The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University Medical School, Jerusalem, Israel.
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 7610001, Israel.
Sci Rep. 2017 Oct 12;7(1):13090. doi: 10.1038/s41598-017-12998-w.
Natural Killer (NK) cells employ activating receptors like the Natural Cytotoxicity Receptors (NCRs: NKp30, NKp44 and NKp46), of which only NKp46 has a mouse orthologue (Ncr1), to eliminate abnormal cells. NKp46/Ncr1 is considered a selective marker for NK cells, although it is also found on a subset of ILCs, where it appears to be without function. The influenza virus hemagglutinin (HA) was the first ligand identified for Ncr1/NKp46 followed by other viral, bacterial and even fungal ligands. NKp46/Ncr1 also recognizes unknown self and tumor ligands. Here we describe the generation of a transgenic mouse where the Ncr1 gene is expressed in the Rosa locus, preceded by a floxed stop sequence allowing Ncr1/NKp46 expression in various tissues upon crossing with Cre transgenic mouse lines. Surprisingly, while several crossings were attempted, Ncr1 overexpression was successful only where cre recombinase expression was dependent on the Ncr1 promoter. Ncr1 overexpression in NK cells increased NK cell immunity in two hallmark Ncr1 related pathologies, influenza virus infection and B16 melanoma. These data suggest that increasing NK cell cytotoxicity by enforced NKp46/Ncr1 expression serves as a potential therapeutic opportunity for the treatment of various pathologies, and in immunotherapy.
自然杀伤 (NK) 细胞利用激活受体，如自然细胞毒性受体 (NCRs：NKp30、NKp44 和 NKp46)，其中只有 NKp46 具有小鼠同源物 (Ncr1)，以消除异常细胞。NKp46/Ncr1 被认为是 NK 细胞的选择性标志物，尽管它也存在于一部分 ILC 中，在那里它似乎没有功能。流感病毒血凝素 (HA) 是第一个被鉴定为 Ncr1/NKp46 配体的配体，随后是其他病毒、细菌甚至真菌配体。NKp46/Ncr1 还识别未知的自身和肿瘤配体。在这里，我们描述了一种转基因小鼠的产生，其中 Ncr1 基因在 Rosa 基因座中表达，前面有一个 floxed 终止序列，允许在与 Cre 转基因小鼠系杂交时在各种组织中表达 Ncr1/NKp46。令人惊讶的是，尽管进行了多次杂交尝试，但只有在 cre 重组酶表达依赖于 Ncr1 启动子时，Ncr1 过表达才成功。NK 细胞中 Ncr1 的过表达增加了两种与 Ncr1 相关的标志性病理学（流感病毒感染和 B16 黑色素瘤）中的 NK 细胞免疫。这些数据表明，通过强制表达 NKp46/Ncr1 增加 NK 细胞的细胞毒性可能成为治疗各种病理学和免疫疗法的潜在治疗机会。
