Structural and dynamic control of T-cell receptor specificity, cross-reactivity, and binding mechanism

Summary Over the past two decades, structural biology has shown how T‐cell receptors engage peptide/major histocompatibility complex (MHC) complexes and provided insight into the mechanisms underlying antigen specificity and cross‐reactivity. Here we review and contextualize our contributions, which have emphasized the influence of structural changes and molecular flexibility. A repeated observation is the presence of conformational melding, in which the T‐cell receptor (TCR), peptide, and in some cases, MHC protein cooperatively adjust in order for recognition to proceed. The structural changes reflect the intrinsic dynamics of the unligated proteins. Characterization of the dynamics of unligated TCR shows how binding loop motion can influence TCR cross‐reactivity as well as specificity towards peptide and MHC. Examination of peptide dynamics indicates not only peptide‐specific variation but also a peptide dependence to MHC flexibility. This latter point emphasizes that the TCR engages a composite peptide/MHC surface and that physically the receptor makes little distinction between the peptide and MHC. Much additional evidence for this can be found within the database of available structures, including our observations of a peptide dependence to the TCR binding mode and structural compensations for altered interatomic interactions, in which lost TCR‐peptide interactions are replaced with TCR‐MHC interactions. The lack of a hard‐coded physical distinction between peptide and MHC has implications not only for specificity and cross‐reactivity but also the mechanisms underlying MHC restriction as well as attempts to modulate and control TCR recognition.