Natural killer (NK) cells recognize infected cells and tumor cells by binding to cell-surface markers of stress on the target cell. The activating receptor NKG2D is triggered by binding to its ligand MICA on the surface of the target cell. An immune synapse forms at the contact point between the cells, and a cytotoxic response is initiated. Chauveau et al. used confocal microscopy to show that when NK cells moved away from their targets, a small proportion remained connected by long membranous tethers, termed nanotubes, which contained a junction along the length of the tube or close to either cell. Nanotubes formed only when contact between the NK cell and its target was sustained, and they contained polymerized actin and microtubules. The number of NK cells that formed nanotubes with transfected target cells was proportional to the amount of MICA at the surface of the targets, and blockade of NKG2D prevented nanotube formation. Cytokines that stimulate NK cells increased the number of nanotubes formed, in part by increasing the abundance of NKG2D. Microscopic analysis of fluorescent molecules showed that MICA, DAP10 (an NKG2D-associated adaptor protein), and tyrosine-phosphorylated proteins accumulated at nanotube junctions. Some target cells moved along the nanotube to form close contacts with NK cells and were killed, whereas other cells were killed while still connected by nanotubes; breaking the nanotubes with a micromanipulator substantially decreased the number of target cells that were killed. Cell death by nanotube took almost four times as long as death by close contact and accounted for some 12% of cell death events. Together, these data suggest that nanotubes contain immune synapse–like structures that contribute to NK cell–mediated killing of target cells.
A. Chauveau, A. Aucher, P. Eissmann, E. Vivier, D. M. Davis, Membrane nanotubes facilitate long-distance interactions between natural killer cells and target cells. Proc. Natl. Acad. Sci. U.S.A. 107, 5545–5550 (2010). [Abstract] [Full Text]