Mouse Ly49 NK receptors: balancing activation and inhibition

Previous studies from numerous laboratories have demonstrated that inhibitory class I binding NK receptors dominate functional interactions in vitro. Our previous studies have shown that in addition to lysis, a major consequence of triggering the murine activating NK receptor Ly49D is the expression of cytokines and chemokines. We have recently shown that the activating Ly49D murine NK cell receptor can potently synergize during co-stimulation with IL-12 and IL-18 for selective production of IFN-γ. Activation both in vitro and in vivo and synergistic production of IFN-γ by Ly49D expressing NK cells results from cytokine stimulation combined with co-receptor ligation. In addition, IL-12 is capable of overriding the inhibitory receptor blockade for cytokine production, both in vitro and in vivo. Our current studies will expand this finding of IL-12 synergy to other receptors in the NK repertoire and evaluate potential biochemical mechanisms involved in this synergy. These findings place NK cells and their activating Ly49 receptors as important initiators of microbial, antiviral and anti-tumor immunity and provide a mechanism for the release of activating Ly49 receptors from an inhibitory receptor blockade. Discussion of how activation of the innate immune system provides important initiators of adaptive immune responses by receptor cross-linking and cytokine co-receptor engagement will ensue.