Development of Functional Human NK Cells in an Immunodeficient Mouse Model with the Ability to Provide Protection against Tumor Challenge

Studies of human NK cells and their role in tumor suppression have largely been restricted to in vitro experiments which lack the complexity of whole organisms, or mouse models which differ significantly from humans. In this study we showed that, in contrast to C57BL/6 Rag2−/−/γc−/− and NOD/Scid mice, newborn BALB/c Rag2−/−/γc−/− mice can support the development of human NK cells and CD56+ T cells after intrahepatic injection with hematopoietic stem cells. The human CD56+ cells in BALB/c Rag2−/−/γc−/− mice were able to produce IFN-γ in response to human IL-15 and polyI:C. NK cells from reconstituted Rag2−/−/γc−/− mice were also able to kill and inhibit the growth of K562 cells in vitro and were able to produce IFN-γ in response to stimulation with K562 cells. In vivo, reconstituted Rag2−/−/γc−/− mice had higher survival rates after K562 challenge compared to non-reconstituted Rag2−/−/γc−/− mice and were able to control tumor burden in various organs. Reconstituted Rag2−/−/γc−/− mice represent a model in which functional human NK and CD56+ T cells can develop from stem cells and can thus be used to study human disease in a more clinically relevant environment.

有关人类自然杀伤细胞（natural killer cells）及其肿瘤抑制功能的研究，目前大多局限于缺乏完整生物体复杂性的体外实验，或是与人类差异显著的小鼠模型。本研究证实，与C57BL/6 Rag2−/−/γc−/−及NOD/Scid小鼠不同，新生BALB/c Rag2−/−/γc−/−小鼠在接受肝内注射造血干细胞（hematopoietic stem cells）后，可支持人类NK细胞与CD56+ T细胞的发育。该小鼠体内的人类CD56+细胞，可在人类白细胞介素15（interleukin-15，IL-15）与聚肌胞苷酸（polyI:C）的刺激下产生干扰素γ（interferon-γ，IFN-γ）。经造血干细胞重建的Rag2−/−/γc−/−小鼠来源的NK细胞，体外可杀伤并抑制K562细胞的增殖，同时也能在K562细胞的刺激下产生干扰素γ。体内实验中，经重建的Rag2−/−/γc−/−小鼠在受到K562细胞攻击后的存活率显著高于未重建的同品系小鼠，且可有效控制多器官内的肿瘤负荷。经重建的Rag2−/−/γc−/−小鼠是一种可使功能性人类NK细胞与CD56+ T细胞从干细胞发育分化的动物模型，因此可用于在更具临床相关性的环境中开展人类疾病相关研究。