Regulated vesicle fusion generates signaling nanoterritories that control T cell activation at the immunological synapse

How the vesicular traffic of signaling molecules contributes to T cell receptor (TCR) signal transduction at the immunological synapse remains poorly understood. In this study, we show that the protein tyrosine kinase Lck, the TCR. subunit, and the adapter LAT traffic through distinct exocytic compartments, which are released at the immunological synapse in a differentially regulated manner. Lck vesicular release depends on MAL protein. Synaptic Lck, in turn, conditions the calcium-and synaptotagmin-7-dependent fusion of LAT and TCR zeta containing vesicles. Fusion of vesicles containing TCR zeta and LAT at the synaptic membrane determines not only the nanoscale organization of phosphorylated TCR zeta, ZAP70, LAT, and SLP76 clusters but also the presence of phosphorylated LAT and SLP76 in interacting signaling nanoterritories. This mechanism is required for priming IL-2 and IFN-gamma production and may contribute to fine-tuning T cell activation breadth in response to different stimulatory conditions.