Impact of calcium and adenine nucleotide signaling on education and functionality of NK cells

人类自然杀伤（NK）细胞在先天免疫防御中起着核心作用。在被定义为NK细胞教育的发育过程中，NK细胞发展其对自身的耐受性，并获得其对改变的自身或外来细胞作出反应的功能能力。然而，NK细胞教育的分子机制和途径还不清楚。在我们发表的和初步的数据中，我们已经表明受过教育的NK细胞具有更强的功能和代谢活性，并表现出更高的Ca 2+反应。此外，未受过教育的NK细胞显示出ATP门控阳离子通道P2 X4和P2 X7以及外核苷酸酶CD 39的更高表达。细胞内腺嘌呤核苷酸的作用，如烟酸腺嘌呤二核苷酸磷酸（NAADP）和3 '，5'-环AMP（cAMP）尚未在初级教育与未教育的NK细胞中研究。在这里，我们的初步数据表明，NAADP不仅是重要的短期效应功能，但也下游细胞因子在NK细胞的表达和胞质cAMP的增加几乎完全阻断NK细胞毒性。在这个项目中，我们建议解开Ca 2+和腺嘌呤核苷酸信号在人类NK细胞教育和功能之间的相互作用。了解NK细胞教育的分子机制和途径将确定免疫干预的新目标，旨在利用NK细胞对抗肿瘤和病毒感染。

Human natural killer (NK) cells play a central role in the innate immune defence. In a developmental process defined as NK-cell education, NK cells develop their tolerance towards self and gain their functional capacity to respond to altered self or foreign cells. However, the molecular mechanisms and pathways of NK cell education are not well understood. In our published and preliminary data, we already show that educated NK cells have stronger functional and metabolic activities, and exhibit higher Ca2+ responses. Furthermore, uneducated NK cells showed higher expression of the ATP gated cation channels P2X4 and P2X7 as well as the ectonucleotidase CD39. The role of intracellular adenine nucleotides, like nicotinic acid adenine dinucleotide phosphate (NAADP) and 3’,5’-cyclic AMP (cAMP) have not been studied in primary educated vs uneducated NK cells. Here, our preliminary data suggests that NAADP is not only important for short-term effector function but also downstream cytokine expression in NK cells and that an increase in cytosolic cAMP almost completely blocks NK cytotoxicity. In this project, we propose to disentangle the interplay between Ca2+- and adenine nucleotide signaling in human NK cell education and function. Understanding the molecular mechanisms and pathways underlying NK cell education will identify novel targets for immunotherapeutic interventions aimed at harnessing NK cells against tumors and viral infections.