Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control
Open Access
- 7 December 2017
- journal article
- case report
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 2 (23)
- https://doi.org/10.1172/jci.insight.95128
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.Keywords
Funding Information
- NIH (1K08AI085030)
- NIH (R01AI127752)
- Rheumatology Research Foundation (n/a)
- The Children’s Discovery Institute and St. Louis Children’s Hospital (n/a)
- American Association of Immunologists (Careers in Immunology Fellowship)
- NIH (T32 GM07200)
- NIH (R01AI102924)
- NIH (R01AI078994)
- NIH (F30AI129110)
This publication has 79 references indexed in Scilit:
- Sex differences in murine susceptibility to systemic viral infectionsJournal of Autoimmunity, 2012
- Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell ProliferationAnnual Review of Cell and Developmental Biology, 2011
- NK cell education after allogeneic transplantation: dissociation between recovery of cytokine-producing and cytotoxic functionsBlood, 2011
- IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell functionJCI Insight, 2011
- Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1Molecular Cell, 2010
- Quantitative measurement of F-actin accumulation at the NK cell immunological synapseJournal of Immunological Methods, 2010
- Understanding the Warburg Effect: The Metabolic Requirements of Cell ProliferationScience, 2009
- Ly49H signaling through DAP10 is essential for optimal natural killer cell responses to mouse cytomegalovirus infectionThe Journal of Experimental Medicine, 2009
- Continuous engagement of a self-specific activation receptor induces NK cell toleranceThe Journal of Experimental Medicine, 2008
- NKG2D-Deficient Mice Are Defective in Tumor Surveillance in Models of Spontaneous MalignancyImmunity, 2008