The granule pathway of CTL killing. The CTL is shown on top and the target cell on the bottom. Perforin and granzymes are stored in polarized lytic granules and are released into the space between cells. On the left is the earliest model which states that perforin forms pores in the plasma membrane of target cells. In this model, perforin secreted by the effector cell polymerizes in the presence of calcium and forms a channel through which granzymes pass into the target cell. On the right side are two more recent models in which perforin enters the target cell membrane and enters the cell through repair-mediated endocytosis. GrB is thought to enter the cell by binding to the cation-independent mannose-6-P receptor (CI-MPR) followed by receptor internalization or through some other uptake mechanism independent of CI-MPR. In both models granzyme is released into an endolysosomal compartment where it is rendered harmless. Internalized perforin provides a signal for GrB to leave the compartment. GrB released into the cell cleaves cytoplasmic and nuclear substrates leading to apoptosis.