Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46
Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46
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DOI：
10.1073/pnas.0609692104
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发表时间：
2007-02-27
影响因子：
11.1
通讯作者：
Vivier, Eric
中科院分区：
文献类型：
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作者：
Walzer, Thierry;Blery, Mathieu;Vivier, Eric
自然杀伤细胞（NIK）有助于对病毒、肿瘤和异体细胞的各种先天免疫反应。然而，我们对NIK细胞生物学的理解受到严重限制，因为缺乏跨物种这些细胞的一致表型定义，缺乏在原位可视化它们的特定标记，以及缺乏INK细胞可以选择性消融的遗传模型。NKp46/CD335是一种参与人NK细胞活化的igg样超家族细胞表面受体。除了人类，我们在这里发现，NIKp46在所有被分析的小鼠品系以及三种常见的猴子物种的INK细胞中都表达，这促使了基于NKp46细胞表面表达的跨物种INK细胞的统一表型定义。小鼠NKp46触发NK细胞效应功能，允许原位检测INK细胞。NKp46的表达与细胞参与NK分化程序相似，因为它在所有未成熟CD122(+)NK1.1(+)DX5（-）阶段的NK细胞和一小部分ink样T细胞上都能检测到，但在cd1限制性NKT细胞上却没有。此外，人类NKp46启动子在体外和体内均可驱动NK细胞的选择性表达。利用NKp46启动子，我们在INK细胞中产生了表达EGIFP和白喉毒素（DT）受体的转基因小鼠。DT注射在这些小鼠中导致INK细胞完全和选择性消融。该模型为INK细胞生物学功能的体内表征和临床前评估铺平了道路。
Natural killer (NIK) cells contribute to a variety of innate immune responses to viruses, tumors and allogeneic cells. However, our understanding of NIK cell biology is severely limited by the lack of consensus phenotypic definition of these cells across species, by the lack of specific markerto visualize them in situ, and by the lack of a genetic model where INK cells may be selectively ablated. NKp46/CD335 is an Ig-like superfamily cell surface receptor involved in human NK cell activation. In addition to human, we show here that NIKp46 is expressed by INK cells in all mouse strains analyzed, as well as in three common monkey species, prompting a unifying phenotypic definition of INK cells across species based on NKp46 cell surface expression. Mouse NKp46 triggers NK cell effector f unction and allows the detection of INK cells in situ. NKp46 expression parallels cell engagement into NK differentiation programs because it is detected on all NK cells from the immature CD122(+)NK1.1(+)DX5(-) stage and on a minute fraction of INK-like T cells, but not on CD1d-restricted NKT cells. Moreover, human NKp46 promoter drives NK cell selective expression both in vitro and in vivo. Using NKp46 promoter, we generated transgenic mice expressing EGIFP and the diphtheria toxin (DT) receptor in INK cells. DT injection in these mice leads to a complete and selective INK cell ablation. This model paves a way for the in vivo characterization and preclinical assessment of INK cell biological function.