Germline-encoded amino acids in the αβ T-cell receptor control thymic selection

An alpha beta T-cell response depends on the recognition of antigen plus major histocompatibility complex (MHC) proteins(1) by its antigen receptor (TCR). The ability of peripheral alpha beta T cells to recognize MHC is at least partly determined by MHC-dependent thymic selection, by which an immature T cell survives only if its TCR can recognize self MHC2-7. This process may allow MHC-reactive TCRs to be selected from a repertoire with completely random and unbiased specificities. However, analysis of thymocytes before positive selection indicated that TCR proteins might have a predetermined ability to bind MHC8-11. Here we show that specific germline-encoded amino acids in the TCR promote 'generic' MHC recognition and control thymic selection. In mice expressing single, rearranged TCR beta-chains, individual mutation of amino acids in the complementarity-determining region (CDR) 2 beta to Ala reduced development of the entire TCR repertoire. Altogether, these results show that thymic selection is controlled by germline-encoded MHC contact points in the alpha beta TCR and indicate that the diversity of the peripheral T-cell repertoire is enhanced by this 'built-in' specificity.