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

Abstract

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.

Figure 1. Functional outcomes for NK cells developing under conditions where inhibitory receptor engagement occurs, or does not occur, and interpreted according to the arming model or the disarming model

Interactions of MHC class I molecules (on normal cells) with specific inhibitory receptors (on NK cells) results in high NK cell responsiveness (top). Absence of MHC class I interactions with specific inhibitory receptors, either because the NK cell lacks a corresponding receptor (middle) or because the environment lacks MHC class I molecules (bottom) results in hyporesponsiveness. The outcome in each scenario is interpreted according to either the arming model or the disarming model (right). Note that for reasons of clarity, only one stimulatory and/or one inhibitory interaction is shown for each cell.

Figure 2. Predictions of the arming and disarming models in mixed MHC class I⁺/classI⁻ chimeras

NK cells developing in a chimeric environment consisting of class I⁺ and class I⁻ cells will encounter both types of cells as shown in the figure. The arming model and the disarming model make different predictions regarding the outcome in this situation. The arming model predicts that the NK cells will attain high responsiveness, which should result in elimination of co-developing class I⁻ cells and rejection of class I-deficient grafts, whereas the disarming model predicts that hyporesponsiveness will be induced, codeveloping class I⁻ cells will be tolerated and there will be no rejection of class I–deficient grafts.

Figure 3. Tuning NK cell responsiveness: an educational “rheostat”

The responsiveness of NK cells is tuned to quantitatively different levels by the quantity of inhibitory and stimulatory interactions to which the cells are exposed during development. One indication of this is that NK cells that express a greater number of self MHC-specific inhibitory receptors acquire a higher degree of potential responsiveness. a) Expression of two inhibitory receptors counters stimulatory signals from neighboring normal cells, lowering the level of persistent stimulation and therefore preventing the induction of hyporesponsiveness. b) Expression of one receptor only partially counters stimulatory signals resulting in partial hyporesponsiveness. c) When no inhibitory receptors are expressed, strong persistent stimulation induces greater hyporesponsiveness. d) In instances where NK cells express inhibitory receptors for self MHC class I, but are exposed to excessive persistent stimulation (as in transgenic mice expressing stimulatory ligands at high levels), the excess stimulatory signaling induces hyporesponsiveness.