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

Sander De Kivit,Demi Both,Ilana Berlin,Rico J E Derks,Jannie Borst,Mark Mensink,Celia R Berkers,Anna T Hoekstra,Muhammad A Aslam,Derk Amsen

doi:10.1038/s42255-020-00271-w

Abstract

Following activation, conventional T (Tconv) cells undergo an mTOR-driven glycolytic switch. Regulatory T (Treg) cells reportedly repress the mTOR pathway and avoid glycolysis. However, here we demonstrate that human thymus-derived Treg (tTreg) 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 tTreg cells, but not in Tconv cells. Glycolysis in CD3-TNFR2-activated tTreg cells is driven by PI3-kinase-mTOR signalling and supports tTreg cell identity and suppressive function. In contrast to glycolytic Tconv cells, glycolytic tTreg cells do not show net lactate secretion and shuttle glucose-derived carbon into the tricarboxylic acid cycle. Ex vivo characterization of blood-derived TNFR2hiCD4+CD25hiCD127lo effector T cells, which were FOXP3+IKZF2+, revealed an increase in glucose consumption and intracellular lactate levels, thus identifying them as glycolytic tTreg cells. Our study links TNFR2 costimulation in human tTreg cells to metabolic remodelling, providing an additional avenue for drug targeting.

Highlights

Among CD4+ regulatory T (Treg) cells, thymus-derived (t)Treg cells develop from T cell precursors, recognize selfantigens and protect against autoimmunity[1]
Among CD4+ T cells, naïve Tconv cells were purified by flow cytometry on the basis of a CD25lowCD127highCD45RA+GPA33int phenotype and naïve tTreg cells on the basis of a CD25highCD127lowCD45RA+GPA33high phenotype (Extended Data Figure 1a)
Phenotypic analysis of these populations indicated that the naïve tTreg cells could be discriminated from Tconv cells as previously defined[34] by expression of FOXP3, IKZF2 (HELIOS), and CTLA4 (Extended Data Figure 1b)

Summary

Introduction

Among CD4+ regulatory T (Treg) cells, thymus-derived (t)Treg cells develop from T cell precursors, recognize selfantigens and protect against autoimmunity[1]. Induced (p)Treg cells, arise from mature conventional T (Tconv) cells that respond to foreign antigens and exert negative feedback on such responses[2]. The transcription factor FOXP3 dictates Treg differentiation fate[3, 4]. In tTreg cells, FOXP3 expression is stable, while pTreg cells can lose FOXP3 expression and convert back to Tconv cells[5]. Treg cells are used therapeutically, against transplant rejection, graft-versus-host disease and autoimmunity[6, 7]. Stable tTreg cells must be used, since pTreg cells may convert to Tconv cells and exacerbate, rather than attenuate disease[6,7,8]

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