Chronic lymphocytosis of functionally immature natural killer cells
Chronic lymphocytosis of functionally immature natural killer cells
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DOI：
10.1016/j.jaci.2007.05.022
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发表时间：
2007-10-01
影响因子：
14.2
通讯作者：
Yokoyama, Wayne M.
中科院分区：
文献类型：
--
作者：
French, Anthony R.;Kim, Sungjin;Yokoyama, Wayne M.
背景：骨髓中自然杀伤 (NK) 细胞的发育尚不清楚。我们最近描述了一种小鼠（称为 NK 细胞缺陷 [NKD] 小鼠），该小鼠由于将转基因构建体插入基本亮氨酸拉链转录因子 ATF-2 的遗传位点而导致 NK 细胞选择性缺陷。该小鼠的 NK 细胞在表型和功能上均不成熟，并且在野生型小鼠中发生组成型 NK 细胞增殖的阶段在骨髓中积累。目的：我们假设过量的 IL-15 可能会克服这种发育障碍，使成熟 NK 细胞能够正常地从骨髓迁移到外周。方法：将NKD小鼠与过表达IL-15的转基因小鼠杂交产生双转基因小鼠。结果：双转基因小鼠的骨髓中以及随后的血液、肝脏和脾脏中表型未成熟的 NK 细胞大量积累。这些双转基因小鼠的 NK 细胞表现出与 NKD 小鼠的 NK 细胞相似的功能缺陷，通过细胞因子产生和细胞毒性的减少进行评估。结论：过量的 IL-15 并没有绕过 NKD 小鼠中观察到的发育缺陷，而是导致骨髓和外周表型和功能不成熟的 NK 细胞大量积累。临床意义：我们建议这些双转基因小鼠将作为人类患者慢性 NK 细胞淋巴细胞增多症的小鼠模型。
Background: The development of natural killer (NK) cells in the bone marrow is not well characterized. We recently described a mouse (referred to as an NK cell-deficient [NKD] mouse) with a selective deficiency in NK cells caused by the insertion of a transgene construct into the genetic locus for the basic leucine zipper transcription factor ATF-2. NK cells in this mouse were both phenotypically and functionally immature and accumulated in the bone marrow at a stage at which constitutive NK cell proliferation occurs in wild-type mice. Objective: We hypothesized that excess IL-15 could potentially overcome this developmental block, allowing normal emigration of mature NK cells from the bone marrow to the periphery. Methods: Double-transgenic mice were generated by crossing the NKD mice with transgenic mice overexpressing IL-15. Results: The double-transgenic mice had a dramatic accumulation of phenotypically immature NK cells in the bone marrow and subsequently in the blood, liver, and spleen. NK cells from these double-transgenic mice manifested functional deficits similar to those observed in NK cells from NKD mice, as assessed by decreased cytokine production and cytotoxicity. Conclusion: Rather than bypass the observed developmental defect in NKD mice, excess IL-15 drove a massive accumulation of phenotypically and functionally immature NK cells in the bone marrow and periphery. Clinical implications: We propose that these double-transgenic mice will serve as a murine model of chronic NK cell lymphocytosis in human patients.