LFA-1 (red) molecules surround central TCRs (green) in a live synapse.

Signaling between a T cell and an antigen-presenting cell (APC) is orchestrated through a bull's eye–like structure known as the immunological synapse. But no one had ever spotted these structures in vivo, causing many to wonder whether they are immunology's equivalent of the Loch Ness monster. Synapse devotees can now rest easy, thanks to Barcia et al., who provide the first in vivo glimpse of these elusive cellular structures on page 2095.

When first described, immunological synapses—their centers rich with T cell receptor (TCR)-MHC/peptide complexes and their outer rings with stabilizing integrins and adhesion molecules—provided a satisfying spatial model of how T cells get activated and signal to target APCs. But although these structures formed readily when T cells bumped into artificial lipid bilayers or cultured APCs, they have proven difficult to capture in real-life settings—in part due to limitations of live imaging and the touch-and-go nature of T cell–APC interactions.

Barcia et al. used a well-characterized model of viral brain infection in rats to help them pinpoint when and where to look for cytotoxic T cells engaging infected brain cells. The use of a nonreplicating virus—which infected brain cells but did not destroy them—also aided the synapse hunt. Three-dimensional reconstructions of confocal images revealed both the polarization of phosphorylated signaling kinases toward the T cell–APC contact site (an early sign of T cell activation) and—voilà!—the characteristic bull's-eye structure of the synapse.

The formation of synapses preceded viral clearance, suggesting that these ordered structures might indeed be necessary for T cell activation and subsequent elimination of infected cells. Formal proof of this, however, awaits the development of inhibitors or genetic mutations that selectively interfere with synapse formation. At least now we can rest assured that synapses really are more than just visually pleasing in vitro phenomena.