title: mTORC1-dependent metabolic reprogramming is a prerequisite for NK cell effector function.
abstract: The mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cellular metabolism and also has fundamental roles in controlling immune responses. Emerging evidence suggests that these two functions of mTORC1 are integrally linked. However, little is known regarding mTORC1 function in controlling the metabolism and function of NK cells, lymphocytes that play key roles in antiviral and antitumor immunity. This study investigated the hypothesis that mTORC1-controlled metabolism underpins normal NK cell proinflammatory function. We demonstrate that mTORC1 is robustly stimulated in NK cells activated in vivo and in vitro. This mTORC1 activity is required for the production of the key NK cell effector molecules IFN-γ, which is important in delivering antimicrobial and immunoregulatory functions, and granzyme B, a critical component of NK cell cytotoxic granules. The data reveal that NK cells undergo dramatic metabolic reprogramming upon activation, upregulating rates of glucose uptake and glycolysis, and that mTORC1 activity is essential for attaining this elevated glycolytic state. Directly limiting the rate of glycolysis is sufficient to inhibit IFN-γ production and granzyme B expression. This study provides the highly novel insight that mTORC1-mediated metabolic reprogramming of NK cells is a prerequisite for the acquisition of normal effector functions.
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Donnelly
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;
authors.forename: Róisín M
authors.initials: RM
authors.lastname: Loftus
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;
authors.forename: Sinéad E
authors.initials: SE
authors.lastname: Keating
authors.affiliation: Division of Biology and Medicine; Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912; and.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Liou
authors.affiliation: Division of Biology and Medicine; Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912; and.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Biron
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;
authors.forename: Clair M
authors.initials: CM
authors.lastname: Gardiner
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland finlayd@tcd.ie.
authors.forename: David K
authors.initials: DK
authors.lastname: Finlay
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D015870:Gene Expression; D006019:Glycolysis; D053804:Granzymes / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D007371:Interferon-gamma; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D053804:Granzymes; D011070:Poly I-C