Laboratory of Viral Immunobiology, and Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY, USA.
Blood. 2010 Nov 18;116(20):4158-67. doi: 10.1182/blood-2010-02-270678. Epub 2010 Jul 29.
To investigate human natural killer (NK)-cell reactivity in vivo we have reconstituted human immune system components by transplantation of human hematopoietic progenitor cells into NOD-scid IL2Rγ(null) mice. We demonstrate here that this model allows the development of all NK-cell subsets that are also found in human adult peripheral and cord blood, including NKp46(+)CD56(-) NK cells. Similar to human cord blood, NK cells from these reconstituted mice require preactivation by interleukin-15 to reach the functional competence of human adult NK cells. Mainly the terminally differentiated CD16(+) NK cells demonstrate lower reactivity without this stimulation. After preactivation, both CD16(+) and CD16(-) NK cells efficiently produce interferon-γ and degranulate in response to stimulation with NK cell-susceptible targets, including K562 erythroleukemia cells. NK-cell lines, established from reconstituted mice, demonstrate cytotoxicity against this tumor cell line. Importantly, preactivation can as well be achieved by bystander cell maturation via poly I:C stimulation in vitro and injection of this maturation stimulus in vivo. Preactivation in vivo enhances killing of human leukocyte antigen class I negative tumor cells after their adoptive transfer. These data suggest that a functional, but resting, NK-cell compartment can be established in immune-compromised mice after human hematopoietic progenitor cell transfer.
为了研究体内人类自然杀伤 (NK) 细胞的反应性，我们通过将人类造血祖细胞移植到 NOD-scid IL2Rγ(null) 小鼠中来重建人类免疫系统成分。我们在此证明，该模型允许所有 NK 细胞亚群的发育，这些亚群也存在于人类成人外周血和脐带血中，包括 NKp46(+)CD56(-) NK 细胞。与人类脐带血相似，来自这些重建小鼠的 NK 细胞需要通过白细胞介素-15 预先激活才能达到人类成人 NK 细胞的功能能力。主要是终末分化的 CD16(+) NK 细胞在没有这种刺激的情况下反应性较低。在预先激活后，CD16(+)和 CD16(-) NK 细胞都能有效地产生干扰素-γ并在受到 NK 细胞易感靶标的刺激时脱颗粒，包括 K562 红白血病细胞。从重建小鼠中建立的 NK 细胞系对该肿瘤细胞系表现出细胞毒性。重要的是，通过体外多聚 I:C 刺激和体内注射这种成熟刺激物，也可以实现体内的预激活。体内预激活增强了人白细胞抗原 I 类阴性肿瘤细胞在过继转移后的杀伤作用。这些数据表明，在人类造血祖细胞移植后，免疫功能低下的小鼠中可以建立具有功能但处于休眠状态的 NK 细胞群。
