Dynamic Allostery in T Cell Receptor Specificity: A Role for Peptides and MHC Polymorphisms in Allosterically Tuning...

T cell receptor (TCR) recognition of peptide/MHC complexes is fundamental for adaptive immunity. Many studies have described the importance of peptide/MHC motion or dynamics in TCR recognition. A role for dynamics in recognition intersects with the concept of dynamic allostery, which describes how alterations to a protein's energy landscape and thus motions influence function, often in the absence of conformational changes. Tuning of MHC protein energy landscapes by different peptides has clearly been shown. Evidence is mounting, however, that MHC polymorphisms also alter the protein's energy landscape. Here, we address this concept, summarizing findings that suggest that, in addition to dictating peptide binding and selection, naturally occurring variations within MHC proteins promote differential peptide and protein dynamics, altering TCR recognition in an MHC allele-dependent manner. We hypothesize that MHC polymorphisms have been selected evolutionarily in part to tune the protein's dynamic response, altering immune specificity and further diversifying immune responses across populations.