Natural Killer (NK) cells are a type of cytotoxic lymphocytes that play an important role in the innate immune system. They are of particular interest for their role in elimination of intracellular pathogens, viral infection and tumor cells. As such, numerous strategies are being investigated in order to potentiate their functions. One of these techniques aims at promoting the function of their activating receptors. However, different observations have revealed that providing activation signals could actually be counterproductive and lead to NK cells’ hyporesponsiveness. This phenomenon can occur during the NK cell education process, under pathological conditions, but also after treatment with different agents, including cytokines, that are promising tools to boost NK cell function. In this review, we aim to highlight the different circumstances where NK cells become hyporesponsive and the methods that could be used to restore their functionality.
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