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Ulf H Beier, Alessia Angelin, Jing Jiao, Haiyan Xiao, Liqing Wang, Satinder Dahiya, Andrew D Wells, Douglas C Wallace, Wayne W Hancock, Foxp3 controls oxidative phosphorylation in regulatory T cells, The Journal of Immunology, Volume 196, Issue 1_Supplement, May 2016, Page 211.3, https://doi.org/10.4049/jimmunol.196.Supp.211.3
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Abstract
Many T cell subsets have distinct metabolic requirements. Activated CD4 helper and cytotoxic CD8 T cells require glycolysis for optimal function, whereas Foxp3+ T-regulatory (Treg) cells are thought to be dependent on oxidative phosphorylation. We questioned if Foxp3 is involved with re-programming T cell metabolism. We retrovirally transduced murine T cells with Foxp3 or empty vector (EV), and also cultured CD4+Foxp3− T cells from Foxp3YFPcre mice under polarizing conditions with TGFβ to form induced Tregs, using YFP to track Foxp3 expression. Our analysis of FACS-sorted YFP+ iTreg and YFP− non-iTreg showed that both iTreg and Foxp3-transduced T cells had significantly higher basal oxygen consumption rates than non-iTreg or EV transduced T cell controls (44.1±49% and 76.1±76.5%, respectively, p<0.05, n=4), despite equal mitochondrial mass. Using Foxp3 ChIP-seq and microarray studies, we identified multiple binding sites of Foxp3 and Foxp3-dependent transcripts among key genes involved in control of oxidative phosphorylation as well as nuclear encoded electron transport chain genes. FACS-sorted YFP+ iTreg showed increased protein expression of electron transport chain complexes, especially complex I, compared to YFP− non-iTreg. We found that mice deficient in ND6, a mitochondrial encoded gene of complex I, have deficient Treg function. Furthermore, 50 nM rotenone, a complex I inhibitor, could selectively inhibit Treg suppressive function without affecting Tconv cell proliferation. The effects of Foxp3 on Treg metabolism may be physiological important to enable Tregs operating in low glucose environments such as the tumor microenvironment, and could offer an opportunity for therapeutic immune modulation.
