Microclusters of active KIR (red) keep NK cells from killing their targets.

Inhibitory signaling in natural killer (NK) cells is restricted to microclusters of cell surface receptors rather than being evenly distributed across the immune synapse, report Treanor et al. on page 153.

Natural killer (NK) cells survey the body looking for infected or damaged cells. Activation of their killing function can be achieved by any one of a number of cell surface proteins, but this is reversed if the killer Ig-like receptor (KIR) on the NK cell surface recognizes a major histocompatibility complex I protein on the surface of the cell under investigation. Then the KIR is phosphorylated and produces a strong inhibitory signal, preventing the NK cell from killing the surveyed cell.

To look at the distribution of KIR activity in the immune synapse, Treanor et al. detected FRET between GFP-tagged KIR and a fluorescently labeled antiphosphotyrosine antibody. At any given point in time, a subset of the KIR molecules were active in microclusters. Lck, which is important for phosphorylation of KIR, was also found in microclusters.

Based on these data and recent reports showing a similar punctate distribution for activated T cell receptors, Treanor et al. hypothesize that the uneven distribution has important functional consequences. For example, it could be that such localization of signal somehow allows the cell to integrate information from multiple activating and inhibitory receptors within an immune synapse. With that possibility in mind, the group is now trying to see how both activating and inhibitory signals distribute across the contact region at the same time.