MHC restriction: Where are we now?

From the initial observations by Zinkernagel and Doherty over 40 years ago of the need for T cells to recognize "altered self," our understanding of TCR recognition of peptide+ MHC has made significant advances. However, alongside a more detailed understanding of the interaction comes additional questions around precisely why T cells must limit themselves to MHC, when a greater range of ligand binding is demonstrably possible, and mechanistically, how MHC restriction achieves the necessary T cell survival and activation signals. The answer may well lie in the study of noncanonical or poorly signaling TCRs to understand the absolute requirements for effective TCR-pMHC recognition, continued advances in structural biology providing resolution of multimolecular complexes, and cryo-EM providing information on the dynamics of molecular localization and organization before and after TCR ligation of pMHC.