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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 NKG2C\u2212 and NKG2C+ NK cells from HCMV+ donors relative to those from HCMV\u2212 donors, demonstrating a correlation between higher mTORC1 activity and synthesis of key metabolites for cell growth and division.<\/jats:p>","DOI":"10.4049\/jimmunol.2200851","type":"journal-article","created":{"date-parts":[[2023,6,21]],"date-time":"2023-06-21T13:06:16Z","timestamp":1687352776000},"page":"539-550","source":"Crossref","is-referenced-by-count":7,"title":["NK Cells from Human Cytomegalovirus\u2013Seropositive Individuals Have a Distinct Metabolic Profile That Correlates with Elevated mTOR Signaling"],"prefix":"10.1093","volume":"211","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8953-4110","authenticated-orcid":false,"given":"John R","family":"Lozada","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Minnesota , Minneapolis, MN"},{"name":"Medical Scientist Training Program, University of Minnesota Medical School , Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1717-3218","authenticated-orcid":false,"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Minnesota , Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0339-4944","authenticated-orcid":false,"given":"Jeffrey S","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Minnesota , Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3043-0653","authenticated-orcid":false,"given":"Frank","family":"Cichocki","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Minnesota , Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,6,21]]},"reference":[{"key":"2025020406062837400_r1","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/ijc.2910160204","article-title":"Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. 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