Research ArticleImmunology

Confinement of Activating Receptors at the Plasma Membrane Controls Natural Killer Cell Tolerance

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Science Signaling  05 Apr 2011:
Vol. 4, Issue 167, pp. ra21
DOI: 10.1126/scisignal.2001608

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Corralling Receptors

Coordination of the signaling of activating and inhibitory surface receptors determines the responsiveness of natural killer (NK) cells. The engagement of inhibitory receptors specific for self major histocompatibility complex (MHC) class I is critical to the “education” of NK cells so that they can recognize “self” and become competent effector cells. However, NK cells lacking such inhibitory receptors do not become autoreactive; instead, they become unresponsive to stimulation of their activating receptors. Guia et al. used fluorescence correlation spectroscopy to determine the membrane distribution of activating and inhibitory receptors in mouse NK cells that were either hyporesponsive or competent. This analysis revealed that in the absence of self MHC class I–specific inhibitory receptors, activating and other inhibitory receptors were confined to areas of membrane associated with an actin-rich meshwork. However, engagement of self MHC class I–specific inhibitory receptors triggered the movement of activating receptors out of the actin-rich region and into distinct membrane nanodomains that were more favorable for signaling. Thus, NK cells that fail to become educated remain unresponsive because of the confinement of their activating receptors.