NK cell self tolerance, responsiveness and missing self recognition

Abstract

Natural Killer (NK) cells represent a first line of defense against pathogens and tumor cells. The activation of NK cells is regulated by the integration of signals deriving from activating and inhibitory receptors expressed on their surface. However, different NK cells respond differently to the same stimulus, be it target cells or agents that crosslink activating receptors. The processes that determine the level of NK cell responsiveness have been referred to collectively as NK cell education. NK cell education plays an important role in steady state conditions, where potentially auto-reactive NK cells are rendered tolerant to the surrounding environment. According to the “tuning” concept, the responsiveness of each NK cell is quantitatively adjusted to ensure self tolerance while at the same time ensuring useful reactivity against potential threats. MHC-specific inhibitory receptors displayed by NK cells play a major role in tuning NK cell responsiveness, but recent studies indicate that signaling from activating receptors is also important, suggesting that the critical determinant is an integrated signal from both types of receptors. An important and still unresolved question is whether NK cell education involves interactions with a specific cell population in the environment. Whether hematopoietic and/or non-hematopoietic cells play a role is still under debate. Recent results demonstrated that NK cell tuning exhibits plasticity in steady state conditions, meaning that it can be re-set if the MHC environment changes. Other evidence suggests, however, that inflammatory conditions accompanying infections may favor high responsiveness, indicating that inflammatory agents can over-ride the natural tendency of NK cells to adjust to the steady state environment. These findings raise many questions such as whether viruses and tumor cells manipulate NK cell responsiveness to evade immune-recognition. As knowledge of the underlying processes grows, the possibility of modulating NK cell responsiveness for therapeutic purposes is becoming increasingly attractive, and is now under serious investigation in clinical studies.

Immunoreceptor tyrosine-based inhibitory motif–dependent functions of an MHC class I-specific NK cell receptor

“…The "disarming" hypothesis resolves these seemingly opposing functions by proposing that Ly49s promote NK-cell responsiveness through inhibiting overstimulation by endogenous activating ligands. In contrast, the "arming" hypothesis predicts that binding between Ly49s and MHC-I triggers a signaling pathway distinct from inhibitory signaling to educate NK cells (36). Our results here show that both inhibition and licensing of NK cells require signaling through the same ITIM, which rules out the possibility that Ly49s might educate NK cells through a previously unidentified signaling motif.…”

Expression and Functional Role of α7 Nicotinic Receptor in Human Cytokine-stimulated Natural Killer (NK) Cells

“…NK cells are crucial components of the immune response against tumors and virus-infected cells (49), and they play a key role in the regulation of the adaptive immune response (19,25). The stimulation of NK cells can occur through various cytokines, such as IL-12, IL-18, IL-2, IL-15, and type I IFNs (23,33), and through the engagement of activating receptors (23,26), triggering their effector functions. We found that activation of ␣7 nAChR in cytokine-stimulated NK cells decreases the expression of NKG2D, which constitutes the underlying mechanism for the observed decrease of the NKG2D-dependent cytotoxicity against MICA-expressing target cells.…”

“…Accumulating evidence indicates that NK cells may also play an important role during autoimmune disorders (19,24,25). The activity of NK cells is controlled by a dynamic balance of signals elicited upon engagement of activating and inhibitory receptors by discrete ligands expressed on target cells (23,26). Very limited information suggests that cholinergic receptors may modulate NK cell activity (27,28).…”

Cytokine therapy reverses NK cell anergy in MHC-deficient tumors

“…Several lines of evidence support a role for NK cells in antitumor immunity (8). The activation of NK cells is regulated by the integration of signals from activating and inhibitory cell surface receptors (9,10). Inhibitory receptors specific for MHC class I molecules, including the Ly49 family members and the CD94/NKG2A heterodimer in mice, play a key role in this process.…”

“…Inhibitory receptors specific for MHC class I molecules, including the Ly49 family members and the CD94/NKG2A heterodimer in mice, play a key role in this process. As a result of loss of inhibitory signals, target cells with low or no expression of MHC class I molecules become highly sensitive to killing by NK cells (9)(10)(11).…”