Bryceson Yenan T, March Michael E, Ljunggren Hans-Gustaf, Long Eric O
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
Immunol Rev. 2006 Dec;214:73-91. doi: 10.1111/j.1600-065X.2006.00457.x.
Natural killer (NK) cells possess potent perforin- and interferon-gamma-dependent effector functions that are tightly regulated. Inhibitory receptors for major histocompatibility complex class I display variegated expression among NK cells, which confers specificity to individual NK cells. Specificity is also provided by engagement of an array of NK cell activation receptors. Target cells may express ligands for a multitude of activation receptors, many of which signal through different pathways. How inhibitory receptors intersect different signaling cascades is not fully understood. This review focuses on advances in understanding how activation receptors cooperate to induce cytotoxicity in resting NK cells. The role of activating receptors in determining specificity and providing redundancy of target cell recognition is discussed. Using Drosophila insect cells as targets, we have examined the contribution of individual receptors. Interestingly, the strength of activation is not determined simply by additive effects of parallel activation pathways. Combinations of signals from different receptors can have different outcomes: synergy, no enhancement over individual signals, or additive effects. Cytotoxicity requires combined signals for granule polarization and degranulation. The integrin leukocyte function-associated antigen-1 contributes a signal for polarization but not for degranulation. Conversely, CD16 alone or in synergistic combinations, such as NKG2D and 2B4, signals for phospholipase-C-gamma- and phosphatidylinositol-3-kinase-dependent degranulation.
自然杀伤（NK）细胞具有强大的穿孔素和干扰素γ依赖性效应功能，且这些功能受到严格调控。主要组织相容性复合体I类的抑制性受体在NK细胞中呈现多样化表达，这赋予了单个NK细胞特异性。一系列NK细胞活化受体的结合也提供了特异性。靶细胞可能表达多种活化受体的配体，其中许多通过不同途径发出信号。抑制性受体如何与不同的信号级联相互作用尚不完全清楚。本综述聚焦于在理解活化受体如何协同诱导静息NK细胞产生细胞毒性方面取得的进展。讨论了活化受体在确定特异性和提供靶细胞识别冗余方面的作用。我们以果蝇昆虫细胞为靶标，研究了单个受体的作用。有趣的是，活化强度并非简单地由平行活化途径的累加效应决定。来自不同受体的信号组合可能产生不同的结果：协同作用、不超过单个信号的增强作用或累加效应。细胞毒性需要颗粒极化和脱颗粒的联合信号。整合素白细胞功能相关抗原-1为极化提供信号，但不为脱颗粒提供信号。相反，单独的CD16或与NKG2D和2B4等协同组合，为磷脂酶Cγ和磷脂酰肌醇3激酶依赖性脱颗粒发出信号。
