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What fuels NK cells when they kill their targets

2020_07 Shengli Group Photo
From left: Guan Di, Dr Xu Shengli, Prof Lam Kong Peng, Wang Zixi

Authors

Zixi Wang1,2, Di Guan2,3, Shu Wang4, Louis Yi Ann Chai5,6, Shengli Xu2,7 and Kong-Peng Lam1,2

1 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
2 Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore
3 NUS Graduate School for Integrative Sciences & Engineering (NGS), National University of Singapore, Singapore
4 Department of Biological Sciences, National University of Singapore, Singapore
5 Division of Infectious Diseases, University Medicine Cluster, National University Health System, Singapore
6 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
7 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Published in Frontiers in Immunology 2020 11: 202 (Online Version)

 

Abstract

Natural Killer (NK) cells are a type of white blood cell and an important component of the immune system. They patrol in the blood stream and tissues to detect and rapidly eradicate virally infected and tumour cells without any priming or prior activation. The target cell recognition and the following activation of NK cells are mainly mediated by the molecules expressed on NK cell surface, i.e. NK cell receptors. Once the virus-infected or tumour cells are detected by NK cells, these receptors bind unique molecules expressed on the target cells and help NK cells identify and subsequently destroy these cells. This is a relatively fast process as it only takes a few hours for NK cells to become stimulated and kill the target cells upon target detection. These features make NK cell an attractive cell type in the fast-growing field of immunotherapy.

Just like how an army needs provisions, cells take in nutrients, such as glucose and proteins, and convert these nutrients into energy for cell activity, building blocks for cell growth and cell signals for controlling cell behaviours through cell metabolism. In the past few years, a number of studies showed that cell metabolism has a significant impact on the development and function of immune cells including NK cells. For example, it was found that cytokines, a group of small secreted proteins, can dramatically affect NK cell metabolism. In response to stimulatory or inhibitory cytokines, NK cells could increase or decrease their cell metabolism demands and in consequence the effector functions of NK cells are changed.

However, what fuels NK cells to support their effector functions, such as identifying and eliminating target cells, remains unclear. In this report, we studied the metabolic changes in NK cells when their activating receptors were triggered, which mimic the process of NK cell activation in our body. We found that NK cells shifted to a more vibrant metabolic state when their activating receptors were engaged. NK cells consumed more glucose and raised their respiration rate to support cytokine production by NK cells. More interestingly, we found that glucose metabolism is more important in promoting the killing function of NK cells. It was observed that NK cells consumed more glucose to enhance their killing capability by increasing expression of death molecules on the cell surface and delivering more lethal materials into the target cells. Our findings reveal how metabolism contributes to the activation of NK cells when they encounter target cells, such as tumour cells, and how NK cells adjust their various metabolic programs for the different effector functions. Thus, our study provides some important insights on how to metabolically improve NK cell performance during immunotherapy.

2020_07 Shengli Fig 1
Figure 1. Glycolysis and OXPHOS both fuel NK cells for cell activation induced by NK cell receptor stimulation.
Resting NK cells have low metabolic rates. In contrast, activated NK cells have more vibrant metabolic states, as they upregulate both glycolysis and OXPHOS in response to NK cell receptor stimulation. Increased OXPHOS mainly supply energy for NK cells, while elevated glycolysis not only provide ATP molecules but also precursors for biomass synthesis