Identification of human NK cells that are deficient for signaling adaptor FcRγ and specialized for antibody-dependent immune functions
Identification of human NK cells that are deficient for signaling adaptor FcRγ and specialized for antibody-dependent immune functions
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DOI：
10.1093/intimm/dxs080
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发表时间：
2012-12-01
影响因子：
4.4
通讯作者：
Kim, Sungjin
中科院分区：
文献类型：
--
作者：
Hwang, Ilwoong;Zhang, Tianxiang;Kim, Sungjin
NK细胞直接通过几种活化受体（包括天然细胞毒性受体）对肿瘤和病毒感染的细胞作出反应，或间接通过抗体包被细胞的活化Fc受体CD16作出反应。通过这些受体触发NK细胞效应子功能取决于物理相关的跨膜信号转导衔接子，如FcR（也称为FceRI）和CD3？，传统上认为所有成熟NK细胞都表达这两种蛋白。然而，我们已经确定了一个独特的人NK细胞亚群，它们缺乏FcR表达，但表达正常水平的CD3？。FcR缺陷型NK细胞在约三分之一的健康个体中很容易检测到。缺陷仅限于CD56（dim）群体，是由于低FcR mRNA。FcR缺陷型NK细胞显示天然细胞毒性受体NKp46和NKp30的表达显著降低，但仍表达大量水平的CD16。与表达FcR的NK细胞相比，FcR缺陷型NK细胞对肿瘤靶点的直接反应性较差，如通过细胞因子产生和脱粒所测量的。然而，出乎意料的是，与表达FcR的NK细胞相比，FcR缺陷型NK细胞在通过CD16刺激时表现出显著更稳健的响应性，特别是对于细胞因子产生。因此，我们的研究揭示了FcR缺陷型NK细胞作为人类NK细胞的一个新的亚群，对抗体包被的靶点具有非常有效的反应。这些研究结果还说明了差异贡献的FcR和CD3？用于其相关受体的表达和功能活性。
NK cells respond to tumor and virus-infected cells directly through several activation receptors, including natural cytotoxicity receptors, or indirectly through the activating Fc receptor CD16 for antibody-coated cells. Triggering of NK-cell effector functions through these receptors depends on physically associated transmembrane signaling adaptors, such as FcR (also known as FceRI) and CD3?, both of which have been traditionally believed to be expressed by all mature NK cells. However, we have identified a distinct subset of human NK cells that are deficient for FcR expression but express normal levels of CD3?. FcR-deficient NK cells were readily detectable in about one-third of the healthy individuals examined. The deficiency was confined to the CD56(dim) population and was due to low FcR mRNA. FcR-deficient NK cells displayed dramatically reduced expression of the natural cytotoxicity receptors NKp46 and NKp30 but still expressed substantial levels of CD16. Compared to FcR-expressing NK cells, FcR-deficient NK cells showed poor direct reactivity toward tumor targets as measured by cytokine production and degranulation. Unexpectedly, however, FcR-deficient NK cells exhibited significantly more robust responsiveness upon stimulation through CD16, particularly for cytokine production, compared to FcR-expressing NK cells. Thus, our study reveals FcR-deficient NK cells as a novel subset of human NK cells that have remarkably potent responses toward antibody-coated targets. These findings also illustrate a differential contribution of FcR and CD3? for the expression and functional activity of their associated receptors.