Dichloroacetate at therapeutic concentration alters glucose metabolism and induces regulatory T-cell differentiation in alloreactive human lymphocytes

Abstract

DCA inhibits aerobic glycolysis and induces Treg differentiation in human alloreactive lymphocytes. This could result in decreased immunosurveillance in case of its use as an anticancer drug. However, DCA could play a role as an immunosuppressant in the fields of transplantation and autoimmunity.

The Glucose Transporter Glut1 Is Selectively Essential for CD4 T Cell Activation and Effector Function

“…Mechanisms that control cell metabolism to support the specific functional needs of these cells have been described only recently (MacIver et al, 2013), but have proven promising (Bian et al, 2009; Eleftheriadis et al, 2013; Ostroukhova et al, 2012; Shi et al, 2011). To date, pharmacologic approaches have provided limited mechanistic insight, and the role of glucose uptake has been uncertain.…”

Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation

“…DCA has also been shown to reduce proinflammatory cytokine production and promote FoxP3 expression in vitro and in several in vivo inflammatory models (19)(20)(21), although the mechanisms involved have not been established.…”

“…While DCA has been previously shown to suppress inflammation in arthritis, asthma, and alloreactivity (19)(20)(21), the specific effect on the differentiated CD4 + T cell subsets has not been examined in vivo. We therefore tested the ability of DCA to suppress the Th17-mediated inflammatory diseases.…”

“…DCA also can promote ROS in several cancer models that may drive cancer cell senescence (15,38,42). In the immune system, treatment of human peripheral blood mononuclear cells (PBMCs) with DCA inhibited proinflammatory cytokine production and promoted FoxP3 expression in the setting of asthma and alloreactivity (19)(20)(21). However, these studies did not directly examine the role of PDHK or DCA in T cell subsets or establish a mechanism of action.…”

Role of Metabolism in the Immunobiology of Regulatory T Cells

“…Using multiple pharmacological inhibitors and activators, it was shown that differential metabolic programs could regulate Treg cell lineage differentiation both in vivo and in vitro (25, 37, 38). Specifically, inhibition of glycolysis with the glucose analogue 2-deoxyglucose (2-DG) - a prototypical inhibitor of the glycolytic pathway - promoted induction of mouse Treg cells in vitro, in the presence of polarizing cytokines such as transforming growth factor (TGF)-β and IL-2 (5, 25).…”