High Metabolic Function and Resilience of NKG2A-Educated NK Cells.

Andrew J Highton,Christian Körner,Andreas H Guse,Jürgen Sauter,Marcus Altfeld,Alexander H Schmidt,Madeleine J Bunders,Björn-Philipp Diercks,Franziska Möckl,Gloria Martrus

doi:10.3389/fimmu.2020.559576

Abstract

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 C16, a fluorescent palmitate, compared to uneducated NK cells. Comparison of NK cells educated via 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.

Highlights

Natural killer (NK) cells are an integral part of the innate immune system and contribute to the control of viral infections through direct cytotoxicity against infected cells and through the release of cytokines
We investigated metabolic differences between educated and uneducated NK cells and observed that educated NK cells had elevated uptake of nutrients compared to uneducated NK cells, indicating increased metabolic activity of educated NK cells
Further characterization of educated NK cell subsets revealed that NK cells educated through NKG2A exhibit superior metabolic activity, and blockade of metabolic pathways demonstrated that NKG2A+ NK cells were more resilient to reduction in oxidative phosphorylation compared to Killer-cell Immunoglobulin-like Receptors (KIRs)+ NK cells

Summary

Introduction

Natural killer (NK) cells are an integral part of the innate immune system and contribute to the control of viral infections through direct cytotoxicity against infected cells and through the release of cytokines. KIR2DL1/2/3, KIR3DL1, and NKG2A are inhibitory receptors expressed by NK cells that recognize different HLA class I molecules as their ligands. KIR3DL1 binds the HLA-Bw4 epitope, found primarily on HLA-B allotypes, and NKG2A recognizes the non-classical HLA-E molecule [4,5,6]. Together, these inhibitory receptors’ binding specificities cover a large proportion of the expressed HLA class I repertoire. Calcium flux is known to be important for the functional response of NK cells and may underlie some of the functional differences observed between educated and uneducated NK cells [10]

Methods

Results

Conclusion