Inhibitory receptors alter natural killer cell interactions with target cells yet allow simultaneous killing of susceptible targets

Inhibitory receptors expressed on natural killer (NK) cells abrogate positi ve signals upon binding corresponding major histocompatibility complex (MHC ) class I molecules on various target cells. By directly micromanipulating the effector-target cell encounter using an optical tweezers system which a llowed temporal and spatial control, we demonstrate that Ly49-MHC class I i nteractions prevent characteristic cellular responses in NK cells upon bind ing to target cells. Furthermore, using this system, we directly demonstrat e that an NK cell already bound to a resistant target cell may simultaneous ly bind and kill a susceptible target cell. Thus, although Ly49-mediated in hibitory signals can prevent many types of effector responses, they do not globally inhibit cellular function, but rather the inhibitory signal is spa tially restricted towards resistant targets.