Establishing the molecular size threshold of immune synapse penetration: Implications for drug access (P4263)

Abstract Natural Killer (NK) cells survey target cells through activating, inhibitory and adhesion receptors that bind their ligands at the immune synapse. This dense mesh of protein-protein interactions at the intercellular contact may create a seal, or gasket, around the synapse to prevent the leakage of secreted proteins, but this remains poorly understood. Nanometer scale fluorescent dextrans of known sizes were used to determine the size threshold of molecules that could penetrate the immunological synapse between NK and target cells, by measuring fluorescence accumulation within the intercellular region. Dextran was completely excluded from the synapse when its hydrodynamic diameter was above 13nm, whereas a 4nm dextran was able to diffuse in and out of the synapse. This showed that the synapse represents a physical gasket through which molecules can penetrate in a size-dependent manner. This establishes a size threshold of molecules that are able to enter the synapse. Drugs which target proteins within the synapse should be engineered to these dimensions in order to penetrate the synapse.