Natural killer cell cytotoxicity: how do they pull the trigger?

Abstract

Natural killer (NK) cells target and kill aberrant cells, such as virally infected and tumorigenic cells. Killing is mediated by cytotoxic molecules which are stored within secretory lysosomes, a specialized exocytic organelle found in NK cells. Target cell recognition induces the formation of a lytic immunological synapse between the NK cell and its target. The polarized exocytosis of secretory lysosomes is then activated and these organelles release their cytotoxic contents at the lytic synapse, specifically killing the target cell. The essential role that secretory lysosome exocytosis plays in the cytotoxic function of NK cells is highlighted by immune disorders that are caused by the mutation of critical components of the exocytic machinery. This review will discuss recent studies on the molecular basis for NK cell secretory lysosome exocytosis and the immunological consequences of defects in the exocytic machinery.

Figure 1

Secretory lysosome exocytosis. (a) Stage 1: on recognition of a target cell by the natural killer (NK) cell a lytic immunological synapse forms at the point of contact with the target cell, and the actin cytoskeleton is reorganized, forming a ring of F-actin around the pSMAC. (b) Stage 2: the MTOC and secretory lysosomes become polarized towards the lytic synapse. It is likely that the secretory lysosomes move along microtubules to the lytic synapse, but this has not been confirmed in NK cells. (c) Stage 3: secretory lysosomes then move into close apposition with the plasma membrane, a process known as docking. (d) Stage 4: finally, the secretory lysosomes fuse with the plasma membrane, releasing their cytotoxic contents towards the target cell plasma membrane.

Figure 2

The docking and fusion of secretory lysosomes with the plasma membrane. (a) Docking: secretory lysosomes move into close apposition with the plasma membrane. In cytotoxic T lymphocytes (CTLs), and most likely in natural killer (NK) cells, this step requires Rab27a.– Myosin IIa is also required for the docking of secretory lysosomes with the plasma membrane.,, (b) Priming: Munc13-4 is required in CTLs immediately before membrane fusion to prime secretory lysosomes for fusion and may act by enabling soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) proteins to interact with each other.,– Munc13-4 is likely to perform the same function in NK cells. (c) Fusion: the subsequent fusion of the secretory lysosome with the plasma membrane will require the formation of a trans-SNARE complex that bridges the opposing membranes and drives their fusion. The SNAREs that act at this step in NK cells are unknown, but may include syntaxin 11 and VAMP7.,–