Almeida Francisca F, Tognarelli Sara, Marçais Antoine, Kueh Andrew J, Friede Miriam E, Liao Yang, Willis Simon N, Luong Kylie, Faure Fabrice, Mercier Francois E, Galluso Justine, Firth Matthew, Narni-Mancinelli Emilie, Rais Bushra, Scadden David T, Spallotta Francesco, Weil Sandra, Giannattasio Ariane, Kalensee Franziska, Zöller Tobias, Huntington Nicholas D, Schleicher Ulrike, Chiocchetti Andreas G, Ugolini Sophie, Herold Marco J, Shi Wei, Koch Joachim, Steinle Alexander, Vivier Eric, Walzer Thierry, Belz Gabrielle T, Ullrich Evelyn
Division of Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
Oncoimmunology. 2018 Aug 15;7(10):e1475875. doi: 10.1080/2162402X.2018.1475875. eCollection 2018.
NKp46 (CD335) is a surface receptor shared by both human and mouse natural killer (NK) cells and innate lymphoid cells (ILCs) that transduces activating signals necessary to eliminate virus-infected cells and tumors. Here, we describe a spontaneous point mutation of cysteine to arginine (C14R) in the signal peptide of the NKp46 protein in congenic Ly5.1 mice and the newly generated NCR strain. Ly5.1 NK cells expressed similar levels of mRNA as C57BL/6, but showed impaired surface NKp46 and reduced ability to control melanoma tumors . Expression of the mutant NKp46 in 293T cells showed that NKp46 protein trafficking to the cell surface was compromised. Although Ly5.1 mice had normal number of NK cells, they showed an increased number of early maturation stage NK cells. CD49aILC1s were also increased but these cells lacked the expression of TRAIL. ILC3s that expressed NKp46 were not detectable and were not apparent when examined by T-bet expression. Thus, the C14R mutation reveals that NKp46 is important for NK cell and ILC differentiation, maturation and function. Innate lymphoid cells (ILCs) play important roles in immune protection. Various subsets of ILCs express the activating receptor NKp46 which is capable of recognizing pathogen derived and tumor ligands and is necessary for immune protection. Here, we describe a spontaneous point mutation in the signal peptide of the NKp46 protein in congenic Ly5.1 mice which are widely used for tracking cells . This C14R mutation impairs NKp46 surface expression resulting in destabilization of and accumulation of NKp46 in the endoplasmic reticulum. Loss of stable NKp46 expression impaired the maturation of NKp46 ILCs and altered the expression of TRAIL and T-bet in ILC1 and ILC3, respectively.
NKp46（CD335）是人和小鼠自然杀伤（NK）细胞以及固有淋巴细胞（ILC）共有的一种表面受体，它能转导消除病毒感染细胞和肿瘤所需的激活信号。在此，我们描述了同源Ly5.1小鼠和新培育的NCR品系中NKp46蛋白信号肽发生的半胱氨酸到精氨酸的自发点突变（C14R）。Ly5.1 NK细胞表达的mRNA水平与C57BL / 6相似，但表面NKp46表达受损，控制黑色素瘤肿瘤的能力降低。突变型NKp46在293T细胞中的表达表明，NKp46蛋白向细胞表面的转运受到损害。尽管Ly5.1小鼠的NK细胞数量正常，但它们早期成熟阶段的NK细胞数量增加。CD49a ILC1s也增加了，但这些细胞缺乏TRAIL的表达。表达NKp46的ILC3无法检测到，通过T-bet表达检测时也不明显。因此，C14R突变表明NKp46对NK细胞和ILC的分化、成熟及功能很重要。固有淋巴细胞（ILC）在免疫保护中起重要作用。ILC的各个亚群表达激活受体NKp46，该受体能够识别病原体衍生配体和肿瘤配体，是免疫保护所必需的。在此，我们描述了广泛用于细胞追踪的同源Ly5.1小鼠中NKp46蛋白信号肽的自发点突变。这种C14R突变损害了NKp46的表面表达，导致NKp46在内质网中不稳定并积累。稳定的NKp46表达缺失损害了NKp46 ILC的成熟，并分别改变了ILC1和ILC3中TRAIL和T-bet的表达。
