Predominant Development of Mature and Functional Human NK Cells in a Novel Human IL-2-Producing Transgenic NOG Mouse
Predominant Development of Mature and Functional Human NK Cells in a Novel Human IL-2-Producing Transgenic NOG Mouse
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DOI：
10.4049/jimmunol.1401323
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发表时间：
2015-04-01
影响因子：
4.4
通讯作者：
Ito, Mamoru
中科院分区：
文献类型：
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作者：
Katano, Ikumi;Takahashi, Takeshi;Ito, Mamoru
我们产生了一个严重的免疫缺陷NOD/Shi-scid-IL-2 R γ（nun）（NOG）小鼠亚系表达转基因人IL-2基因（NOG IL-2 Tg）。在转移人脐带血来源的造血干细胞（HSC）后，CD 3（-）CD 56（高）CD 16（+/-）细胞出乎意料地发展，主要在NOG IL-2 Tg（hu-HSC NOG IL-2 Tg）中。这些细胞表达各种NK受体，包括NKp 30、NKp 44、NKp 46、NKG 2D和CD 94，以及一组多样的杀伤细胞Ig样受体分子，其水平与来自外周血的正常人NK细胞相当，这是其成熟的证据。它们产生的颗粒酶A水平与人外周血来源的NK细胞一样高，并且在血浆中检测到相当数量的穿孔蛋白。hu-HSC NOG IL-2 Tg中的人NK细胞在刺激后产生IFN-γ，并且IL-2、IL-15或IL-12处理增强了体外细胞毒性。将K562白血病细胞接种到hu-HSC NOG IL-2 Tg中引起肿瘤细胞的完全排斥，而接种到用人B、T和一些NK细胞完全重建的hu-HSC NOG中则没有。此外，当CCR 4（+）霍奇金淋巴瘤细胞系被皮下接种时，在hu-HSC NOG IL-2 Tg中，通过用治疗性人源化抗CCR 4 Ab（mogamulizumab）处理显著抑制肿瘤生长，表明小鼠中的人NK细胞在体内发挥活性Ab依赖性细胞毒性。总之，这些数据表明，新的NOG IL-2 Tg菌株是一种独特的模型，可用于研究体内人NK细胞的生物学和病理学功能。
We generated a severe immunodeficient NOD/Shi-scid-IL-2R gamma(nun) (NOG) mouse substrain expressing the transgenic human IL-2 gene (NOG IL-2 Tg). Upon transfer of human cord blood derived hematopoietic stem cells (HSCs), CD3(-)CD56(high)CD16(+/-) cells developed unexpectedly, predominantly in the NOG IL-2 Tg (hu-HSC NOG IL-2 Tg). These cells expressed various NK receptors, including NKp30, NKp44, NKp46, NKG2D, and CD94, as well as a diverse set of killer cell Ig-like receptor molecules at levels comparable to normal human NK cells from the peripheral blood, which is evidence of their maturity. They produced levels of granzyme A as high as in human peripheral blood derived NK cells, and a considerable amount of perforM protein was detected in the plasma. Human NK cells in hu-HSC NOG IL-2 Tg produced IFN-gamma upon stimulation, and IL-2, IL-15, or IL-12 treatment augmented the in vitro cytotoxicity. Inoculation of K562 leukemia cells into hu-HSC NOG IL-2 Tg caused complete rejection of the tumor cells, whereas inoculation into hu-HSC NOG fully reconstituted with human B, T, and some NK cells did not. Moreover, when a CCR4(+) Hodgkin's lymphoma cell line was inoculated s.c. into hu-HSC NOG IL-2 Tg, the tumor growth was significantly suppressed by treatment with a therapeutic humanized anti-CCR4 Ab (mogamulizumab), suggesting that the human NK cells in the mice exerted active Ab-dependent cellular cytotoxicity in vivo. Taken together, these data suggest that the new NOG IL-2 Tg strain is a unique model that can be used to investigate the biological and pathological functions of human NK cells in vivo.