NK cell inhibitory receptor KLRG1 (blue) binds to cadherins (purple) on target cells.

NK cells must integrate both positive and negative signals—delivered by a variety of activating and inhibitory receptors on their cell surface—to determine whether a target cell should be attacked. Many NK cell inhibitory receptors, including Ly49 receptors (mice) and killer cell immunoglobulin-like receptors (humans), bind to MHC class I molecules on target cells. This allows NK cells to distinguish between normal cells, which express class I molecules, and abnormal cells, which often lack these proteins due to transformation or viral infection. The binding partners for other inhibitory receptors, including KLRG1, had not been identified.

Ito and colleagues now show that KLRG1 pairs up with cadherins (E-, N- and R-cadherin)—adhesion molecules that help form junctions between epithelial and endothelial cells. When the pairing of NK cells and target cells occurs via cadherins, they show, NK cell-mediated killing is inhibited.

Why would NK cells express receptors for adhesion proteins that are normally concealed in cell–cell junctions? One possibility is to promote surveillance of improperly detached cells. These cells, including many tumor cells, have reduced E-cadherin expression, allowing them to sever ties with adjacent cells. But without E-cadherin, tumor cells can no longer send inhibitory signals through KLRG1, possibly making them more prone to NK cell attack.