Like T cells and B cells, NK cells have the potential for autoreactivity even though NK receptor genes do not undergo somatic diversification. This is because some NK cells lack inhibitory receptors that bind to the MHC class I molecules of the host (37
) or they express activating receptors that recognize self ligands, including MHC molecules (39
). These patterns of expression arise because the array of receptors that individual NK cells come to express during development is largely random, and the MHC ligands recognized by these receptors are inherited independently of the receptor genes (42
). Therefore, some NK cells may express activating receptors for a self ligand, yet fail to express inhibitory receptors for self-MHC molecules.
To avoid autoreactivity, an education system exists whereby such NK cells acquire self-tolerance. The potentially autoreactive NK cells are not generally clonally deleted but instead acquire a state of hyporesponsiveness to stimulation through various activating receptors. Thus, in normal mice (38
) or humans (43
), a fraction of NK cells lack inhibitory receptors for self-MHC, and these NK cells are unresponsive to self cells (). A related situation applies in mice or humans that lack MHC class I molecules, where NK cells exist in normal numbers but fail to exert detectable autoimmunity or to kill MHC class I–deficient autologous cells in vivo or in vitro (44
) (). In both cases, the NK cells not only are unresponsive to self cells but also exhibit reduced responses to various other stimuli, including MHC class I–deficient tumor cells or cross-linking antibodies specific for activating receptors (37
). By comparison, by an MHC-dependent education process described as licensing by some investigators, the NK cells that express receptors for self MHC in normal animals or humans exhibit greater responsiveness to stimulation, but their effector function against neighboring normal cells is inhibited by engagement of the MHC-specific inhibitory receptors (37
). Whether NK responsiveness is actively induced by encounters with cells expressing MHC ligands for these NK cells (called “arming”), or hyporesponsiveness is actively induced by encounters with normal cells that lack MHC ligands and at the same time express stimulatory ligands for these NK cells (called “disarming,” or energy), or both, remain unsettled issues (48
). The molecular mechanisms that govern responsiveness are also not established, except that it is clear that changes in responsiveness are not correlated with changes in the expression of the known activating receptors (37
Fig. 4 NK cell tuning. Experimental conditions in which NK cells have been shown to adapt to their environment are schematized. In the absence of detection of MHC class I, such as when NK cells lack cognate MHC class I receptors (A) or in MHC class I–deficient (more ...)
Experimental evidence for NK cell education in an MHC-independent scenario has been obtained using mice engineered to express ligands for activating receptors such as NKG2D () or Ly49H (50
) (). The NK cells in these mice are tolerant to expressed ligand but retain expression of the corresponding receptor. Similarly, in humans, NK cells expressing the KIR2DS1 activating receptor specific for the human lymphocyte antigen (HLA)–C2 allotype are functional only when derived from C1/C2 or C1/C1 donors but hyporesponsive in donors homozygous for C2 (52
). This suggests that in the presence of high levels of activating ligands, a negative tuning effect may occur (53
It is possible that some of the mechanisms that confer tolerance in mice with constitutive expression of activating ligands are the same as those that operate when NK cells lack inhibitory receptors for self-MHC. One possible mechanism for the impaired responsiveness of NK cells that are not inhibited by MHC molecules is the induction of an anergic state, as can occur in autoreactive T cells and B cells. Another is a failure of these NK cells to undergo terminal functional maturation, which may depend on interactions between MHC and inhibitory receptors on NK cells. Other possibilities include the function of inhibitory receptors for non-MHC ligands or the action of suppressor cells, but these are unlikely to fully account for these outcomes.
Whatever the mechanism (or mechanisms), it must account for the existence of intermediate states of responsiveness. NK cells vary in the number and affinity of inhibitory receptors specific for self-MHC, and the functional response of NK cells to activating stimuli was shown to increase commensurately with the number of different inhibitory receptors for self-MHC that the NK cells expressed (53
). Despite exhibiting greater responsiveness, NK cells with more inhibitory receptors are not autoreactive, because interactions of their inhibitory receptors with MHC class I molecules on normal cells inhibits their activity. Thus, NK cells appear to be “tuned” such that the greater effector cell inhibition that accompanies the expression of more inhibitory receptors is balanced by a greater potential responsiveness of the NK cells.
Several findings suggest that the responsiveness of mature NK cells is not fixed but may adapt to a changing environment in vivo. In the absence of infection or other disease, transfer of mature NK cells to mice with no MHC ligands led to a reduced responsiveness of the NK cells, indicating that encounters with cells lacking self-MHC, which would normally stimulate these cells, instead drive them into a hyporesponsive state (55
). Conversely, transfer of NK cells from MHC-deficient mice to MHC class I+
mice resulted in increased responsiveness, specifically of those NK cells with an inhibitory receptor specific for MHC molecules in the new host, indicating that the inhibitory interaction is instrumental in increasing NK responsiveness (55
). Hence, persistent stimulation without inhibition results in NK cell hyporesponsiveness, whereas persistent stimulation coupled with commensurate inhibition results in NK cell responsiveness. These results suggest that NK cell tuning might occur throughout the lifetime of the NK cell under steady-state conditions. In infected animals, however, hyporesponsive NK cells are converted to a higher state of responsiveness. In fact, NK cells lacking self-MHC–specific inhibitory receptors play a more important role than other NK cells in protective responses to mouse cytomegalovirus infections (57
), probably reflecting an increased responsiveness associated with infection coupled with the absence of inhibitory receptor interactions. Taken together, these findings suggest that in steady-state conditions, NK cell tuning enables those NK cells with inhibitory receptors for self-MHC to rapidly eliminate MHC class I–deficient cells that arise in the environment, whereas NK cells with fewer such receptors can be mobilized by inflammatory signals that accompany pathogen infections (38