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

An αβ T cell response depends on the recognition of antigen plus major histocompatibility complex proteins (MHC)1 by its antigen receptor (TCR). The ability of peripheral αβ 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 prior to positive selection, suggested 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 TCRβ chains, individual mutation of amino acids in CDR2β 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 αβ TCR and suggest that the diversity of the peripheral T cell repertoire is enhanced by this “built-in” specificity.