Publication
GABA, glucose and insulin orchestrate CD4+T cells effector functions
Publisher:
Cold Spring Harbor Laboratory
Date:
20-04-2023
DOI:
10.1101/2023.04.18.537327
Abstract: Metabolic programs of immune cells are closely linked to their effector functions 1 , where physiological molecules provide environmental cues and guidance 2–5 . Exactly how it happens is still being unraveled. Insulin maintains normal blood glucose levels 6 and glucose is the main source of energy and a precursor for many biomolecules in T cells 7, 8 , whereas γ-aminobutyric acid (GABA), best known as a neurotransmitter, is increasingly recognized as a regulatory molecule in the immune system 4, 9 . 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. In a glucose concentration-dependent manner, insulin enhanced the GABA A receptors activated currents and GABA-dependent Ca 2+ influx. GABA decreased, whereas insulin maintained glycolysis but in a SGLT (Na + -glucose transporter)-dependent manner, revealing expression of SGLTs in activated CD4 + T cells. The SGLTs antagonist phlorizin, alone or together with GABA, restored the inhibition of IFNγ and IL-10 release in presence of high glucose. 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.