Immunological synapse formation is essential for T cell activation. A recent paper in Science reports that immunological and neurological synapses utilize a common molecule, agrin. and agrin then binds to a receptor on the myocyte, MusK5. In contrast, Rupp and colleagues propose that agrin acts in cis; it is both produced by and acts on the T cell. At the NMJ, agrin activates the tyrosine kinase activity of MusK and this leads to the tyrosine phosphorylation of acetylcholine receptors and their subsequent clustering5. No agrin receptor has been identified on T cells. The activity of agrin at the NMJ is regulated by alternative splicing. The addition of a specific exon generates the Z+ isoform of agrin and only this isoform is active. Although many tissues express agrin, only nerves express the Z+ isoform. Confirming this, Rupp and colleagues showed that T cells only express the Z form of agrin, and this doesn’t change with activation. Although agrin purified from resting T cells is inactive, they found, surprisingly, that agrin purified from activated T cells could induce immunological synapse formation and acetylcholine receptor clusters on myotubes. A pair of monoclonal antibodies were identified that exclusively recognized either the active or inactive agrin molecules, but not both. Analysis of the two forms of agrin revealed that the inactive agrin was highly glycosylated, whereas the active agrin was less glycosylated and migrated more quickly on a gel. Given this, the authors suggest that T cells can rapidly regulate the agrin’s activity by regulating its deglycosylation.

This intriguing work raises many additional questions. The idea that T cell activation can stimulate the rapid and complete deglycosylation of extracellular ligands is remarkable. If it occurs in other systems, it could have a huge impact on our ideas of how signals are propagated between cells. Given that immunological synapse formation occurs within seconds to minutes of T cell contact with an APC, it also seems remarkable that agrin could be deglycosylated quickly enough