Humanized mouse model supports development, function, and tissue residency of human natural killer cells
Humanized mouse model supports development, function, and tissue residency of human natural killer cells
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DOI：
10.1073/pnas.1705301114
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发表时间：
2017-11-07
影响因子：
11.1
通讯作者：
Flavell, Richard A.
中科院分区：
文献类型：
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作者：
Herndler-Brandstetter, Dietmar;Shan, Liang;Flavell, Richard A.
用人类免疫系统重建的免疫缺陷小鼠代表了一种有前途的转化研究工具，因为它们可以在体内对人类疾病进行建模和治疗。然而，人类自然杀伤（NK）细胞和T细胞亚群的发育和功能不足限制了人源化小鼠在研究癌症生物学和治疗方面的适用性。在这里，我们描述了 Rag2(-/-) Il2rg(-/-) 背景 (SRG-15) 上的人白细胞介素 15 (IL15) 和人信号调节蛋白 α (SIRPA) 敲入小鼠。将人类造血干细胞和祖细胞移植到SRG-15小鼠体内，显着改善了循环和组织驻留的人类NK和CD8(+) T细胞的发育和功能成熟，并促进了组织驻留的先天淋巴细胞(ILC)亚群的发育。通过质谱流式分析对人类 NK 细胞亚群进行分析，揭示了 SRG15 小鼠和人类 NK 细胞亚群中杀伤抑制受体和其他候选分子的表达模式高度相似。与非肥胖糖尿病严重联合免疫缺陷Il2rg(-/-) (NSG)小鼠相比，SRG-15小鼠中的人类NK细胞不需要预激活，而是在用治疗性抗体利妥昔单抗治疗后浸润伯基特淋巴瘤异种移植物并有效抑制肿瘤生长。因此，我们的人源化小鼠模型可能可用于新型人类 NK 细胞靶向和组合癌症免疫疗法的临床前测试，并可用于研究它们如何在体内引发人类抗肿瘤免疫反应。
Immunodeficient mice reconstituted with a human immune system represent a promising tool for translational research as they may allow modeling and therapy of human diseases in vivo. However, insufficient development and function of human natural killer (NK) cells and T cell subsets limit the applicability of humanized mice for studying cancer biology and therapy. Here, we describe a human interleukin 15 (IL15) and human signal regulatory protein alpha (SIRPA) knock-in mouse on a Rag2(-/-) Il2rg(-/-) background (SRG-15). Transplantation of human hematopoietic stem and progenitor cells into SRG-15 mice dramatically improved the development and functional maturation of circulating and tissue-resident human NK and CD8(+) T cells and promoted the development of tissue-resident innate lymphoid cell (ILC) subsets. Profiling of human NK cell subsets by mass cytometry revealed a highly similar expression pattern of killer inhibitory receptors and other candidate molecules in NK cell subpopulations between SRG15 mice and humans. In contrast to nonobese diabetic severe combined immunodeficient Il2rg(-/-) (NSG) mice, human NK cells in SRG-15 mice did not require preactivation but infiltrated a Burkitt's lymphoma xenograft and efficiently inhibited tumor growth following treatment with the therapeutic antibody rituximab. Our humanized mouse model may thus be useful for preclinical testing of novel human NK cell-targeted and combinatory cancer immunotherapies and for studying how they elicit human antitumor immune responses in vivo.