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

Author(s):
Kivit, S. de; Mensink, M.; Hoekstra, A.T.; Berlin, I.; Derks, R.J.E.; Both, D.; Aslam, M.A.; Amsen, D.; Berkers, C.R.; Borst, J.
Published
2020
Publication type
Article / Letter to editor

Abstract

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.

Date issued
2020-10-01
Language
English
Publisher
NATURE RESEARCH
Is part of
Nature Metabolism (2020), Vol. 2, no. 10, p. 1046-1061
hdl
1887/3158750
doi
10.1038/s42255-020-00271-w
URL
https://www.nature.com/articles/s42255-020-00271-w