NK cell self tolerance, responsiveness and missing self recognition

Natural killer (NK) cells represent a first line of defense against pathogens and tumor cells. The activation of NI(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 NM cell responsiveness have been referred to collectively as NM cell education. NM cell education plays an important role in steady state conditions, where potentially auto-reactive NM cells are rendered tolerant to the surrounding environment. According to the "tuning" concept, the responsiveness of each NM 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 NM cells play a major role in tuning NM 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 NM 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 NM 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 NM 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. (C) 2014 Elsevier Ltd. All rights reserved.