GABA, glucose and insulin orchestrate CD4+T cells effector functions

Metabolic programs of immune cells are closely linked to their effector functions. Physiological molecules including glucose, insulin and γ-aminobutyric acid (GABA) provide environmental cues and guidance, although how they coordinate to regulate the cells is still being unraveled. Here, we demonstrate that GABA-mediated reduction of metabolic activity and release of inflammatory molecules, including IFNγ and IL-10, was abolished in human CD4 + T cells when the glucose concentration was elevated above normal levels. Insulin enhanced the GABA A receptors-mediated currents and Ca 2+ influx. GABA decreased, whereas insulin sustained glycolysis but in a SGLT (Na + -glucose transporter)-dependent manner. In high glucose (16.7 mM), the SGLTs antagonist phlorizin alone or together with GABA restored the inhibition of IFNγ and IL-10 release. This study exposes concerted effects of GABA, glucose and insulin on CD4 + T cells metabolic activity and release of inflammatory molecules, and identifies a role for SGLTs in CD4 + T cells function.