The interdisciplinary science of T-cell recognition.

The recognition of peptide/MHC antigens by T-cells has continued to challenge the imagination of immunologists, biochemists, and cell biologists alike. This is at least in part because T-cell recognition connects a diversity of issues and transcends many scientific disciplines. A fundamental unsolved issue is how T-cells manage to detect even a single molecule of an agonist pMHC complex, which is vastly outnumbered by endogenous pMHCs, many of which involve the same MHC molecule. They do so although TCRs are cross-reactive and typically low in affinity when measured in isolation. Importantly, T-cell antigen recognition takes place within the contact zone between a T-cell and the antigen-presenting cell, termed the immunological synapse. This bimembrane structure sets the stage for the antigen-binding events and all subsequent molecular recognition events. There is increasing evidence that the molecular dynamics of receptor-ligand interactions are not only dependent on the intrinsic properties of the binding partners but also become transformed by cell biological parameters such as the geometrical constraints within the immune synapse, mechanical forces, and local molecular crowding. To appreciate the complete picture, we think a multidisciplinary approach is imperative, which includes genetics, biochemistry, and structure determination and also biophysical analyses and the latest molecular imaging techniques. Here, we review earlier pioneering work and also recent developments in the fascinating and interdisciplinary science of T-cell antigen recognition. In many ways, this work may present a useful "roadmap" for work in other systems of cell-cell recognition, which underlie many fundamental biological phenomenons of interest.