How TCRS Bind Mhcs, Peptides, and Coreceptors

Abstract

Since the first crystal structure determinations of alphabeta T cell receptors (TCRs) bound to class I MHC-peptide (pMHC) antigens in 1996, a sizable database of 24 class I and class II TCR/pMHC complexes has been accumulated that now defines a substantial degree of structural variability in TCR/pMHC recognition. Recent determination of free and bound gammadelta TCR structures has enabled comparisons of the modes of antigen recognition by alphabeta and gammadelta T cells and antibodies. Crystal structures of TCR accessory (CD4, CD8) and coreceptor molecules (CD3epsilondelta, CD3epsilongamma) have further advanced our structural understanding of most of the components that constitute the TCR signaling complex. Despite all these efforts, the structural basis for MHC restriction and signaling remains elusive as no structural features that define a common binding mode or signaling mechanism have yet been gleaned from the current set of TCR/pMHC complexes. Notwithstanding, the impressive array of self, foreign (microbial), and autoimmune TCR complexes have uncovered the diverse ways in which antigens can be specifically recognized by TCRs.

HCV epitope, homologous to multiple human protein sequences, induces a regulatory T cell response in infected patients

“…Crystal structure analyses of ternary, MHC:epitope:T cell receptor (TcR) complexes indicate that certain amino acid residues of a T cell epitope contact the MHC molecule while other residues contact the TcR [16]. JanusMatrix, a new bioinformatics tool, interrogates a potential T cell epitope from both its HLA-binding and TcR-facing aspects, and assesses TcR cross-reactivity with T cell epitopes encoded by other genomes [13,14].…”

Manipulation of MHC-I/TCR Interaction for Immune Therapy

“…The 8~10 residues peptide in an extended conformation with the termini is buried in specificity pockets that differ from allele to allele (38,39). This binding mode leaves the upward-pointing peptide side chains available for direct interaction with the TCR (40). Longer peptides can either bind by extension at the C terminus (41) or, due to the fixing of their termini, bulge out of the binding groove, providing additional surface area for TCR recognition (42,43).…”

“…Longer peptides can either bind by extension at the C terminus (41) or, due to the fixing of their termini, bulge out of the binding groove, providing additional surface area for TCR recognition (42,43). Thus, the bound peptide is more accessible for TCR inspection in MHC-I due to its ability to bulge out of the groove (40). The TCRs bind pMHC-I with relatively low affinity (~1-100 μM) through CDRs present in their variable domains.…”

Complex divergence at a microsatellite marker C1_2_5 in the lineage of HLA-Cw/-B haplotype

“…2 Most of the extensive polymorphisms in the HLA genes were found at the peptide-binding groove of HLA molecules, thereby defining the bound peptides. 3 The HLA alleles at a given locus differ from each other by 1-30 amino acids at the protein level 4 and have been designated by the four-digit number or more according to the patterns of single-nucleotide polymorphisms (SNPs) and insertion-deletion polymorphisms within the coding sequence. The difference in allele distribution among different ethnic groups may be shaped by selective and demographic history.…”