NK cells are phenotypically and functionally diverse lymphocytes due to variegated expression of a large array of receptors. NK-cell activity is tightly regulated through integration of receptor-derived inhibitory and activating signals. Thus, the receptor profile of each NK cell ultimately determines its ability to sense aberrant cells and subsequently mediate anti-viral or anti-tumor responses. However, an in-depth understanding of how different receptor repertoires enable distinct immune functions of NK cells is lacking. Therefore, we investigated the phenotypic diversity of primary human NK cells by performing extensive phenotypic characterization of 338 surface molecules using flow cytometry (n = 18). Our results showed that NK cells express at least 146 receptors on their surface. Of those, 136 (>90%) exhibited considerable inter-donor variability. Moreover, comparative analysis of CD56bright and CD56dim NK cells identified 70 molecules with differential expression between the two major NK-cell subsets and allowed discrimination of these subsets via unsupervised hierarchical clustering. These receptors were associated with a broad range of NK-cell functions and multiple molecules were not previously associated with predominant expression on either subset (e.g. CD82 and CD147). Altogether, our study contributes to an improved understanding of the phenotypic diversity of NK cells and its potential functional implications on a cellular and population level. While the identified distinct signatures in the receptor repertoires provide a molecular basis for the differential immune functions exerted by CD56bright and CD56dim NK cells, the observed inter-individual differences in the receptor repertoire of NK cells may contribute to a diverging ability to control certain diseases.

由于大量受体的多样化表达，NK细胞是表型和功能多样化的淋巴细胞。NK细胞活性通过受体衍生的抑制和激活信号的整合而受到严格调节。因此，每个NK细胞的受体概况最终决定了其感知异常细胞并随后介导抗病毒或抗肿瘤反应的能力。然而，缺乏对不同受体组成如何使NK细胞具有独特免疫功能的深入了解。因此，我们通过使用流式细胞仪对338个表面分子进行了广泛的表型表征，研究了原代人NK细胞的表型多样性（n = 18）。我们的结果表明，NK细胞在其表面表达至少146种受体。其中136（> 90％）的供体间差异很大。此外，对CD56bright和CD56dim NK细胞的比较分析确定了70个分子，在两个主要NK细胞亚群之间表达差异，并允许区分这些亚群。通过无监督的层次聚类。这些受体与广泛的NK细胞功能有关，并且多个分子以前与任一子集上的主要表达（例如CD82和CD147）都不相关。总之，我们的研究有助于更好地理解NK细胞的表型多样性及其在细胞和群体水平上的潜在功能含义。虽然在受体库中鉴定出的独特特征为CD56bright和CD56dim NK细胞发挥的不同免疫功能提供了分子基础，但在NK细胞的受体库中观察到的个体间差异可能有助于控制某些疾病。