CD28 (Cluster of Differentiation 28) is one of the
moleculeA molecule is defined as an electrically neutral group of at least two atoms in a definite arrangement held together by very strong chemical bonds. Molecules are distinguished from polyatomic ions in this strict sense...
s expressed on T cells that provide
co-stimulatoryDuring 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 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...
activation. CD28 is the receptor for B7.1 (
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 B7.2 (
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...
). When activated by
Toll-like receptorToll-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 B7.1 expression is upregulated in antigen presenting cells (APCs). The B7.2 expression on antigen presenting cells is constitutive. CD28 is the only B7 receptor constitutively expressed on
naive T cellA 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
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....
can provide a potent co-stimulatory signal to T cells for the production of various
interleukinInterleukins are a group of cytokines that were first seen to be expressed by white blood cells , The term interleukine, as a means of communication, deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes...
s (
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...
and
IL-6Interleukin-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 to trauma, especially burns or other tissue damage leading to inflammation...
in particular).
CD28 (Cluster of Differentiation 28) is one of the
moleculeA molecule is defined as an electrically neutral group of at least two atoms in a definite arrangement held together by very strong chemical bonds. Molecules are distinguished from polyatomic ions in this strict sense...
s expressed on T cells that provide
co-stimulatoryDuring 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 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...
activation. CD28 is the receptor for B7.1 (
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 B7.2 (
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...
). When activated by
Toll-like receptorToll-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 B7.1 expression is upregulated in antigen presenting cells (APCs). The B7.2 expression on antigen presenting cells is constitutive. CD28 is the only B7 receptor constitutively expressed on
naive T cellA 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
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....
can provide a potent co-stimulatory signal to T cells for the production of various
interleukinInterleukins are a group of cytokines that were first seen to be expressed by white blood cells , The term interleukine, as a means of communication, deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes...
s (
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...
and
IL-6Interleukin-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 to trauma, especially burns or other tissue damage leading to inflammation...
in particular). Association of 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....
of a naive mature T cell with
MHC-Biology:*Myosin heavy chain - part of the motor protein myosin's quaternary protein structure-Immunology:*Major histocompatibility complex - a highly polymorphic region on chromosome 6 with genes particularly involved in immune functions-Colleges:...
:
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...
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 or 4-hydroxyphenylalanine, is one of the 20 amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group...
170 in particular is critical for the recruitment of
SH2SH2 may stand for:* Silent Hill 2* SH2 domain, Src homology 2 protein domain* The Hitachi SuperH-2 CPU core* SH-2 Seasprite, an American-built ship-based helicopter* SH-2G Super Seasprite, an American-built ship-based helicopter...
-domain containing proteins, especially PI3K,
Grb2Growth 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
GadsGADS 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 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
Grb2Growth 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
GadsGADS 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
GadsGADS 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
Grb2Growth 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
GadsGADS 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
prolineProline 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 humans can synthesize it...
-rich motifs that are able to bind
SH3SH3 or SH-3 may refer to:* SH3 domain, a protein structural domain thought to be involved in the formation of productive protein-protein binding interactions...
-containing proteins. Itk and Tec are able to bind to the N-terminal of these two motifs which immediately succeeds the Y170 YMNM;
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...
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
SH3SH3 or SH-3 may refer to:* SH3 domain, a protein structural domain thought to be involved in the formation of productive protein-protein binding interactions...
and
PHpH is a measure of the acidity or basicity of a solution. It is defined as the cologarithm of the activity of dissolved hydrogen ions . Hydrogen ion activity coefficients cannot be measured experimentally, so they are based on theoretical calculations...
domains to CD28 and PIP3 respectively. The C-terminal proline-rich motif in CD28 is important for bringing
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 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-XLBcl-xl 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. "Bcl-xl" stands for...
.
CD28 as a drug target
The drug
TGN1412TGN1412 is the working name of an immunomodulatory drug which was withdrawn from development, originally intended for the treatment of B cell chronic lymphocytic leukemia and rheumatoid arthritis...
, which was produced by the German biotech company TeGenero and which unexpectedly caused multiple organ failure in trials, is a
superagonistAn 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 recepter is reversible, whereas the binding of an irreversible agonist to a...
of CD28. The first elucidation of the molecular structure of CD28 was achieved in 2005 by the T-cell biology group at the
University of OxfordThe University of Oxford , located in the UK city of Oxford, is the oldest surviving university in the English-speaking world and is regarded as one of the world's leading academic institutions. Although the exact date of foundation remains unclear, there is evidence of teaching there as far back...
, in complex with the Fab fragment of an antibody provided by
TeGeneroTeGenero AG was a pharmaceutical research company in Würzburg, Germany. It had 15 employees and was incorporated as an Aktiengesellschaft from 2002...
. Unfortunately it is often ignored that the same receptors also exist on cells other than
lymphocyteA lymphocyte is a type of white blood cell in the vertebrate immune system.By their appearance under the light microscope, there are two broad categories of lymphocytes, namely the large granular lymphocytes and the small lymphocytes. Functionally distinct subsets of lymphocytes correlate with...
s. CD28 has also been found to stimulate
eosinophil granulocyteEosinophil granulocytes, usually called eosinophils , are white blood cells that are one of the immune system components responsible for combating infection and parasites in vertebrates. Along with mast cells, they also control mechanisms associated with allergy and asthma...
s where its ligation with anti-CD28 leads to the release of
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...
,
IL4Interleukin-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...
,
IL-13Interleukin 13 is a cytokine secreted by many cell types, but especially T helper type 2 cells, that is an important mediator of allergic inflammation and disease.-Functions:...
and
IFN-γInterferon-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 interactions involve not only the direct-contact association of protein molecules but also longer range interactions through the electrolyte, aqueous solution medium surrounding neighbor hydrated proteins over distances from less than one nanometer to distances of several tens of...
with
PIK3R1Phosphatidylinositol 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, VIL2, PIK3CD, GAB1, HRAS,...
,
Grb2Growth 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
GRAP2GRB2-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....
.
Further reading