TCR-pMHC interactions: Two peptide repertoires-one signal.

The peptide (P) ligand seen by the TCR is presented by an MHC-encoded restricting element (R). Peptide is viewed from two perspectives, that of the TCR and that of R. The TCR looks at P using an anti-P site that is somatically generated and selected, whereas R looks at P using a binding site that is germline generated and selected. The two segments of P, the one viewed by the TCR, the other viewed by R divide P into two repertoires, Ptcr and Pr that are recognized independently but function cooperatively. The consequences of this for an understanding of TCR specificity and signalling as well as the role of differential processing are analysed. It is ironic that from the point of view of the immunologist, the TCR is highly polyreactive recognizing over a million peptides, whereas from the point of view of the immune system, the TCR is highly specific recognizing essentially only one epitope.