Current immunosuppressive therapies are limited by non-specificity and toxicities, and new pharmacologic approaches to immunosuppressive therapies are needed. Many T cell subsets have distinct metabolic requirements that offer an opportunity for therapeutic immune modulation. 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 found that compared to wild-type (WT) Treg cells, Tregs from mice deficient in histone deacetylase-6 (HDAC6) had higher basal (196.3%) and uncoupled (194.5%) oxygen consumption rates, respectively (p<0.05, n=4), despite equal mitochondrial mass. In contrast HDAC6-KO and WT conventional T cells (Tconv) had no difference in oxygen consumption, HDAC6-KO Treg and exhibited stronger suppressive function than WT Tregs in vitro and in vivo (homeostatic proliferation, transplantation, autoimmune colitis models) and expressed more acetylated, and transcriptionally active Foxp3. Since the increase in oxygen consumption was observed only in the Tregs, but not Tconv, we hypothesized that Foxp3 might directly control oxidative phosphorylation in Tregs. We therefore retrovirally transduced murine T cells with Foxp3 or empty vector (EV), and also cultured CD4⁺Foxp3^– T cells from Foxp3^YFPcre mice under polarizing conditions with TGFβ to form induced Tregs, using YFP expression 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). 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. In summary, Foxp3 regulates the metabolism of Treg cells, and HDAC6 targeting can further modulate these actions on metabolism, with direct translational benefits for therapeutic immune modulation.

CITATION INFORMATION: Beier U, Angelin A, Jiao J, Xiao H, Wang L, Dahiya S, Wells A, Wallace D, Hancock W. Foxp3 Controls Oxidative Phosphorylation in Regulatory T Cells. Am J Transplant. 2016;16 (suppl 3).

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