1/7/2024 0 Comments Cross reactivity![]() ![]() Longer peptides become increasingly distorted in the central region of the MHC class I molecule as the peptide length increases, resulting in peptide 'bulging' 6, 7. The MHC class I molecule has a closed-ended peptide-binding groove and binds peptides of 8–14 amino acids in length. Typically, MHC class I and class II molecules present peptides from endogenous and exogenous antigens, respectively. The diversity of TCRs is based on the six complementarity-determining regions (CDRs), which engage both the peptide and the MHC molecule 5 ( Fig. The theoretical number of possible TCRs in humans is likely to be orders of magnitude larger, as humans possess 54 TCRβ variable genes as compared with the 35 genes in mice, with all other variables being comparable 4. The 'randomization' of V(D)J junctions and the fact that the TCR is a heterodimer of two separately rearranged chains results in a theoretical repertoire of >10 15 unique αβ TCRs in the mouse 2, 3. This process involves nucleotide insertions and deletions at V(D)J junctions in each chain. The specificity of this recognition is conferred by the clonotypic αβ T cell receptor (TCR), which is made from two separate chains manufactured from variable (V), diversity (D), joining (J) and constant (C) gene fragments through a process of somatic gene rearrangement. T cells recognize peptides bound to MHC class I and class II molecules at the cell surface 1. This 'systems view' of TCR recognition provides a plausible cause for autoimmune disease and substantial scope for multiple therapeutic interventions. Furthermore, any TCR raised against a specific peptide–MHC complex in vivo can only be the best available solution from the naive T cell pool and is unlikely to be the best possible solution from the substantially greater number of TCRs that could theoretically be produced. This compromise on specificity has profound implications because the chance of any natural peptide–MHC ligand being an optimal fit for its cognate TCR is small, as there will almost always be more-potent agonists. However, the repertoire of αβ T cell receptors (TCRs) is dwarfed by the vast array of potential foreign peptide–MHC complexes, and a comprehensive system requires each T cell to recognize numerous peptides and thus be cross-reactive. Clonal selection theory proposed that individual T cells are specific for a single peptide–MHC antigen. ![]()
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