Differential Fuel Requirements of Human NK Cells and Human CD8 T Cells: Glutamine Regulates Glucose Uptake in Strongly Activated CD8 T Cells

Steven R. Presnell, Henry K. Spear, Jerika Durham, Tyce Riddle, Austin Applegate, Charles T. Lutz

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

CD8 T cells and NK cells are the two major cytotoxic lymphocytes that carry out cell-mediated immunity and regulate other immune responses. However, we do not completely understand human CD8 T cell and NK cell metabolic requirements and they have not been compared in the same experiments. We activated human CD8 T cells by two anti–CD3/CD28 mAb methods, and we stimulated both CD8 T cells and NK cells with IL-12/IL-18. When glucose (Glc) could not be used, human CD8 T cells either died or became hypofunctional, depending upon the anti–CD3/CD28 activation method. In contrast, Glc starvation did not decrease the percentage of IL-12/IL-18–stimulated human NK cells that made IFN-g. NK cells were relatively fuel resilient and used Glc, glutamine (Gln), fatty acid, or acetate to power IFN-g expression. Surprisingly, strongly activated human CD8 T cells required Gln for glycolysis and Glc uptake. We showed that human CD8 T cells regulate Glc uptake by a novel mechanism related to the TXNIP pleiotropic protein. These conditions may be relevant to septic patients who have high blood Glc but low Gln. Under the conditions tested, Gln did not change human NK cell TXNIP expression. Our experiments reveal fundamental differences in human CD8 T cell and NK cell metabolism and the fuels needed for IFN-g production.

Original languageEnglish
Pages (from-to)231-244
Number of pages14
JournalImmunoHorizons
Volume4
Issue number5
DOIs
StatePublished - May 1 2020

Bibliographical note

Funding Information:
Received for publication April 3, 2020. Accepted for publication April 13, 2020. Address correspondence and reprint requests to: Dr. Charles T. Lutz, University of Kentucky, 800 Rose Street, Room MS117, Lexington, KY 40536-0298. E-mail address: ctlutz2@uky.edu ORCIDs: 0000-0002-1313-0627 (J.D.); 0000-0002-0035-7822 (A.A.). This work was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences through National Institutes of Health Grant UL1TR000117, the University of Kentucky College of Medicine, and the University of Kentucky Department of Pathology and Laboratory Medicine. T.R. was supported by the University of Kentucky/Appalachian Career Training in Oncology Program (under National Institutes of Health/National Cancer Institute Grant NCI R25CA221765). The University of Kentucky Redox Metabolism Shared Resource Facility is supported by National Cancer Institute/Cancer Center Support Grant P30 CA177558. The University of Kentucky Flow Cytometry facility is supported in part by a National Cancer Institute/Cancer Center Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center. Abbreviations used in this article: 2DG, 2-deoxy-D-Glc; ECAR, extracellular acidification rate; ETO, etomoxir; FA, fatty acid; Gal, galactose; Glc, glucose; Gln, glutamine; MFI, median fluorescence intensity; 2-NBDG, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose; OCR, oxygen consumption rate; TXNIP, thioredoxin-interacting protein. The online version of this article contains supplemental material. This article is distributed under the terms of the CC BY-NC-ND 4.0 Unported license. Copyright © 2020 The Authors

Publisher Copyright:
© 2020 The Authors

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Medicine (all)

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