T-cell receptor
T-cell receptor ( Sheet T cell receptor, TCR), a protein complex that is anchored on the surface of T cells and is responsible for recognition of antigens that are presented by MHC molecules responsible. By the activation of the TCR, the development of the T cell to the T- helper cell or cytotoxic T cell and a change in gene expression, among other things for the secretion of cytokines and surface expression of costimulators decides.
Structure
The TCR is structurally a Fab fragment of the antibody very similar since its subunits are also from the immunoglobulin superfamily. The TCR complex is composed of two protein subunits (mostly α / β, γ about 5 % of the cells / δ ), which in turn each consist of a constant domain (C ) and a variable domain (V H ), a transmembrane domain and a short C- terminal cytoplasmic region exist. The N-terminal ends of the chains which belong to the C domain, by penetrating the cell membrane to the cytoplasmic space and anchor the receptor. The two sub- units are connected to each other via a disulfide bridge extracellularly in the constant region.
The variable domains of the α and β subunit are comprised of the V and J segments or for the β - chain V, D and J segments, with three hypervariable ( and the β - chain of HV4 form a fourth, but without antigen contact) and thus binding of crucial areas (English complementarity determining regions, CDRs). The CDR 2 interacts primarily with the α -helices in the peptide binding cleft of the MHC class I and II complexes, while the CDR 1 of the α - chain to the N- terminus and the CDR 1 of the β - chain of the C- terminus of the antigen binds and help the two CDR3 - sections for the largest proportion of binding the MHC - presented antigen. The latter have mainly through the combinatorial diversity in V (D) J recombination to a greater diversity. The CDR4 not interact with antigens, however, interactions are described with superantigens.
Whether a TCR capable of binding an antigen or not, is a very complex process. In general, the key - lock principle, if you can fit the structure of an antigen presented in the context of the presenting MHC molecule at the α - and β - chain of the TCR, so it comes to binding. Computer-aided molecular and binding simulations are an area of responsibility of bioinformatics. The specificity of the TCR can be determined by epitope mapping.
Formation
In addition to the structure, the origin of the T- cell receptors that of the antibodies of B- cells is similar. The two subunits are caused by genetic V ( D) J recombination ( VJ in the α - or γ - chain VDJ in the β - or δ - chain). There is a quasi-random arrangement of the genes in order to ensure the greatest possible diversity. Additionally be insertions of N or P nucleotides. This is the basic component of the adaptive immune response in T cells. T cell clones, each with unique T cell receptor subject to positive and negative selection in the thymus to screen the T cells with non-functional or self-reactive products of recombination.
Co - receptors
By binding the resulting signal is amplified by the simultaneous binding of co- receptors. Two examples are the CD4 and CD8 receptor. The CD4 receptor binds exclusively MHC II, while the CD8 receptor is specific for MHC-I. The co-receptors are not only responsible for the specificity of the TCR, but also for a continuous bond between the antigen presenting cell and the T cell. In addition, a further differentiation of the T cell is induced: if CD4 recruited by TCR - MHC II complex, results in a T helper cell. However, binding of the TCR to MHC I, it leads to the recruitment of CD8 what the differentiation of cytotoxic T- cell ( obsolete: "T- killer cell") has the consequence.
Signal transduction
In addition, the TCR interacts with CD3, consisting of γ -, δ -, and ε - chain in mammals and in addition of complexes of ζ2 or ζ / η chains. The entire complex is known as the T-cell receptor complex. After activation of the TCR are different intracellular effector proteins such as Lck ( CD4 ), Fyn ( on immunoglobulin tyrosine activation motif of the Ig-α/β-Regionen, ITAM ), tyrosine phosphatase CD45 as and Zap70 ( at ITAM phosphorylation by Lck and Fyn by ) bound. CD45 activates Fyn through dephosphorylation. Fyn phosphorylates ITAMs on CD3 and ζ chains. Then ZAP- 70 binds to the ITAM in the vicinity of Lck on CD4. Lck phosphorylated ZAP-70, which via the binding of the adapter protein LAT PLC - γ is activated.