Stable human regulatory T cells switch to glycolysis following TNF receptor 2 costimulation

Following activation, conventional T (T conv ) cells undergo an mTOR-driven glycolytic switch. Regulatory T (T reg ) cells reportedly repress the mTOR pathway and avoid glycolysis. However, here we demonstrate that human thymus-derived T reg (tT reg ) cells can become glycolytic in response to tumou...

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Bibliographic Details
Published in:Nature metabolism Vol. 2; no. 10; pp. 1046 - 1061
Main Authors: de Kivit, Sander, Mensink, Mark, Hoekstra, Anna T., Berlin, Ilana, Derks, Rico J. E., Both, Demi, Aslam, Muhammad A., Amsen, Derk, Berkers, Celia R., Borst, Jannie
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.10.2020
Nature Publishing Group
Subjects:
1-Phosphatidylinositol 3-kinase
631/250/1619/554
631/250/2152
631/443/319
631/45/320
Antigens
Biomedical and Life Sciences
Blood
Carbon
CD25 antigen
CD3 antigen
CD3 Complex - metabolism
Cell activation
Cell proliferation
Citric Acid Cycle - drug effects
Effector cells
Flow cytometry
Foxp3 protein
Glucose
Glucose - metabolism
Glucose - pharmacology
Glycolysis
Glycolysis - drug effects
Humans
Immunoregulation
Kinases
Lactic acid
Lactic Acid - blood
Lactic Acid - metabolism
Life Sciences
Lymphocytes
Lymphocytes T
Metabolism
Metabolites
Metabolome
Monoclonal antibodies
Phosphatidylinositol 3-Kinases - metabolism
Proteins
Protocol
Receptors, Tumor Necrosis Factor, Type II - drug effects
Receptors, Tumor Necrosis Factor, Type II - metabolism
RNA - chemistry
Sequence Analysis, RNA
Signal Transduction
Statistical analysis
T-Lymphocytes, Regulatory - metabolism
Thymus
TOR protein
TOR Serine-Threonine Kinases - metabolism
Tricarboxylic acid cycle
Tumor necrosis factor receptors
Tumor necrosis factor-TNF
Variance analysis
ISSN:2522-5812, 2522-5812
Online Access:Get full text
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Summary:Following activation, conventional T (T conv ) cells undergo an mTOR-driven glycolytic switch. Regulatory T (T reg ) cells reportedly repress the mTOR pathway and avoid glycolysis. However, here we demonstrate that human thymus-derived T reg (tT reg ) cells can become glycolytic in response to tumour necrosis factor receptor 2 (TNFR2) costimulation. This costimulus increases proliferation and induces a glycolytic switch in CD3-activated tT reg cells, but not in T conv cells. Glycolysis in CD3–TNFR2-activated tT reg cells is driven by PI3-kinase–mTOR signalling and supports tT reg cell identity and suppressive function. In contrast to glycolytic T conv cells, glycolytic tT reg cells do not show net lactate secretion and shuttle glucose-derived carbon into the tricarboxylic acid cycle. Ex vivo characterization of blood-derived TNFR2 hi CD4 + CD25 hi CD127 lo effector T cells, which were FOXP3 + IKZF2 + , revealed an increase in glucose consumption and intracellular lactate levels, thus identifying them as glycolytic tT reg cells. Our study links TNFR2 costimulation in human tT reg cells to metabolic remodelling, providing an additional avenue for drug targeting. After activation, conventional T cells undergo metabolic reprogramming. de Kivit et al. show that in human thymic regulatory T cells, TNFR2 stimulation promotes a glycolytic switch with a preferential glucose-derived carbon flux into the TCA cycle to support suppressive functions.
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ISSN:2522-5812
2522-5812
DOI:10.1038/s42255-020-00271-w