Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control
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
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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Research Article Immunology

Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control

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 6

ALT-803 rescue of 2DG-treated mice requires NK cells, and ALT-803 priming can eliminate susceptibility to MCMV caused by mTOR inhibition.

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ALT-803 rescue of 2DG-treated mice requires NK cells, and ALT-803 primin...
(A) Mice were either depleted of NK cells using α-NK1.1 or treated with IgG2a; they were given 2 doses of ALT-803 and infected with 1 × 105 PFU murine cytomegalovirus (MCMV). 2-Deoxy-ᴅ-glucose (2DG) was given every 24 hours, and mice were euthanized on day 2 for assessment of (B) clearance of m157-transgenic targets from the spleen and (C) viral copy number from the spleen and liver; they were measured by quantitative PCR and log-transformed (n = 10 individuals/group, 2 separate experiments, 2-tailed t test). (D) To assess susceptibility, an additional NK depletion was given at day 3 (red, n = 30); control mice were treated with IgG2a (black, n = 23). Mice were followed for 10 days (3 separate experiments). (E) Mice were infected with MCMV, given daily i.p. injections of 1.5 mg/kg rapamycin (green) or vehicle (black), and monitored for susceptibility (n = 10/group, 1 experiment). (F) ALT-803 was given to MCMV-infected, rapamycin-treated mice on the same schedule as for 2DG-treated mice, with doses at –3, –1, and +2 days relative to infection (n = 10/group, 1 experiment). Data show mean ± SEM or survival in D–F analyzed by log-rank Mantel-Cox test. ***P < 0.001. Asterisks in A and D indicate treatment with ALT-803.