Foxp3-mediated inhibition of Akt inhibits Glut1 (glucose transporter 1) expression in human T regulatory cells

CD4(+)CD25(+)Foxp3(+)T(regs) have a diminished capacity to activate the PI3K/Akt pathway. Although blunted Akt activity is necessary to maintain T-reg function, the consequences of this altered signaling are unclear. Glut1 is a cell-surface receptor responsible for facilitating glucose transport across plasma membranes, whose expression is tightly coupled to costimulatory signals and Akt phosphorylation. Freshly isolated human T-regs were unable to up-regulate Glut1 in response to TCR and costimulatory signals compared with T-conv. Consequently, the ability of T-regs to use glucose was also reduced. Introduction of Foxp3 into T-conv inhibited Akt activation and Glut1 expression, indicating that Foxp3 can regulate Glut1. Finally, pharmacologic activation of Akt in T-regs can induce Glut1, overcoming the effects of Foxp3. Together, these results illustrate the molecular basis behind differential glucose metabolism in T-regs.