title: Metabolic Reprogramming Supports IFN-γ Production by CD56bright NK Cells.
abstract: Human NK cells can be classified into phenotypically and functionally distinct subsets based on levels of CD56 receptor. CD56(dim) cells are generally considered more cytotoxic, whereas the CD56(bright) cells are potent producers of IFN-γ. In this study, we define the metabolic changes that occur in peripheral blood NK cells in response to cytokine. Metabolic analysis showed that NK cells upregulate glycolysis and oxidative phosphorylation in response to either IL-2 or IL-12/15 cytokine combinations. Despite the fact that both these cytokine combinations robustly upregulated mammalian Target of Rapamycin Complex 1 in human NK cells, only the IL-2-induced metabolic changes were sensitive to mammalian Target of Rapamycin Complex 1 inhibition by rapamycin. Interestingly, we found that CD56(bright) cells were more metabolically active compared with CD56(dim) cells. They preferentially upregulated nutrient receptors and also differed substantially in terms of their glucose metabolism. CD56(bright) cells expressed high levels of the glucose uptake receptor, Glut1 (in the absence of any cytokine), and had higher rates of glucose uptake compared with CD56(dim) cells. Elevated levels of oxidative phosphorylation were required to support both cytotoxicity and IFN-γ production in all NK cells. Finally, although elevated glycolysis was not required directly for NK cell degranulation, limiting the rate of glycolysis significantly impaired IFN-γ production by the CD56(bright) subset of cells. Overall, we have defined CD56(bright) NK cells to be more metabolically active than CD56(dim) cells, which supports their production of large amounts of IFN-γ during an immune response.
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and.
authors.forename: Sinéad E
authors.identifier: http://orcid.org/0000-0002-0460-3410
authors.initials: SE
authors.lastname: Keating
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Zaiatz-Bittencourt
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and.
authors.forename: Roisín M
authors.identifier: http://orcid.org/0000-0001-9137-6625
authors.initials: RM
authors.lastname: Loftus
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and.
authors.forename: Ciara
authors.initials: C
authors.lastname: Keane
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and.
authors.forename: Kiva
authors.identifier: http://orcid.org/0000-0003-4960-7076
authors.initials: K
authors.lastname: Brennan
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland clair.gardiner@tcd.ie finlayd@tcd.ie.
authors.forename: David K
authors.identifier: http://orcid.org/0000-0003-2716-6679
authors.initials: DK
authors.lastname: Finlay
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and clair.gardiner@tcd.ie finlayd@tcd.ie.
authors.forename: Clair M
authors.identifier: http://orcid.org/0000-0001-5643-9432
authors.initials: CM
authors.lastname: Gardiner
mesh_terms: D019002:CD56 Antigen / Q000096:biosynthesis / Q000276:immunology; D005434:Flow Cytometry; D006019:Glycolysis / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D016131:Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D019002:CD56 Antigen; C522918:NCAM1 protein, human; D007371:Interferon-gamma