An alternative to current thinking about positive selection, negative selection and activation of T cells.

Given that recognition by the T-cell receptor (TCR) of allele-specific determinants on major histocompatibility complex (MHC)-encoded restricting elements (Rs) is germline encoded, whereas recognition of peptide (P) is somatically encoded, two combining site repertoires, anti-R and anti-P, are implied. As a consequence, the three pathways of T cells, positive selection, negative selection and activation, must be signalled by qualitatively distinct interactions engaging the TCR. These are spelled out as they provide an alternative to the current thinking that these pathways depend on affinity-based quantitatively distinguishable interactions.