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.