Cytolytic synapses control effectiveness of target cell destruction by CTL

Abstract We have investigated the stability of cytolytic synapses as well as patterns of cytolytic granule polarization and kinetics of their release by CTL with different potency to kill target cells. Less potent CTL form unstable cytolytic synapses, accounting for a third of the difference in potency providing the best evidence that stable synapse is important for cytotoxicity. To determine what other unknown mechanistic components may account for the distinct potency of target cell killing, we evaluated differences related to various pathways of granule delivery to the secretory domain of these CTL. Visualization of lytic granule delivery shows that the granules can take long or short paths to the secretory domain. The difference in path is dictated by the kinetics of early TCR signaling. Rapid and robust early signaling causes swift granule concentration near the MTOC and subsequent delivery directly to the secretory domain - the shortest and fastest path. Indolent signaling leads to late recruitment of the granules that move first to the periphery of the synapse and then move tangentially to fuse at the outer edge of the secretory domain - a longer path. The short pathway of granule delivery is associated with more efficient killing. Thus, rapid granule delivery to the secretory domain and containment of released granules within a stable synapse determines the potency of CTL to destroy target cells.