Minato N, Reid L, Bloom B R
J Exp Med. 1981 Sep 1;154(3):750-62. doi: 10.1084/jem.154.3.750.
The heterogeneity of cells capable exerting spontaneous cytotoxicity in vitro was explored using antisera to several genetically determined surface markers on mouse lymphocytes. Four phenotypes of cells derived either from fresh or cultured murine lymphoid tissue were found to exert natural killer (NK) activity in vitro. One affector cell subset, termed NKI cells, had the serological phenotype of Thy-1-, Lyt-2-, Qa5+, and lysed measles virus persistently infected target cells (HeLa-Ms) but not P815 mastocytoma cells. It corresponds with the NK cells described in most systems in which lymphoma targets are commonly used. A second subset, with the same target cell specificity, termed NKT is a thymus-independent cell with the phenotype Thy-1+, Lyt-2-, Qa-5+, Ly-5+. A third subset of NK cells, termed T killer (TK) cells deriving from cultures of conventional but not nude mouse spleens, mediated spontaneous cytotoxicity of P815 mastocytoma cells, but not of virus-infected targets. It has a phenotype of Thy-1+, Lyt-2+, Qa-5-, Ly-5+, apparently identical with that of conventional, antigen-specific cytotoxic T lymphocytes. The fourth phenotype of NK cells, termed NKM, derived primarily from cultures of bone marrow, is cytotoxic for HeLa-measles but not P815, and expresses only Ly-5+ among the various markers tested. Beige mice possess normal TK and NKM activities, but had normal NKI, NKT as well as NKM activity. All NK cell subsets express the Ly-5 surface marker. The existence of four phenotypically distinct NK effector cells was strengthened by studies on selective regulation of their activity by two different biological factors. Interferon (IFN) augmented NK activity of primarily one of the subsets examined, the NKI cell; the activity of IFN on NKT cells could not be directly tested, but IFN was without positive effect on TK or NKM cells. In contrast, partially purified IFN-free interleuken 2 (IL-2) augmented the activities of both the TK and NKT subsets, but not of NKI or NKM cell. IL-2 was active in augmenting NK activity in spleen cells obtained from both conventional and nu/nu mice, but was without effect on spleens of nu/nu mice depleted of Thy-1+ cells. These and other data suggest that IL-2 acts primarily, if not exclusively, on THy-1+ cells. These results strengthen the view that natural cytotoxicity in vitro can be mediated by several distinct cell populations under different genetic and regulatory control and indicate the importance of defining and delineating the cell lineages of each and the role of the independent subsets in resistance to virus infections and tumors in vivo.
利用针对小鼠淋巴细胞上几种遗传决定的表面标志物的抗血清，对体外具有自发细胞毒性的细胞异质性进行了研究。发现源自新鲜或培养的鼠类淋巴组织的四种细胞表型在体外具有自然杀伤（NK）活性。一个效应细胞亚群，称为NKI细胞，其血清学表型为Thy-1-、Lyt-2-、Qa5+，能裂解持续感染麻疹病毒的靶细胞（HeLa-Ms），但不能裂解P815肥大细胞瘤细胞。它与大多数使用淋巴瘤靶标的系统中描述的NK细胞相对应。第二个亚群，具有相同的靶细胞特异性，称为NKT，是一种非胸腺依赖性细胞，表型为Thy-1+、Lyt-2-、Qa-5+、Ly-5+。第三个NK细胞亚群，称为T杀伤（TK）细胞，源自常规而非裸鼠脾脏的培养物，介导P815肥大细胞瘤细胞的自发细胞毒性，但不介导病毒感染靶标的细胞毒性。它的表型为Thy-1+、Lyt-2+、Qa-5-、Ly-5+，显然与常规的、抗原特异性细胞毒性T淋巴细胞相同。NK细胞的第四种表型，称为NKM，主要源自骨髓培养物，对HeLa-麻疹细胞具有细胞毒性，但对P815细胞无毒性，并且在所测试的各种标志物中仅表达Ly-5+。米色小鼠具有正常的TK和NKM活性，但NKI、NKT以及NKM活性正常。所有NK细胞亚群均表达Ly-5表面标志物。通过研究两种不同生物因子对其活性的选择性调节，进一步证实了四种表型不同的NK效应细胞的存在。干扰素（IFN）主要增强了所检测的一个亚群即NKI细胞的NK活性；无法直接测试IFN对NKT细胞的活性，但IFN对TK或NKM细胞没有积极作用。相反，部分纯化的无IFN白细胞介素2（IL-2）增强了TK和NKT亚群的活性，但对NKI或NKM细胞无增强作用。IL-2在增强常规和nu/nu小鼠脾脏细胞的NK活性方面具有活性，但对去除了Thy-1+细胞的nu/nu小鼠脾脏无作用。这些以及其他数据表明，IL-2主要（如果不是唯一）作用于Thy-1+细胞。这些结果强化了这样一种观点，即体外自然细胞毒性可由不同遗传和调节控制下的几个不同细胞群体介导，并表明定义和描绘每个细胞谱系以及独立亚群在体内抵抗病毒感染和肿瘤中的作用的重要性。
