GABA-mediated inhibition of human CD4+ T cell functions is enhanced by insulin but impaired by high glucose levelsResearch in context
Zhe Jin,
Hayma Hammoud,
Amol Keshavasa Bhandage,
Sergiy Vasylyovych Korol,
Olivia Trujeque-Ramos,
Stasini Koreli,
Zhitao Gong,
Azasul Islam Chowdhury,
Friederike Andrea Sandbaumhüter,
Erik Tomas Jansson,
Robin Sean Lindsay,
Gustaf Christoffersson,
Per Erik Andrén,
Per-Ola Carlsson,
Peter Bergsten,
Masood Kamali-Moghaddam,
Bryndis Birnir
Affiliations
Zhe Jin
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Hayma Hammoud
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Amol Keshavasa Bhandage
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Sergiy Vasylyovych Korol
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Olivia Trujeque-Ramos
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Stasini Koreli
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Zhitao Gong
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Azasul Islam Chowdhury
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Friederike Andrea Sandbaumhüter
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
Erik Tomas Jansson
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
Robin Sean Lindsay
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Gustaf Christoffersson
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Per Erik Andrén
Department of Pharmaceutical Biosciences, Spatial Mass Spectrometry, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Per-Ola Carlsson
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Peter Bergsten
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Masood Kamali-Moghaddam
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Bryndis Birnir
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; Corresponding author. Department of Medical Cell Biology, Uppsala University, Uppsala, 75124, Sweden.
Summary: 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. 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.
