Department of Immunobiology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai 980-8575, Japan.
Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9421-6. doi: 10.1073/pnas.1300140110. Epub 2013 May 20.
The natural killer group 2 membrane D (NKG2D) activating receptor plays crucial roles not only in host defense against tumors and viral infections, but also in autoimmune diseases. After NKG2D-mediated activation, Natural killer (NK) cells must be regulated to avoid potentially harmful reactivity. However, the negative regulation of these activated NK cells is poorly understood. Here, we reveal that the engagement of NKG2D by its ligand elicits not only target cell lysis, but also NK cell fratricide. Conventional mouse NK cells underwent cell death when cocultured with RMA cells expressing the NKG2D ligand retinoic acid early-inducible protein 1 (Rae-1), but not with RMA cells lacking MHC class I. NK cells from mice deficient for DAP10 and DAP12 or perforin did not undergo death, highlighting the importance of the NKG2D pathway for NK cell death. However, NKG2D does not transmit direct death signals in NK cells. Rather, the interaction between NKG2D and Rae-1 allowed NK cells to acquire tumor-derived Rae-1 by a membrane transfer process known as "trogocytosis," which was associated with clathrin-dependent NKG2D endocytosis. NK cells dressed with Rae-1 were lysed by neighboring NK cells through the NKG2D-induced perforin pathway in vitro and in vivo. These results provide the unique NKG2D function in negative regulation of activated NK cells.
自然杀伤细胞群 2 膜 D（NKG2D）激活受体不仅在宿主防御肿瘤和病毒感染方面发挥着至关重要的作用，而且在自身免疫性疾病中也起着重要作用。在 NKG2D 介导的激活后，自然杀伤（NK）细胞必须受到调节，以避免潜在的有害反应。然而，这些激活的 NK 细胞的负调控机制还知之甚少。在这里，我们揭示了 NKG2D 与其配体的结合不仅引发了靶细胞的裂解，还引发了 NK 细胞的自噬。当与表达 NKG2D 配体维甲酸早期诱导蛋白 1（Rae-1）的 RMA 细胞共培养时，常规的小鼠 NK 细胞会发生细胞死亡，但与缺乏 MHC Ⅰ类的 RMA 细胞共培养时则不会。缺乏 DAP10 和 DAP12 或穿孔素的 NK 细胞不会发生死亡，这突出了 NKG2D 途径对 NK 细胞死亡的重要性。然而，NKG2D 并不能在 NK 细胞中传递直接的死亡信号。相反，NKG2D 与 Rae-1 的相互作用使 NK 细胞能够通过一种称为“胞噬作用”的膜转移过程获得肿瘤衍生的 Rae-1，这与网格蛋白依赖性 NKG2D 内吞作用有关。用 Rae-1 包裹的 NK 细胞通过体外和体内的 NKG2D 诱导的穿孔素途径被相邻的 NK 细胞溶解。这些结果提供了 NKG2D 在激活的 NK 细胞负调控中的独特功能。
