Cytolytic granules supply Ca(2+) for their own exocytosis via NAADP and resident two-pore channels

When cytotoxic T-lymphocytes (CTLs) kill infected or cancerous cells they secrete cytolytic proteins (perforin and granzymes) into the target cell. These “death factors” are pre-stored in cytolytic granules within the CTL until an increase in the intracellular Ca(2+) drives granule exocytosis. However, not all sources of Ca(2+) stimulate exocytosis: we have recently demonstrated that it is the cytolytic granules themselves that are the source of the Ca(2+) that most efficiently drives their own exocytosis; release of Ca(2+) from the granules is only activated by the Ca(2+)-mobilizing messenger NAADP (nicotinic acid adenine dinucleotide phosphate) that acts upon target two-pore channels (TPCs) present on the granules. That NAADP is a unique stimulus of exocytosis may be of fundamental importance not only to immunology but to cell biology in general.