The Structural Biology of T-Cell Antigen Detection at Close Contacts

T cells physically interrogate their targets using tiny membrane protrusions called microvilli, forming junctions ~400 nm in diameter and ~ 15 nm deep, referred to as "close contacts". These contacts, which are stabilized by the binding of the small adhesion protein CD2 to its ligand, CD58 and locally exclude large proteins such as the phosphatase CD45, are the sites of antigen recognition by the T-cell receptor (TCR) and very early signaling by T cells. With our collaborators, we have characterized the molecular structures of several of the key proteins mediating these early events: i.e., CD2 and its ligands, CD45, the αβ- and γδ-TCRs, and the accessory proteins CD28, CTLA-4, and PD-1. Here, we review our structural work and the insights it offers into the early events underpinning T-cell responsiveness that take place in the confined space of the close contact. We reflect on the crucial roles that the structural organization and dimensions of these proteins are likely to have in determining the sequence of events leading to antigen recognition at close contacts and consider the general implications of the structural work for explanations of how immune receptor signaling is initiated.