GABA-mediated inhibition of human CD4+ T cell functions is enhanced by insulin but impaired by high glucose levels
eBioMedicine, 2024
Jin Z., Hammoud H., Bhandage A., Korol S., Trujeque-Ramos O., Koreli S., Gong Z., Chowdhury A., Sandbaumhüter F., Jansson E., Lindsay R., Christoffersson G., Andrén P., Carlsson P., Bergsten P., Kamali-Moghaddam M., Birnir B.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Metabolic Diseases Immunological & Inflammatory Diseases | Pathophysiology | Cell Culture Supernatant |  Olink Target 96 |
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 Ca2+ 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 GABAA receptor-subunit ρ2 expression, enhanced the GABAA receptors-mediated currents and Ca2+ 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.