Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455;
J Immunol. 2014 Apr 15;192(8):3889-97. doi: 10.4049/jimmunol.1302601. Epub 2014 Mar 14.
Acquisition of a functional NK cell repertoire, known as education or licensing, is a complex process mediated through inhibitory receptors that recognize self. We found that NK cells containing self-killer Ig-like receptors for cognate HLA ligand in vivo were less susceptible to apoptosis. In vitro IL-15 withdrawal showed that uneducated NK cells upregulated Bim and Fas. Conversely, educated NK cells upregulated Fas ligand (FasL) under these conditions. Induction of cell death and Bim expression on uneducated cells correlated with increased IL-2Rα expression. Overexpression and knockdown studies showed that higher IL-2Rα limits NK cell survival in a novel manner that is independent from the role of IL-2 in activation-induced cell death. To study the role of FasL in induction of IL-2Rα(hi) NK cell death, a coculture assay with FasL-blocking Abs was used. IL-15 withdrawal led to FasL-dependent killing of IL-2Rα(hi) NK cells by more educated IL-2Rα(lo) NK cells. Finally, CMV reactivation induces a potent long-lasting population of licensed NK cells with enhanced survival. These findings show that education-dependent NK cell survival advantages and killing of uneducated NK cells result in the maintenance of a functional repertoire, which may be manipulated to exploit NK cells for cancer immunotherapy.
获得功能性 NK 细胞库，即所谓的教育或许可，是一个通过识别自身的抑制性受体介导的复杂过程。我们发现，体内含有与自身 HLA 配体匹配的杀手 Ig 样受体的 NK 细胞对凋亡的敏感性降低。体外 IL-15 撤出表明，未受教育的 NK 细胞上调了 Bim 和 Fas。相反，在这些条件下，受过教育的 NK 细胞上调了 Fas 配体 (FasL)。未受教育细胞的细胞死亡和 Bim 表达的诱导与 IL-2Rα 表达的增加相关。过表达和敲低研究表明，较高的 IL-2Rα 以一种新颖的方式限制 NK 细胞的存活，这种方式独立于 IL-2 在激活诱导的细胞死亡中的作用。为了研究 FasL 在诱导 IL-2Rα(hi)NK 细胞死亡中的作用，使用 FasL 阻断 Ab 进行共培养测定。IL-15 撤出导致 FasL 依赖性杀伤 IL-2Rα(hi)NK 细胞，而更具教育意义的 IL-2Rα(lo)NK 细胞。最后，CMV 再激活诱导出具有增强存活能力的功能齐全的许可 NK 细胞的强大且持久的群体。这些发现表明，教育依赖性 NK 细胞存活优势和未受教育 NK 细胞的杀伤导致功能库的维持，这可能被操纵以利用 NK 细胞进行癌症免疫治疗。
