Halfteck Gili G, Elboim Moran, Gur Chamutal, Achdout Hagit, Ghadially Hormas, Mandelboim Ofer
Lautenberg Center for General and Tumor Immunology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel.
J Immunol. 2009 Feb 15;182(4):2221-30. doi: 10.4049/jimmunol.0801878.
The in vitro elimination of virus-infected and tumor cells by NK cells is regulated by a balance between signals conveyed via specific inhibitory and activating receptors. Whether NK cells and specifically the NK-activating receptor NKp46 (NCR1 in mice) are directly involved in tumor eradication in vivo is still largely unknown. Since the NKp46/NCR1 tumor ligands have not been identified yet, we use a screening technique to identify functional ligands for NKp46/NCR1 which is based on a cell reporter assay and discover a NCR1 ligand in the PD1.6 lymphoma line. To study whether NKp46/NCR1 is important for the eradication of PD1.6 lymphoma in vivo, we used the Ncr1 knockout Ncr1(gfp/gfp) mice generated by our group. Strikingly, all Ncr1 knockout mice developed growing PD1.6 tumors, whereas initial tumor growth was observed in the wild-type mice and tumors were completely rejected as time progressed. The growth of other lymphoma cell lines such as B10 and EL4 was equivalent between the Ncr1 knockout and wild-type mice. Finally, we show that PD1.6 lymphoma cells are less killed both in vitro and in vivo in the absence of NKp46/NCR1. Our results therefore reveal a crucial role for NKp46/NCR1 in the in vivo eradication of some lymphoma cells.
自然杀伤（NK）细胞对病毒感染细胞和肿瘤细胞的体外清除作用，受特定抑制性受体和激活性受体所传递信号之间平衡的调节。NK细胞，特别是NK激活性受体NKp46（小鼠中的NCR1）是否直接参与体内肿瘤的清除，目前仍不清楚。由于NKp46/NCR1的肿瘤配体尚未被鉴定出来，我们采用一种基于细胞报告基因检测的筛选技术来鉴定NKp46/NCR1的功能性配体，并在PD1.6淋巴瘤细胞系中发现了一种NCR1配体。为了研究NKp46/NCR1在体内清除PD1.6淋巴瘤中的重要性，我们使用了本研究团队构建的Ncr1基因敲除的Ncr1(gfp/gfp)小鼠。令人惊讶的是，所有Ncr1基因敲除小鼠都出现了PD1.6肿瘤的生长，而野生型小鼠最初观察到肿瘤生长，但随着时间推移肿瘤被完全排斥。在Ncr1基因敲除小鼠和野生型小鼠之间，其他淋巴瘤细胞系如B10和EL4的生长情况相当。最后，我们发现，在没有NKp46/NCR1的情况下，PD1.6淋巴瘤细胞在体外和体内都较少被杀伤。因此，我们的结果揭示了NKp46/NCR1在体内清除某些淋巴瘤细胞中起着关键作用。
