NK Cells from Human Cytomegalovirus Seropositive Individuals Have a Distinct Metabolic Profile That Correlates with Elevated mTOR Signaling

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Abstract

CMV can elicit adaptive immune features in both mouse and human NK cells. Mouse Ly49H+ NK cells expand 100- to 1000-fold in response to mouse CMV infection and persist for months after exposure. Human NKG2C+ NK cells also expand after human CMV (HCMV) infection and persist for months. The clonal expansion of adaptive NK cells is likely an energy-intensive process, and the metabolic requirements that support adaptive NK cell expansion and persistence remain largely uncharacterized. We previously reported that NK cells from HCMV-seropositive donors had increased maximum capacity for both glycolysis and mitochondrial oxidative phosphorylation relative to NK cells from HCMV-seronegative donors. In this article, we report an extension of this work in which we analyzed the metabolomes of NK cells from HCMV-seropositive donors with NKG2C+ expansions and NK cells from HCMV seronegative donors without such expansions. NK cells from HCMV+ donors exhibited striking elevations in purine and pyrimidine deoxyribonucleotides, along with moderate increases in plasma membrane components. Mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that, as a part of mTOR complex 1 (mTORC1), bridges nutrient signaling to metabolic processes necessary for cell growth. Signaling through mTORC1 induces both nucleotide and lipid synthesis. We observed elevated mTORC1 signaling on activation in both NKG2C2 and NKG2C+ NK cells from HCMV+ donors relative to those from HCMV2 donors, demonstrating a correlation between higher mTORC1 activity and synthesis of key metabolites for cell growth and division.

Original languageEnglish (US)
Pages (from-to)539-550
Number of pages12
JournalJournal of Immunology
Volume211
Issue number4
DOIs
StatePublished - Aug 2023

Bibliographical note

Funding Information:
This work was supported by the National Institute of General Medical Sciences, National Institutes of Health Grant T32 GM008244 (to J.R.L.); National Heart, Lung, and Blood Institute, National Institutes of Health Grant R01 HL155150 (to F.C.); and National Cancer Institute, National Institutes of Health Grants P01 CA111412, P01 CA65493, and R35 CA197292 (to J.S.M.).

Publisher Copyright:
Copyright © 2023 by The American Association of Immunologists, Inc. 0022-1767/23/$37.50.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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