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...

Celý popis

Uloženo v:

Podrobná bibliografie
Vydáno v:	Nature metabolism Ročník 2; číslo 10; s. 1046 - 1061
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 01.10.2020 Nature Publishing Group
Témata:	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
On-line přístup:	Získat plný text
Tagy:	Přidat tag Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!

Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2522-5812 2522-5812
DOI:	10.1038/s42255-020-00271-w