T-Cell Receptor and CD3 Complex
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T-Cell Receptor and CD3 Complex

Lymphocytes are one of the five kinds of white blood cells or leukocytes, circulating in the blood. Although mature lymphocytes all look pretty much alike, they are extraordinarily diverse in their functions. The most abundant lymphocytes are: B-Lymphocytes (often simply called B-Cells) and T-Lymphocytes (likewise called T-Cells). T-Cells are produced in bone marrow. The precursors of T-Cells leave the bone marrow and mature in the thymus. T-Cells recognize antigen through a cell surface receptor known as the TCR (T-Cell Receptor), which has a structural and functional similarilities to the membrane-bound Immunoglobulin that serve as the BCR (B-Cell Receptor) for antigen. TCRs are heterodimeric glycoproteins in which each polypeptide chain consist of a variable domain and a constant domain, similar to those found in Immunoglobulin chains, and a membrane-spanning region. The three dimensional structure of the extracellular domains of the TCR resembles that of the antigen binding Fab fragment of IgG (Ref.1).

There are two types of T-Cells- TH (T-Helper) Cells and CTLs (Killer cells, or Cytotoxic T-lymphocytes). TCR on both these types of T-Cells are two chain molecules built similarly to antibodies. The chains of the most common TCRs are called Alpha and Beta; they are 40,000MW glycoproteins, both anchored in the T-Cell membrane. A second TCR, found on a minor population of T-Cells, is made of Gamma and Delta chains. Although its function is poorly understood, this receptor appears to be a key player in immunity to certain bacteria (Ref.2).

TCR are integral membrane proteins. They are present in thousands of identical copies exposed at the cell surface. They are made before the cell ever encounters an antigen. They are encoded by genes assembled by the recombination of segments of DNA. They have a unique binding site. This site binds to a portion of the antigen called an antigenic determinant or epitope. The binding depends on complementarity of the surface of the receptor and the surface of the epitope. The binding occurs by non-covalent forces. Successful binding of the antigen receptor to the epitope, if accompanied by additional "signals", results in stimulation of the cell to leave G0 and enter the cell cycle (Ref.3).

The TCR complex of transmembrane proteins includes the T-Cells Receptor that recognizes antigen and a set of proteins called CD3 involved in signal transduction. The T-Cell antigen receptor complex consists of a TCR-Alpha and TCR-Beta chain heterodimer, two CD3-Epsilon chains, a CD3-Gamma chain, a CD3-Delta chain and a CD3-Zeta chain homodimer. The complex mediates antigen recognition, ultimately resulting in T-Cell activation. The intracellular portions of the CD3{Gamma, Delta, Epsilon and Zeta subunits) contain copies of a sequence motif termed ITAMs (Immunoreceptor Tyrosine-based Activation Motifs). ITAMs can serve as protein tyrosine kinase substrates and, after phosphorylation, as binding sites for SH2 domains of yet other kinases. TCR-Alpha and Beta chains have a variable region. Together, the variable regions of the TCR form a surface that binds to an antigen that has been processed by macrophages and related cells. These  Antigen-Presenting Cells display antigen fragments to T-Cells in conjunction with a molecule called the MHC (Major Histocompatibility Complex) (Ref.4). T-Cell receptors only recognize antigen on the surface of other cells, not antigen in solution, by requiring antigen to be bound to MHC proteins on the surface of other cells to be recognized. CTLs recognize antigen bound to MHC-I on the surface of other cells and helper T cells recognize antigen bound to MHC-II on antigen-presenting cells. CD4 (Helper T-Cells) and CD8 (Cytotoxic T-Cells) are cofactors in MHC recognition. In general, the role of the CD8+ T cells is to monitor all the cells of the body, ready to destroy any that express foreign antigen fragments in their Class I molecules. CD4+ T cells bind an epitope consisting of an antigen fragment lying in the groove of a class II Histocompatibility molecule. CD4+ T cells are essential for both the cell-mediated and antibody-mediated branches of the immune system. Upon productive binding of the TCR to the MHC molecule complexed with a peptide antigen, the TCR is activated, leading to the initiation of a signal transduction pathway (Ref.5).