Tough antigens trigger immunity

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. The harder a protein is to chop up, say Delamarre and colleagues on page 2049, the more vigorous an immune response it will trigger. This suggests that the most durable antigens—or those attached to degradation-resistant carrier proteins— might make the best vaccines. The correlation between stability and immunogenicity may seem coun-terintuitive, given that the very products of lysosomal degradation—antigenic peptides or epitopes—bind to class II MHC molecules for presentation to CD4 + T cells. And many (but not all) in vitro studies show that blocking lyso-somal function in vitro inhibits antigen presentation. To determine which kind of antigen elicits the strongest immune response, Delamarre …