and IL-6
in particular). Association of the T cell receptor
of a naive T cell
with MHC
:antigen
complex without CD28:B7 interaction results in a T cell that is anergic.
170 in particular is critical for the recruitment of SH2
-domain containing proteins, especially PI3K, Grb2
and Gads
. The Y170 residue is important for the induction of Bcl-XL via mTOR and enhancement of IL-2
transcription via PKCθ, but has no effect on proliferation and results a slight reduction in IL-2 production. The N172 residue (as part of the YMNM) is important for the binding of Grb2
and Gads
and seems to be able to induce IL-2 mRNA stability but not NF-κB translocation. The induction of NF-κB seems to be much more dependent on the binding of Gads
to both the YMNM and the two proline-rich motifs within the molecule. However, mutation of the final amino acid of the motif, M173, which is unable to bind PI3K but is able to bind Grb2 and Gads, gives little NF-κB or IL-2, suggesting that those Grb2
and Gads
are unable to compensate for the loss of PI3K . IL-2 transcription appears to have two stages; a Y170-dependent, PI3K-dependent initial phase which allows transcription and a second phase which is dependent on formation of an immune synapse and PI3K-independent which results in enhancement of IL-2 mRNA stability. Both are required for full production of IL-2.
CD28 also contains two proline
-rich motifs that are able to bind SH3
-containing proteins. Itk and Tec are able to bind to the N-terminal of these two motifs which immediately succeeds the Y170 YMNM; Lck
binds the C-terminal. Both Itk and Lck are able to phosphorylate the tyrosine residues which then allow binding of SH2 containing proteins to CD28. Binding of Tec to CD28 enhances IL-2 production, dependent on binding of its SH3 and PH
domains to CD28 and PIP3 respectively. The C-terminal proline-rich motif in CD28 is important for bringing Lck
and lipid rafts into the immune synapse via filamin-A. Mutation of the two prolines within the C-terminal motif results in reduced proliferation and IL-2 production but normal induction of Bcl-XL
.
.
, which was produced by the German biotech company TeGenero and which unexpectedly caused multiple organ failure in trials, is a superagonist
of CD28. Unfortunately it is often ignored that the same receptors also exist on cells other than lymphocyte
s. CD28 has also been found to stimulate eosinophil granulocyte
s where its ligation with anti-CD28 leads to the release of IL-2
, IL4
, IL-13
and IFN-γ
.
with PIK3R1
, Grb2
and GRAP2
.
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
s expressed on T cells that provide co-stimulatory
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 :...
signals, which are required for T cell
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...
activation. CD28 is the receptor for 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...
(B7.1) and 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...
(B7.2). When activated by Toll-like receptor
Toll-like receptor
Toll-like receptors are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes...
ligands, the CD80 expression is upregulated in antigen presenting cells (APCs). The CD86 expression on antigen presenting cells is constitutive. CD28 is the only B7 receptor constitutively expressed on naive T cell
Naive T cell
A 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...
s.
Stimulation through CD28 in addition to the 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...
can provide a potent co-stimulatory signal to T cells for the production of various interleukin
Interleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...
s (IL-2
Interleukin 2
Interleukin-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...
and IL-6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
in particular). Association of the T cell 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...
of a naive T cell
Naive T cell
A 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...
with 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...
: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...
complex without CD28:B7 interaction results in a T cell that is anergic.
Signalling
CD28 possesses an intracellular domain with several residues that are critical for its effective signalling. The YMNM motif beginning at tyrosineTyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
170 in particular is critical for the recruitment of SH2
SH2 domain
The SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
-domain containing proteins, especially PI3K, Grb2
Grb2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
and Gads
GADS
GADS may refer to:* Gateway Algorithms and Data Structures* Generating Availability Data System, US power plant information* Gilliam Asperger's Disorder Scale, a diagnostic tool for Asperger Syndrome...
. The Y170 residue is important for the induction of Bcl-XL via mTOR and enhancement of IL-2
Interleukin 2
Interleukin-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...
transcription via PKCθ, but has no effect on proliferation and results a slight reduction in IL-2 production. The N172 residue (as part of the YMNM) is important for the binding of Grb2
Grb2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
and Gads
GADS
GADS may refer to:* Gateway Algorithms and Data Structures* Generating Availability Data System, US power plant information* Gilliam Asperger's Disorder Scale, a diagnostic tool for Asperger Syndrome...
and seems to be able to induce IL-2 mRNA stability but not NF-κB translocation. The induction of NF-κB seems to be much more dependent on the binding of Gads
GADS
GADS may refer to:* Gateway Algorithms and Data Structures* Generating Availability Data System, US power plant information* Gilliam Asperger's Disorder Scale, a diagnostic tool for Asperger Syndrome...
to both the YMNM and the two proline-rich motifs within the molecule. However, mutation of the final amino acid of the motif, M173, which is unable to bind PI3K but is able to bind Grb2 and Gads, gives little NF-κB or IL-2, suggesting that those Grb2
Grb2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
and Gads
GADS
GADS may refer to:* Gateway Algorithms and Data Structures* Generating Availability Data System, US power plant information* Gilliam Asperger's Disorder Scale, a diagnostic tool for Asperger Syndrome...
are unable to compensate for the loss of PI3K . IL-2 transcription appears to have two stages; a Y170-dependent, PI3K-dependent initial phase which allows transcription and a second phase which is dependent on formation of an immune synapse and PI3K-independent which results in enhancement of IL-2 mRNA stability. Both are required for full production of IL-2.
CD28 also contains two proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
-rich motifs that are able to bind SH3
SH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
-containing proteins. Itk and Tec are able to bind to the N-terminal of these two motifs which immediately succeeds the Y170 YMNM; Lck
Lck
Lck 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...
binds the C-terminal. Both Itk and Lck are able to phosphorylate the tyrosine residues which then allow binding of SH2 containing proteins to CD28. Binding of Tec to CD28 enhances IL-2 production, dependent on binding of its SH3 and PH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
domains to CD28 and PIP3 respectively. The C-terminal proline-rich motif in CD28 is important for bringing Lck
Lck
Lck 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 lipid rafts into the immune synapse via filamin-A. Mutation of the two prolines within the C-terminal motif results in reduced proliferation and IL-2 production but normal induction of Bcl-XL
Bcl-xL
B-cell lymphoma-extra large is a transmembrane molecule in the mitochondria. It is involved in the signal transduction pathway of the FAS-L. It is one of several anti-apoptotic proteins which are members of the Bcl-2 family of proteins. It has been implicated in the survival of cancer cells. Other...
.
Structure
The first structure of CD28 was obtained in 2005 by the T-cell biology group at the University of OxfordUniversity of Oxford
The University of Oxford is a university located in Oxford, United Kingdom. It is the second-oldest surviving university in the world and the oldest in the English-speaking world. Although its exact date of foundation is unclear, there is evidence of teaching as far back as 1096...
.
CD28 as a drug target
The drug TGN1412TGN1412
TGN1412 is the working name of an immunomodulatory drug which was withdrawn from development after inducing severe inflammatory reactions in the first human subjects to receive the drug....
, which was produced by the German biotech company TeGenero and which unexpectedly caused multiple organ failure in trials, is a superagonist
Superagonist
An irreversible agonist is a type of agonist that binds permanently to a receptor in such a manner that the receptor is permanently activated. It is distinct from a mere agonist in that the association of an agonist to a receptor is reversible, whereas the binding of an irreversible agonist to a...
of CD28. Unfortunately it is often ignored that the same receptors also exist on cells other than lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s. CD28 has also been found to stimulate eosinophil granulocyte
Eosinophil granulocyte
Eosinophil granulocytes, usually called eosinophils or eosinophiles , are white blood cells that are one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells, they also control mechanisms associated with...
s where its ligation with anti-CD28 leads to the release of IL-2
Interleukin 2
Interleukin-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...
, IL4
Interleukin 4
Interleukin-4, abbreviated IL-4, is a cytokine that induces differentiation of naive helper T cells to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4. The cell that initially produces IL-4, thus inducing Th0 differentiation, has not been identified, but recent...
, IL-13
Interleukin 13
Interleukin 13 is a protein that in humans is encoded by the IL13 gene. IL-13 is cytokine secreted by many cell types, but especially T helper type 2 cells, that is a mediator of allergic inflammation and disease.-Functions:...
and IFN-γ
Interferon-gamma
Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...
.
Interactions
CD28 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with PIK3R1
PIK3R1
Phosphatidylinositol 3-kinase regulatory subunit alpha is an enzyme that in humans is encoded by the PIK3R1 gene.-Interactions:PIK3R1 has been shown to interact with EPH receptor A2, KHDRBS1, Lymphocyte cytosolic protein 2, Janus kinase 2, GAB2, CD117, BCAR1, CD28, SHB, EZR, PIK3CD, GAB1, HRAS,...
, Grb2
Grb2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
and GRAP2
GRAP2
GRB2-related adapter protein 2 is a protein that in humans is encoded by the GRAP2 gene.-Interactions:GRAP2 has been shown to interact with CD28, STAMBP, CCNDBP1, Linker of activated T cells, Lymphocyte cytosolic protein 2 and MAP4K1....
.