What is TCR?

T cells are the main functional cells in the acquired immune system, which are responsible for identifying antigens and directing other immune cells to immune responses. T cell receptor (TCR) on the surface of T cells plays a key role in antigen recognition. According to the different expression of TCR, T cells can be divided into two main categories: αβT cells and γ δ (gamma delta) T cells. αβ T cells are the majority of T cells in peripheral lymphoid tissue and peripheral blood, while γ δT cells are relatively small.

TCR structure

The amino acid sequence deduced from the T cell receptor cDNA clearly shows that both strands of the T cell receptor have a variable region (V region) homologous to the immunoglobulin V region at the amino terminus, and immunoglobulin C The region's homologous constant region (C region), as well as a short hinge region, contains a cysteine that forms an interchain disulfide bond. Each strand spans the lipid bilayer membrane through a hydrophobic transmembrane domain and ends with a short intracellular tail. Based on these similarities between the T cell receptor peptide chain and the immunoglobulin heavy and light chains, it was initially inferred that the structure of the heterodimer of the T cell receptor is similar to the Fab fragment of the immunoglobulin. Recently, the three-dimensional structure of T cell receptors has been determined. Its structure is indeed similar to the antibody Fab fragment, as the results of earlier studies based on its coding gene are consistent. The folding of the T cell receptor peptide chain is much shorter than that of the Fab fragment, which is only slightly shorter and slightly wider. However, there are also some significant differences between T cell receptors and Fab fragments. The biggest difference is that in the Cα domain, the folding of the Cα domain is different from the folding of any other immunoglobulin-like domain. In two juxtaposed Cα domains, half of the Cα domain forms a beta sheet, which is similar to that found in other immunoglobulin-like structures, but the other half of the Cα domain is formed. Loosely curled peptide chain and a small alpha helix. The intermolecular disulfide bond is in the immunoglobulin-like domain, normally linking the two beta sheets, while in the Cα domain is the alpha helix connecting a beta strand and this fragment.

The primary function of the immune system is to identify and remove non-autologous substances. However, non-self-contained substances are in tens of thousands and exist in hundreds of millions. This gives the immune system a big problem: how to use a limited number of DNA sequences to produce such diverse receptors to specifically respond to these antigens? After hundreds of millions of years of evolution, mammalian adaptive immune systems have acquired genes. The ability to rearrange, thus solving this problem. The V(D)J rearrangement of the TCR gene is mainly mediated by lymphocyte-specific recombinases and widely expressed DNA repair proteins, which plays an important role in the normal development and maturity of lymphocytes.

Recognition of antigen by T cell antigen receptor

The aβTCR mainly recognizes the polypeptide antigen (pept-ide-MHC, pMHC) presented by MHC. Polypeptide antigens vary widely, and TCR also produces a wide variety of TCRs by gene rearrangement to specifically recognize these antigens. The MHC molecule forms an antigen-binding cavity at its top, and consists of two a-helices in two weeks (a1 and a2 helices in MHCII, a1 and β1 helices in MHCII), and the bottom consists of multiple folds. Such antigen presenting cavities can bind a wide variety of antigenic polypeptides. The recognition of pMHC by aβTCR involves two bindings: binding of TCR to MHC molecules and binding of TCR to polypeptide antigens. The binding surface on the TCR is from six regions: the respective CDR1, CDR2 and CDR3 on the TCR a β chain. CDR1 and CDR2 are encoded by the V region on the TCR, and the sequence is relatively conserved; whereas CDR3 is encoded by recombinant V(D)J with hyper-denaturation. CDR1 and CDR2 mainly bind to relatively conserved MHC molecules, while CDR3 mainly binds to variable antigenic polypeptides. This mode of binding is a good way to ensure that the TCR specifically binds to MHC molecules and recognizes variable antigens.

Why does TCR have MHC specificity?

From the perspective of protein interaction, TCR-MHC does not have good structural complementarity, so the affinity is not high. But this combination is certainly specific and carries important physiological functions. Although it has been reported in the literature that TCR can recognize non-MHC molecules in the absence of MHC I, MHC II, CD4 and CD8. But this may be because in the absence of MHC, TCRs with variable CDR3 regions are able to randomly identify many other proteins. Since TCR is MHC-specific, is this specificity inherent in TCR, or is TCR-initiated without MHC-specific, but screened for MHC-specific TCR in the thymus by yin-yang selection? Current experimental data supports the first possibility that the MHC specificity of TCR is congenital.

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