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With the detailed description and analysis of several inhibitory receptor systems on lymphoid and myeloid cells, a central paradigm has emerged in which the pairing of activation and inhibition is necessary to initiate, amplify, and then terminate immune responses. In some cases, the activating and inhibitory receptors recognize similar ligands, and the net outcome is determined by the relative strength of these opposing signals. The importance of this modulation is demonstrated by the sometimes fatal autoimmune disorders observed in mice with targeted disruption of inhibitory receptors. The significance of these receptors is further evidenced by the conservation of immunoreceptor tyrosine-based inhibitory motifs during their evolution.
A hallmark of the vertebrate immune system is its ability to maintain a precarious equilibrium between the extremes of reactivity and quiescence-at any moment poised to unleash an arsenal of cytotoxic cells and molecules, yet capable of maintaining control over these potentially lethal responses. A key aspect of this ability is encoded in the specificity of the response that can target molecules alien to the organism while sparing the organism itself. Equally critical is the capacity to limit and ultimately terminate a response, inactivating or eliminating the relevant pathways when they are no longer required.
Although many aspects of positive signaling in the generation of effective immunity have been clarified, our knowledge about the counterbalancing inhibitory pathways has remained quite limited until recently. From the detailed analysis of some inhibitory receptor systems, a central paradigm has emerged in which the pairing of activation and inhibition is necessary to modulate immune responses (1-3). Loss of inhibitory signaling is often associated with autoreactivity and unchecked inflammatory responses, illustrating the essential role these systems play in immune regulation (4-6).
The common feature that identifies receptors as members of the inhibitory class is their ability to attenuate activation signals initiated by other receptors that are often of the immunoreceptor tyrosine-based activation motif (ITAM) class (7, 8). Inhibitory receptors mediate this function only upon their clustering with an activating counterpart on the cell surface. In some cases, the activating and inhibitory receptors recognize different ligands, whereas in other circumstances cells simultaneously express pairs of activating and inhibitory receptors with closely related extracellular domains binding similar ligands. When both activating and inhibitory receptors are coengaged...