Why must T cells be cross-reactive?

Clonal selection theory proposed that individual T cells are specific for a single peptide–MHC antigen. 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. 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. 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 'systems view' of TCR recognition provides a plausible cause for autoimmune disease and substantial scope for multiple therapeutic interventions. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nri3279) contains supplementary material, which is available to authorized users.