TY - JOUR
T1 - Cutting Edge
T2 - TGF-β and Phosphatidylinositol 3-Kinase Signals Modulate Distinct Metabolism of Regulatory T Cell Subsets
AU - Priyadharshini, Bhavana
AU - Loschi, Michael
AU - Newton, Ryan H.
AU - Zhang, Jian Wen
AU - Finn, Kelsey K.
AU - Gerriets, Valerie A
AU - Huynh, Alexandria
AU - Rathmell, Jeffrey C.
AU - Blazar, Bruce R
AU - Turka, Laurence A.
PY - 2018/10/15
Y1 - 2018/10/15
N2 - Murine Foxp3+ regulatory T cells (Tregs) differentiated in vitro (induced Tregs [iTregs]) in the presence of antiinflammatory 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 Hk2 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.
AB - Murine Foxp3+ regulatory T cells (Tregs) differentiated in vitro (induced Tregs [iTregs]) in the presence of antiinflammatory 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 Hk2 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.
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U2 - 10.4049/jimmunol.1800311
DO - 10.4049/jimmunol.1800311
M3 - Article
C2 - 30209190
AN - SCOPUS:85054776972
SN - 0022-1767
VL - 201
SP - 2215
EP - 2219
JO - Journal of Immunology
JF - Journal of Immunology
IS - 8
ER -