Shifrin Nataliya, Raulet David H, Ardolino Michele
Department of Molecular and Cell Biology and Cancer Research Laboratory, Division of Immunology, University of California at Berkeley, Berkeley, CA 94720, USA.
Department of Molecular and Cell Biology and Cancer Research Laboratory, Division of Immunology, University of California at Berkeley, Berkeley, CA 94720, USA.
Semin Immunol. 2014 Apr;26(2):138-44. doi: 10.1016/j.smim.2014.02.007. Epub 2014 Mar 12.
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.
自然杀伤（NK）细胞是抵御病原体和肿瘤细胞的第一道防线。NK细胞的激活受其表面表达的激活受体和抑制受体所产生信号整合的调控。然而，不同的NK细胞对相同刺激（无论是靶细胞还是交联激活受体的因子）的反应各不相同。决定NK细胞反应性水平的过程被统称为NK细胞教育。NK细胞教育在稳态条件下起重要作用，在此条件下，潜在的自身反应性NK细胞对周围环境产生耐受。根据“微调”概念，每个NK细胞的反应性会进行定量调整，以确保自身耐受，同时确保对潜在威胁具有有效的反应性。NK细胞展示的MHC特异性抑制受体在调节NK细胞反应性方面起主要作用，但最近的研究表明，激活受体发出的信号也很重要，这表明关键决定因素是来自这两种受体的整合信号。一个重要且尚未解决的问题是，NK细胞教育是否涉及与环境中特定细胞群体的相互作用。造血细胞和/或非造血细胞是否发挥作用仍存在争议。最近的结果表明，NK细胞微调在稳态条件下具有可塑性，这意味着如果MHC环境发生变化，它可以重新设定。然而，其他证据表明，感染伴随的炎症状态可能有利于高反应性，这表明炎症因子可以克服NK细胞适应稳态环境的自然倾向。这些发现引发了许多问题，例如病毒和肿瘤细胞是否操纵NK细胞反应性以逃避免疫识别。随着对潜在过程的了解不断增加，为治疗目的调节NK细胞反应性的可能性越来越具有吸引力，目前正在临床研究中进行认真调查。
