![]() There are only 10 12 T cells in a human, and more recent studies have estimated that there are 10 15) ( Box 1). Indeed, put in the context of 10 15 T cells weighing >500 kilograms, the notion of immune coverage by a naive pool of 10 15 monospecific TCRs as suggested by the clonal selection theory is clearly absurd 10. Many of the reasons for this paradigm shift were based on the simple arithmetic of effective immunity requiring the recognition of >10 15 potential foreign peptides. Most notably, Don Mason called for the abandonment of such a notion in his seminal thesis on the topic (see Ref. However, several workers questioned this concept 10, 11, 12, 13. ![]() For many years the concept of huge numbers of TCRs successfully providing immunity to all foreign peptides in a 'one-clonotype– one-specificity' paradigm was accepted. The clonal selection theory 8, 9 proposed that individual lymphocytes are specific for a single antigen and that the recognition of alternative ligands is unlikely. However, the small structural database that has been compiled to date already contains examples in which CDR1 and CDR2 make substantial interactions with the peptide and in which CDR3 has an important role in contacting the MHC molecule 98, 99. In general, the germline-encoded CDR1 and CDR2 loops interact mainly with the MHC molecule itself, whereas the hypervariable CDR3 loops sit over the peptide. The colours indicate the docking footprints of the AS01 TCR96 and MSC-2C8 TCR97 on their cognate peptide–MHC complexes and show the 'footprints' on the MHC complex of the six CDR loops. TCRs dock on a peptide–MHC complex in a diagonal mode that is conserved for binding to MHC class I and class II molecules. d,e | The images show HLA-A*0201 (in grey) presenting the immunodominant GLCTLVAML peptide (stick model) from Epstein–Barr virus and HLA-DR4 (in grey) presenting a peptide from myelin basic protein (MBP). By contrast, the ends of the MHC class II binding cleft are open, which allows the accommodation of much longer peptides without the need for peptide kinking. The closed ends of the MHC class I binding groove cause long peptides to 'bulge' out of the binding groove, and this bulging increases with each additional amino acid in the peptide. b,c | MHC class I and class II molecules can accommodate antigenic peptides of different lengths. 1b,c).Ī | Depicted is a ribbon model of an αβ T cell receptor (TCR) showing the positions of the six variable complementarity-determining region (CDR) loops. By contrast, the ends of the MHC class II peptide-binding cleft are open, allowing even longer peptides to extend beyond this groove without bulging ( Fig. 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.
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