Peptide-dependent tuning of major histocompatibility complex motional properties and the consequences for cellular immunity.

T cell receptors (TCRs) and other receptors of the immune system recognize peptides presented by class I or class II major histocompatibility complex (MHC) proteins. Although we generally distinguish between the MHC protein and its peptide, at an atomic level the two form a structural composite, which allows peptides to influence MHC properties and vice versa. One consequence is the peptide-dependent tuning of MHC structural dynamics, which contributes to protein structural adaptability and influences how receptors identify and bind targets. Peptide-dependent tuning of MHC protein dynamics can impact processes such as antigenicity, TCR cross-reactivity, and T cell repertoire selection. Motional tuning extends beyond the binding groove, influencing peptide selection and exchange, as well as interactions with other immune receptors. Here, we review recent findings showing how peptides can affect the dynamic and adaptable nature of MHC proteins. We highlight consequences for immunity and demonstrate how MHC proteins have evolved to be highly sensitive dynamic reporters, with broad immunological consequences.