Recycling endosomes allow cytotoxic T cells to deploy their cell-slaying weapons, Marshall et al. reveal.
Cytotoxic T cells can dispatch tumor cells and cells infected by pathogens, killing their target within minutes by releasing the contents of specialized lysosomes known as cytotoxic granules. In general, exocytosis requires that R-SNARE proteins on vesicles interlock with Q-SNARE proteins on the plasma membrane, enabling the two membranes to fuse. One SNARE protein involved in granule release is the Q-SNARE syntaxin-11 (Stx11). Evidence from knockout mice also implicates VAMP8, which belongs to a family of R-SNARE proteins.
Marshall et al. found that VAMP8 built up at the immunological synapse, the junction between a cytotoxic T cell and its victim. To their surprise, the researchers found that VAMP8 did not associate with cytotoxic granules. Instead, it rode on recycling endosomes, organelles that normally return proteins to the plasma membrane. These endosomes fused with the plasma membrane at the immunological synapse.
Depleting VAMP8 not only prevented recycling endosomes from fusing with the plasma membrane, but it also abolished cytotoxic granule exocytosis. The team discovered that the VAMP8-carrying recycling endosomes arrived at the synapse before the cytotoxic granules and brought an important cargo—Stx11.
The study indicates that recycling endosomes outfitted with VAMP8 deliver Stx11 to the immunological synapse. The researchers hypothesize that Stx11 then latches onto an unidentified SNARE on cytotoxic granules, connecting them to the plasma membrane and allowing them to jettison their contents.
Text by Mitch Leslie