Cutting Edge: TGF-β and Phosphatidylinositol 3-Kinase Signals Modulate Distinct Metabolism of Regulatory T Cell Subsets

Abstract

Murine Foxp3 regulatory T cells (Tregs) differentiated in vitro (induced Tregs [iTregs]) in the presence of anti-inflammatory cytokine TGF-β rely predominantly upon lipid oxidation to fuel mitochondrial oxidative phosphorylation. Foxp3 expression underlies this metabolic preference, as it suppresses glycolysis and drives oxidative phosphorylation. In this study, we show that in contrast to iTregs, thymic-derived Tregs (tTregs), engage in glycolysis and glutaminolysis at levels comparable to effector T cells despite maintained Foxp3 expression. Interestingly, exposure of tTregs to the anti-inflammatory cytokine TGF-β represses PI3K-mediated mTOR signaling, inhibits glucose transporter and expression, and reprograms their metabolism to favor oxidative phosphorylation. Conversely, replicating the effects of inflammation via elevation of PI3K signaling has minimal effects on tTregs but dramatically enhances the glycolysis of normally oxidative iTregs, resulting in reduction of Foxp3 expression. Collectively, these findings suggest both extrinsic and intrinsic factors govern the unique metabolic signature of Treg subsets.

αKG inhibits Regulatory T cell differentiation by coupling lipidome remodelling to mitochondrial metabolism

“…Interestingly, the basal oxygen consumption rate (OCR, correlating with OXPHOS) was significantly lower in Treg-than Th1-polarizing conditions (p<0.01; Figure 6A). These data are in accord with a recent study that reported a lower OXPHOS and glycolysis in activated tTreg as well as TGFβ-induced Treg as compared to Th0 and Th1 polarized cells (Priyadharshini et al, 2018). The lower OXPHOS in Treg cells (as compared to Th1) was associated with an augmented glycolysis, measured as a function of the extracellular acidification rate (ECAR, Figure 6A).…”

“…Tregs have been found to exhibit increased OXPHOS as compared to Teff subsets (Angelin et al, 2017;Gerriets et al, 2016;Gerriets et al, 2015;Michalek et al, 2011) but within tumors, Tregs exhibit a gene signature consistent with glycolysis (Pacella et al, 2018). Furthermore, while thymic Treg (tTreg) function was found to be dependent on mitochondrial complex III function (Koch et al, 2009), the level of OXPHOS in induced Tregs was reported to be significantly lower than in either tTreg or Th1 cells (Priyadharshini et al, 2018). In accord with the latter study, we detected significantly lower levels of OXPHOS following activation under Treg-polarizing than Th1-polarizing conditions.…”

TCR Dependent Metabolic Programming Regulates Autocrine IL-4 Production Resulting in Self-Tuning of the CD8+ T Cell Activation Setpoint

“…Treatment with Etx did not impact differentiation of other T effector cell populations (62). This dependence on OXPHOS for iTreg differentiation is not observed for thymic Tregs which rely on glycolysis (64). Together with our data, these findings support the use of the OXPHOS pathway in T cells as a mechanism to drive differentiation of T cells along pathways that dampen the immune response, either through Treg differentiation or decreased sensitivity.…”

Extracellular Vesicles isolated from Mesenchymal Stromal Cells Modulate CD4+ T Lymphocytes Toward a Regulatory Profile

“…Cells with high ψ m produced four times more IFN-γ compared to low ψ m cells and cells with low ψ m showed a reduction in mTORC1 activity [103]. In another study, the addition of TGF-β reduced glycolytic metabolism in thymus Tregs, as a consequence of the reduction of mTOR pathway activation [104]. These data corroborate our findings that cells producing less IFN-γ, after treatment with MSC-EVs, have lower ψ m and may also suggest the participation of TGF-β pathway in this regulation.…”