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CD3 (
cluster of differentiation The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...
3) is a
protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain. Protein c ...
and
T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
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. Properties The ...
that is involved in activating both the
cytotoxic T cell A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...
(CD8+ naive T cells) and
T helper cells The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
(CD4+ naive T cells). It is composed of four distinct chains. In mammals, the complex contains a CD3γ chain, a CD3δ chain, and two CD3ε chains. These chains associate with the
T-cell receptor The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding b ...
(TCR) and the
CD3-zeta T-cell surface glycoprotein CD3 zeta chain also known as T-cell receptor T3 zeta chain or CD247 (Cluster of Differentiation 247) is a protein that in humans is encoded by the ''CD247'' gene. Some older literature mention a similar protein called " ...
(ζ-chain) to generate an activation signal in
T lymphocytes A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...
. The TCR, CD3-zeta, and the other CD3 molecules together constitute the TCR complex.


Structure

The CD3γ, CD3δ, and CD3ε chains are highly related cell-surface proteins of the
immunoglobulin superfamily The immunoglobulin superfamily (IgSF) is a large protein superfamily of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily ...
containing a single
extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
immunoglobulin domain. A structure of the extracellular and transmembrane regions of the CD3γε/CD3δε/CD3ζζ/TCRαβ complex was solved with
CryoEM Cryogenic electron microscopy (cryo-EM) is a cryomicroscopy technique applied on samples cooled to cryogenic temperatures. For biological specimens, the structure is preserved by embedding in an environment of vitreous ice. An aqueous sample sol ...
, showing for the first time how the CD3 transmembrane regions enclose the TCR transmembrane regions in an open barrel. Containing aspartate residues, the transmembrane region of the CD3 chains is negatively charged, a characteristic that allows these chains to associate with the positively charged TCR chains. The intracellular tails of the CD3γ, CD3ε, and CD3δ molecules each contain a single conserved motif known as an ''
immunoreceptor tyrosine-based activation motif An immunoreceptor tyrosine-based activation motif (ITAM) is a conserved sequence of four amino acids that is repeated twice in the cytoplasmic tails of non-catalytic tyrosine-phosphorylated receptors, cell-surface proteins found mainly on immune cel ...
'' or ITAM for short, which is essential for the signaling capacity of the TCR. The intracellular tail of CD3ζ contains 3 ITAM motifs.


Regulation

Phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of the ITAM on CD3 renders the CD3 chain capable of binding an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
called
ZAP70 ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of lymphocytes (T cells, natural killer cells, and a subset of B cells). It is most prominently known to be recruited upon antigen binding to ...
(zeta associated protein), a
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
that is important in the signaling cascade of the T cell.


As a drug target

Because CD3 is required for
T cell activation A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
, drugs (often
monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ca ...
) that target it are being investigated as
immunosuppressant Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be classified in ...
therapies (e.g.,
otelixizumab Otelixizumab, also known as TRX4, is a monoclonal antibody, which is being developed for the treatment of type 1 diabetes and other autoimmune diseases. The antibody is being developed by Tolerx, Inc. in collaboration with GlaxoSmithKline and ...
,
teplizumab Teplizumab, sold under the brand name Tzield, is a humanized anti-CD3 monoclonal antibody that is the first approved treatment indicated to delay the onset of stage 3 type 1 diabetes (T1D) in people with stage 2 T1D. The Fc region of this antibod ...
) for
type 1 diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar ...
and other
autoimmune disease An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
s.


As a drug target in cancer research

New anticancer drug treatments are being developed based upon the CD3 T cell co-receptor, with molecules being designed for altering the co-stimulatory signal to help get the T-cell to recognize the cancer cell and become fully activated. Cancers that possess the B7-H3 immunoregulatory checkpoint receptor on the tumor cell have been one such target in clinical trials. This B7-H3 protein is expressed on cancer cell for several types of cancer. Often, the drug will contain two domains, one binding the T-cell's CD3 and the other targeting and binding cancer cells.


Immunohistochemistry

CD3 is initially expressed in the cytoplasm of pro-thymocytes, the
stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
s from which T-cells arise in the
thymus The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...
. The pro-thymocytes differentiate into common
thymocyte A Thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood. Thymopoiesis describes the process which turns thymo ...
s, and then into medullary thymocytes, and it is at this latter stage that CD3 antigen begins to migrate to the cell membrane. The antigen is found bound to the membranes of all mature T-cells, and in virtually no other cell type, although it does appear to be present in small amounts in
Purkinje cell Purkinje cells, or Purkinje neurons, are a class of GABAergic inhibitory neurons located in the cerebellum. They are named after their discoverer, Czech people, Czech anatomist Jan Evangelista Purkyně, who characterized the cells in 1839. Stru ...
s. This high specificity, combined with the presence of CD3 at all stages of T-cell development, makes it a useful
immunohistochemical Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to ant ...
marker for T-cells in tissue sections. The antigen remains present in almost all T-cell
lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...
s and
leukaemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
s, and can therefore be used to distinguish them from superficially similar B-cell and myeloid
neoplasm A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s.


References


Further reading

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External links

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Mouse CD Antigen Chart
{{DEFAULTSORT:Cd3 (Immunology) Clusters of differentiation T cells Immunology