Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
Front Immunol. 2024 Nov 13;15:1477776. doi: 10.3389/fimmu.2024.1477776. eCollection 2024.
Human memory NK cells represent a heterogeneous CD56 population that expands and persists in human cytomegalovirus (HCMV)-seropositive healthy individuals. They are characterized by the preferential, not fully overlapping, expression of NKG2C (activating receptor for HLA-E) and CD57 maturation marker, and by the lack of FcεRIγ adaptor chain. Hyperresponsiveness to Fcγ receptor IIIA (CD16) engagement represents the distinctive functional signature of memory NK cells. Although CD16 engagement was shown to acutely enhance glycolytic and oxidative pathways, its capability to induce a persisting metabolic reprogramming of human NK cells is poorly understood yet.
Here, we describe the peculiar nutrient transporter expression pattern of FcεRIγ memory NK cells, characterized by higher levels of CD98 neutral amino acid antiporter and CD71 transferrin receptor, and lower expression of GLUT1 glucose transporter, with respect to FcεRIγ conventional NK cells. Although CD16 engagement acutely enhances glycolytic and oxidative pathways, its capability to induce a persisting metabolic reprogramming of human NK cells is poorly understood yet. Our results firstly show that sustained CD16 engagement by contact with IgG-opsonized target cells induces the mTORC1-dependent upregulation of CD98 and CD71 nutrient receptors on CD56 NK cells, in a transporter-specific fashion, that is finely tuned by cell-dependent (grade of functional maturation, and memory or conventional lineage) and stimulus-dependent (time length and cooperation with cytokines) factors. We also demonstrate that CD98 antiporter function is required for CD16-dependent IFN-γ production, and that enhanced CD98-mediated neutral amino acid uptake associates with heightened memory NK cell functional response.
Collectively, our work documents that CD16 engagement leads to a metabolic rewiring of human NK cells and suggests that a distinct nutrient transporter expression pattern may contribute to memory NK cell peculiar functional features.
人类记忆 NK 细胞代表了一种异质性的 CD56 群体，在人类巨细胞病毒（HCMV）阳性的健康个体中扩增并持续存在。它们的特征是优先表达（但不完全重叠）NKG2C（HLA-E 的激活受体）和 CD57 成熟标志物，并且缺乏 FcεRIγ 衔接链。对 Fcγ 受体 IIIA（CD16）结合的高反应性代表了记忆 NK 细胞的独特功能特征。尽管已经表明 CD16 结合可以急性增强糖酵解和氧化途径，但对其诱导人类 NK 细胞持续代谢重编程的能力仍知之甚少。
在这里，我们描述了 FcεRIγ 记忆 NK 细胞独特的营养转运蛋白表达模式，其特征是更高水平的 CD98 中性氨基酸转运蛋白和 CD71 转铁蛋白受体，以及更低水平的 GLUT1 葡萄糖转运蛋白，与 FcεRIγ 常规 NK 细胞相比。尽管 CD16 结合可以急性增强糖酵解和氧化途径，但对其诱导人类 NK 细胞持续代谢重编程的能力仍知之甚少。我们的研究结果首先表明，与 IgG 包被的靶细胞接触时持续的 CD16 结合会诱导 mTORC1 依赖性上调 CD56NK 细胞上的 CD98 和 CD71 营养受体，以一种特定于转运蛋白的方式，该方式受到细胞依赖性（功能成熟程度和记忆或常规谱系）和刺激依赖性（时间长度和与细胞因子的合作）因素的精细调节。我们还证明了 CD98 转运蛋白的功能对于 CD16 依赖性 IFN-γ 产生是必需的，并且增强的 CD98 介导的中性氨基酸摄取与记忆 NK 细胞功能反应的增强相关。
总之，我们的工作证明 CD16 结合导致人类 NK 细胞的代谢重编程，并表明独特的营养转运蛋白表达模式可能有助于记忆 NK 细胞的独特功能特征。
