Research Department Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
The Calcium Signaling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Front Immunol. 2020 Sep 30;11:559576. doi: 10.3389/fimmu.2020.559576. eCollection 2020.
Natural killer (NK) cells are an important component of the innate immune system for the control of intracellular pathogens and cancer cells. NK cells demonstrate heterogeneous expression of inhibitory surface receptors. Signaling through these various receptors during NK cell development promotes functionality, referred to as NK cell education. Here we investigated the impact of education on NK cell metabolism through functional assessment of critical metabolic pathways and calcium signaling. Educated NK cells had an increased uptake of the metabolic substrates 2-NBDG, a fluorescent glucose analog, and BODIPY FL C, a fluorescent palmitate, compared to uneducated NK cells. Comparison of NK cells educated KIRs or NKG2A showed that NKG2A-educated NK cells were the main contributor to these differences in uptake of metabolites, and that NKG2A-educated NK cells were functionally more resilient in response to metabolic blockade of oxidative phosphorylation. Furthermore, NKG2A-educated NK cells exhibited higher peak calcium concentration following stimulation, indicating stronger signaling events taking place in these educated NK cells. These results demonstrate that cellular metabolism plays an important role in the functional differences observed between educated and uneducated NK cells, and show that NKG2A-educated NK cells remain more functionally competent than KIR-educated NK cells when oxidative phosphorylation is restricted. Understanding metabolic programming during NK cell education may unveil future targets to manipulate NK cell function for use in clinical settings, such as cancer therapies.
自然杀伤 (NK) 细胞是固有免疫系统控制细胞内病原体和癌细胞的重要组成部分。NK 细胞表现出抑制性表面受体的异质性表达。在 NK 细胞发育过程中，这些不同受体的信号传递促进了功能，即 NK 细胞的教育。在这里，我们通过对关键代谢途径和钙信号的功能评估，研究了教育对 NK 细胞代谢的影响。与未受教育的 NK 细胞相比，受过教育的 NK 细胞对代谢底物 2-NBDG（荧光葡萄糖类似物）和 BODIPY FL C（荧光棕榈酸）的摄取增加。对受 KIR 或 NKG2A 教育的 NK 细胞的比较表明，NKG2A 教育的 NK 细胞是这些代谢物摄取差异的主要贡献者，并且 NKG2A 教育的 NK 细胞在氧化磷酸化代谢阻断的反应中具有更强的功能弹性。此外，NKG2A 教育的 NK 细胞在刺激后表现出更高的钙峰浓度，表明这些受过教育的 NK 细胞中发生了更强的信号事件。这些结果表明，细胞代谢在受教育和未受教育的 NK 细胞之间观察到的功能差异中起着重要作用，并表明在氧化磷酸化受到限制时，NKG2A 教育的 NK 细胞比 KIR 教育的 NK 细胞保持更高的功能能力。了解 NK 细胞教育过程中的代谢编程可能会揭示未来用于操纵 NK 细胞功能的临床应用的靶点，例如癌症治疗。
