Proposed sequential model for cytotoxic lymphocyte exocytosis. (A) After target cell recognition, numerous small recycling endosomes (RE) carrying VAMP8 and Stx11 (1) traffic to the CTL immune synapse and (2) undergo VAMP8-dependent fusion with the plasma membrane, possibly through interaction with plasma membrane Stx4 and SNAP-23 SNARE complex partners. Such exocytosis of recycling endosomes deposits high amounts of Stx11 molecules in the plasma membrane, which may (3) lead to the formation of Stx11 and SNAP-23 SNARE complexes. Initial activity at the immune synapse thus forms “active zones” where (4) docking through interactions of R-SNARE proteins on larger cytotoxic granules (CGs) with plasma membrane Stx11–SNAP-23 complexes can facilitate (5) cytotoxic granule exocytosis that releases cargo necessary for target cell killing.