Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institute of Health, Rockville, MD 20852, USA.
Immunity. 2010 Feb 26;32(2):175-86. doi: 10.1016/j.immuni.2010.02.004.
Natural killer (NK) cell cytotoxicity toward target cells depends on synergistic coactivation by NK cell receptors such as NKG2D and 2B4. How synergy occurs is not known. Synergistic phosphorylation of phospholipase PLC-gamma2, Ca(2+) mobilization, and degranulation triggered by NKG2D and 2B4 coengagement were blocked by Vav1 siRNA knockdown, but enhanced by knockdown of c-Cbl. c-Cbl inhibited Vav1-dependent signals, given that c-Cbl knockdown did not rescue the Vav1 defect. Moreover, c-Cbl knockdown and Vav1 overexpression each circumvented the necessity for synergy because NKG2D or 2B4 alone became sufficient for activation. Thus, synergy requires not strict complementation but, rather, strong Vav1 signals to overcome inhibition by c-Cbl. Inhibition of NK cell cytotoxicity by CD94-NKG2A binding to HLA-E on target cells was dominant over synergistic activation, even after c-Cbl knockdown. Therefore, NK cell activation by synergizing receptors is regulated at the level of Vav1 by a hierarchy of inhibitory mechanisms.
自然杀伤 (NK) 细胞对靶细胞的细胞毒性依赖于 NK 细胞受体（如 NKG2D 和 2B4）的协同共激活。协同作用是如何发生的尚不清楚。NKG2D 和 2B4 共交联触发的 PLC-γ2 磷脂酶协同磷酸化、Ca(2+)动员和脱颗粒被 Vav1 siRNA 敲低阻断，但被 c-Cbl 敲低增强。c-Cbl 抑制 Vav1 依赖性信号，因为 c-Cbl 敲低不能挽救 Vav1 缺陷。此外，c-Cbl 敲低和 Vav1 过表达都规避了协同作用的必要性，因为 NKG2D 或 2B4 单独就足以激活。因此，协同作用不需要严格的互补，而是需要强大的 Vav1 信号来克服 c-Cbl 的抑制。即使在 c-Cbl 敲低后，CD94-NKG2A 与靶细胞上 HLA-E 的结合对 NK 细胞细胞毒性的抑制作用也超过了协同激活作用。因此，协同激活受体的 NK 细胞激活在 Vav1 水平受到抑制机制的层次调节。
