Figure 3. Models of NK education.

Natural killer cells stochastically express activating and inhibitory receptors. The quantity of inhibitory input triggered by “self” MHC in each NK cell programs its education. Three models exist to describe the process of education. (A) The licensing/arming model postulates that developing NK cells capable of binding self-MHC class I molecules are endowed with higher effector potential, while those that cannot bind self-MHC class I molecules will be programmed for lower reactivity. (B) The disarming model postulates that all developing NK cells are initially capable of high effector responses, but only those that are capable of inhibition by self-MHC binding can rescue themselves from activation-induced anergy. As a result, those NK cells which are sensitive to “self” class I remain highly reactive, while those that cannot bind “self” class I lose effector potential, becoming comparatively hyporesponsive. (C) The rheostat model postulates that the avidity of the total interactions between inhibitory receptors and class I molecules tunes the reactivity of each NK cell. Those with fewer interactions with self-MHC class I binding exhibit the lowest effector potential, while those with intermediate and high numbers of interactions with self-MHC molecules exhibit intermediate and strong reactivity, respectively. (D) All three models are compatible with “tuning”, wherein the reactivity of an NK cell can be adjusted up or down in response to changes in the local environment.