Natural killer (NK) cells sometimes target a friend instead of a foe. Abeyweera et al. reveal how healthy cells call off a misdirected attack.
An NK cell hunts down and destroys tumor cells and cells infected by viruses. Once it detects the characteristic surface proteins that betray one of these abnormal cells, an NK cell delivers the kiss of death, glomming onto its target and forming a cytolytic synapse. But the killer checks for an additional form of ID—the class I MHC protein, which is mainly expressed by healthy cells. A mystery is how an NK cell's inhibitory receptors, which halt an attack in response to class I MHC, override the activating receptors that spur the cell to kill.
Abeyweera et al. crafted an HLA protein—the human version of the class I MHC molecule—that fit a specific inhibitory receptor on NK cells only after exposure to UV radiation. Thus, the researchers could switch on the attack-canceling mechanism with a flash of light.
Contact with a would-be victim triggers a series of responses in an NK cell. Actin polymerizes and forms a ring at the edge of the cytolytic synapse. Clusters of activating receptors gather in the synapse, and cytosolic calcium levels rise, enabling the cell to release cytotoxic proteins. Switching on the customized HLA protein reversed all these changes except for the calcium surge, and NK cells let go of the target surface. However, the cells held tight if their inhibitory receptors lacked signaling activity. These results suggest that inhibitory receptors countermand attack signals by undermining the cytolytic synapse.