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Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control
Annelise Y. Mah, … , Anthony R. French, Megan A. Cooper
Annelise Y. Mah, … , Anthony R. French, Megan A. Cooper
Published December 7, 2017
Citation Information: JCI Insight. 2017;2(23):e95128. https://doi.org/10.1172/jci.insight.95128.
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Research Article Immunology

Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control

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Abstract

NK cell activation has been shown to be metabolically regulated in vitro; however, the role of metabolism during in vivo NK cell responses to infection is unknown. We examined the role of glycolysis in NK cell function during murine cytomegalovirus (MCMV) infection and the ability of IL-15 to prime NK cells during CMV infection. The glucose metabolism inhibitor 2-deoxy-ᴅ-glucose (2DG) impaired both mouse and human NK cell cytotoxicity following priming in vitro. Similarly, MCMV-infected mice treated with 2DG had impaired clearance of NK-specific targets in vivo, which was associated with higher viral burden and susceptibility to infection on the C57BL/6 background. IL-15 priming is known to alter NK cell metabolism and metabolic requirements for activation. Treatment with the IL-15 superagonist ALT-803 rescued mice from otherwise lethal infection in an NK-dependent manner. Consistent with this, treatment of a patient with ALT-803 for recurrent CMV reactivation after hematopoietic cell transplant was associated with clearance of viremia. These studies demonstrate that NK cell–mediated control of viral infection requires glucose metabolism and that IL-15 treatment in vivo can reduce this requirement and may be effective as an antiviral therapy.

Authors

Annelise Y. Mah, Armin Rashidi, Molly P. Keppel, Nermina Saucier, Emily K. Moore, Joshua B. Alinger, Sandeep K. Tripathy, Sandeep K. Agarwal, Emily K. Jeng, Hing C. Wong, Jeffrey S. Miller, Todd A. Fehniger, Emily M. Mace, Anthony R. French, Megan A. Cooper

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Figure 1

Glucose metabolism blockade during activation decreases NK cell proliferation and cytotoxicity.

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Glucose metabolism blockade during activation decreases NK cell prolifer...
Purified NK cells were cultured for 72 hours in 100 ng/ml IL-15 without (black) or with 1 mM 2-deoxy-ᴅ-glucose (2DG, green). (A) Representative extracellular flux assay showing glycolytic rate as estimated by extracellular acidification rate (ECAR); glycolytic stress test shows baseline ECAR in glucose-free media and after addition of glucose, maximal ECAR after addition of oligomycin, and nonglycolytic acidification after 2DG. Summary data shows ECAR, oxygen consumption rate (OCR), and the OCR/ECAR ratio normalized to control (n = 4/group in 3 separate experiments, ratio paired t test performed on raw data). (B) Representative histogram shows CFSE dilution of proliferating NK cells. Summary graph shows the percentage of NK cells proliferated (n = 5 experiments, paired t test). (C) NK cells activated in IL-15 ± 2DG were assessed for their ability to kill Ba/F3-m157 target cells at different effector/target ratios (ratios represent Ly49H+ NK cells/targets), n = 8/group, 4 experiments, 2-way ANOVA. Data show mean ± SEM. *P < 0.05, ***P < 0.001.

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