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

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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.