Regulation of NK cell responsiveness to achieve self‐tolerance and maximal responses to diseased target cells

Summary: Inhibitory receptors specific for major histocompatibility complex (MHC) class I molecules govern the capacity of natural killer (NK) cells to attack class I‐deficient cells (‘missing‐self recognition’). These receptors are expressed stochastically, such that the panel of expressed receptors varies between NK cells. This review addresses how the activity of NK cells is coordinated in the face of this variation to achieve a repertoire that is self‐tolerant and optimally reactive with diseased cells. Recent studies show that NK cells arise in normal animals or humans that lack any known inhibitory receptors specific for self‐MHC class I. These NK cells exhibit self‐tolerance and exhibit functional hyporesponsiveness to stimulation through various activating receptors. Evidence suggests that hyporesponsiveness is induced because these NK cells cannot engage inhibitory MHC class I molecules and are therefore persistently over‐stimulated by normal cells in the environment. Finally, we discuss evidence that hyporesponsiveness is a quantitative trait that varies depending on the balance of signals encountered by developing NK cells. Thus, a tuning process determines the functional set‐point of NK cells, providing a basis for discriminating self from missing‐self, and at the same time endowing each NK cell with the highest inherent responsiveness compatible with self‐tolerance.