GABA-mediated inhibition of human CD4+ T cell functions is enhanced by insulin but impaired by high glucose levels
Zhe Jin, Hayma Hammoud, Amol K. Bhandage, Sergiy V. Korol, Olivia Trujeque-Ramos, Stasini Koreli, Zhitao Gong, Azasul Islam Chowdhury, Friederike A. Sandbaumhüter, Erik T. Jansson, Robin S. Lindsay, Gustaf Christoffersson, Per Erik Andrén, Per-Ola Carlsson, Peter Bergsten, Masood Kamali-Moghaddam, Bryndis Birnir
Abstract
Background γ-aminobutyric acid (GABA), known as the main inhibitory neurotransmitter in the brain, exerts immunomodulatory functions by interaction with immune cells, including T cells. Metabolic programs of T cells are closely linked to their effector functions including proliferation, differentiation, and cytokine production. The physiological molecules glucose and insulin may provide environmental cues and guidance, but whether they coordinate to regulate GABA-mediated T cell immunomodulation is still being examined. Methods CD4 + T cells that were isolated from blood samples from healthy individuals and from patients with type 1 diabetes (T1D) were activated in vitro . We carried out metabolic assays, multiple proximity extension assay (PEA), ELISA, qPCR, immunoblotting, immunofluorescence staining, flow cytometry analysis, MS-based proteomics, as well as electrophysiology and live-cell Ca 2+ imaging. Findings We demonstrate that GABA-mediated reduction of metabolic activity and the release of inflammatory proteins, including IFNγ and IL-10, were abolished in human CD4 + T cells from healthy individuals and patients with T1D when the glucose concentration was elevated above levels typically observed in healthy people. Insulin increased GABA A receptor-subunit ρ2 expression, enhanced the GABA A receptors-mediated currents and Ca 2+ influx. GABA decreased, whereas insulin sustained, hexokinase activity and glycolysis in a glucose concentration-dependent manner. Interpretation These findings support that metabolic factors, such as glucose and insulin, influence the GABA-mediated immunomodulation of human primary T cells effector functions. Funding The Swedish Children's Diabetes Foundation, The Swedish Diabetes Foundation, The Swedish Research Council 2018-02952, EXODIAB, The Ernfors Foundation, The Thurings Foundation and the Science for Life Laboratory.