In recent years, it has become clear that there is an extensive cross-talk between the nervous and the immune system. Somewhat surprisingly, the immune cells themselves do express components of the neuronal neurotransmitters systems. What role the neurotransmitters, their ion channels, receptors and transporters have in immune function and regulation is an emerging field of study. Several recent studies have shown that the immune system is capable of synthesizing and releasing the classical neurotransmitter GABA (γ-aminobutyric acid). GABA has a number of effects on the immune cells such as activation or suppression of cytokine secretion, modification of cell proliferation and GABA can even affect migration of the cells. The immune cells encounter GABA when released by the immune cells themselves or when the immune cells enter the brain. In addition, GABA can also be found in tissues like the lymph nodes, the islets of Langerhans and GABA is in high enough concentration in blood to activate, e.g., GABA-A channels. GABA appears to have a role in autoimmune diseases like multiple sclerosis, type 1 diabetes, and rheumatoid arthritis and may modulate the immune response to infections. In the near future, it will be important to work out what specific effects GABA has on the function of the different types of immune cells and determine the underlying mechanisms. In this review, we discuss some of the recent findings revealing the role of GABA as an immunomodulator.

The neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule in the brain and in pancreatic islets. Here, we demonstrate that GABA regulates cytokine secretion from human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells. In anti-CD3 stimulated PBMCs, GABA (100nM) inhibited release of 47 cytokines in cells from patients with type 1 diabetes (T1D), but only 16 cytokines in cells from nondiabetic (ND) individuals. CD4+ T cells from ND individuals were grouped into responder or non-responder T cells according to effects of GABA (100nM, 500nM) on the cell proliferation. In the responder T cells, GABA decreased proliferation, and inhibited secretion of 37 cytokines in a concentration-dependent manner. In the non-responder T cells, GABA modulated release of 8 cytokines. GABA concentrations in plasma from T1D patients and ND individuals were correlated with 10 cytokines where 7 were increased in plasma of T1D patients. GABA inhibited secretion of 5 of these cytokines from both T1D PBMCs and ND responder T cells. The results identify GABA as a potent regulator of both Th1- and Th2-type cytokine secretion from human PBMCs and CD4+ T cells where GABA generally decreases the secretion.

During acute infection in human and animal hosts, the obligate intracellular protozoan Toxoplasma gondii infects a variety of cell types, including leukocytes. Poised to respond to invading pathogens, dendritic cells (DC) may also be exploited by T. gondii for spread in the infected host. Here, we report that human and mouse myeloid DC possess functional γ-aminobutyric acid (GABA) receptors and the machinery for GABA biosynthesis and secretion. Shortly after T. gondii infection (genotypes I, II and III), DC responded with enhanced GABA secretion in vitro. We demonstrate that GABA activates GABA_A receptor-mediated currents in T. gondii-infected DC, which exhibit a hypermigratory phenotype. Inhibition of GABA synthesis, transportation or GABA_A receptor blockade in T. gondii-infected DC resulted in impaired transmigration capacity, motility and chemotactic response to CCL19 in vitro. Moreover, exogenous GABA or supernatant from infected DC restored the migration of infected DC in vitro. In a mouse model of toxoplasmosis, adoptive transfer of infected DC pre-treated with GABAergic inhibitors reduced parasite dissemination and parasite loads in target organs, e.g. the central nervous system. Altogether, we provide evidence that GABAergic signaling modulates the migratory properties of DC and that T. gondii likely makes use of this pathway for dissemination. The findings unveil that GABA, the principal inhibitory neurotransmitter in the brain, has activation functions in the immune system that may be hijacked by intracellular pathogens. Toxoplasma gondii is an obligate intracellular protozoan parasite and an important food- and water-borne human and veterinary pathogen. Toxoplasmosis is normally self-limiting but severe manifestations occur upon congenital transmission to the developing fetus or during infection in immune-compromised individuals. Toxoplasma invades a variety of cell types and mounting evidence shows that certain white blood cells, e.g. dendritic cells, can shuttle parasites in the infected host by a Trojan horse type of mechanism. Dendritic cells are considered the gatekeepers of the immune system but can, paradoxically, also mediate dissemination of the parasite. Previous work has shown that Toxoplasma induces a hypermigratory state in dendritic cells when they become infected. Here, we show that, shortly after infection by the parasite, dendritic cells start secreting γ-aminobutyric acid (GABA), also known as the major inhibitory neurotransmitter in the brain. We show that dendritic cells express GABA receptors, as well as the machinery to synthesize and transport GABA. When GABA synthesis, transport or receptor function was inhibited, the migration of infected dendritic cells was impaired. In a mouse model of toxoplasmosis, treatment of infected dendritic cells with GABA inhibitors resulted in reduced propagation of the parasite. This study establishes that GABAergic signaling modulates the migratory properties of dendritic cells and that the intracellular pathogen Toxoplasma gondii sequesters the GABAergic signaling of dendritic cells to assure propagation.

Aims/hypothesis γ-Aminobutyric acid (GABA) is a signalling molecule in the interstitial space in pancreatic islets. We examined the expression and function of the GABA signalling system components in human pancreatic islets from normoglycaemic and type 2 diabetic individuals. Methods Expression of GABA signalling system components was studied by microarray, quantitative PCR analysis, immunohistochemistry and patch-clamp experiments on cells in intact islets. Hormone release was measured from intact islets. Results The GABA signalling system was compromised in islets from type 2 diabetic individuals, where the expression of the genes encoding the α1, α2, β2 and β3 GABA_A channel subunits was downregulated. GABA originating within the islets evoked tonic currents in the cells. The currents were enhanced by pentobarbital and inhibited by the GABA_A receptor antagonist, SR95531. The effects of SR95531 on hormone release revealed that activation of GABA_A channels (GABA_A receptors) decreased both insulin and glucagon secretion. The GABA_B receptor antagonist, CPG55845, increased insulin release in islets (16.7 mmol/l glucose) from normoglycaemic and type 2 diabetic individuals. Conclusions/interpretation Interstitial GABA activates GABA_A channels and GABA_B receptors and effectively modulates hormone release in islets from type 2 diabetic and normoglycaemic individuals.

γ-aminobutyric acid (GABA) is the most prominent neuroinhibitory transmitter in the brain, where it activates neuronal GABA-A receptors (GABA-A channels) located at synapses and outside of synapses. The GABA-A receptors are primary targets of many clinically useful drugs. In recent years, GABA has been shown to act as an immunomodulatory molecule. We have examined in human, mouse and rat CD4⁺ and CD8⁺ T cells which subunit isoforms of the GABA-A channels are expressed. The channel physiology and drug specificity is dictated by the GABA-A receptor subtype, which in turn is determined by the subunit isoforms that make the channel. There were 5, 8 and 13 different GABA-A subunit isoforms identified in human, mouse and rat CD4⁺ and CD8⁺ T cells, respectively. Importantly, the γ2 subunit that imposes benzodiazepine sensitivity on the GABA-A receptors, was only detected in the mouse T cells. Immunoblots and immunocytochemistry showed abundant GABA-A channel proteins in the T cells from all three species. GABA-activated whole-cell transient and tonic currents were recorded. The currents were inhibited by picrotoxin, SR95531 and bicuculline, antagonists of GABA-A channels. Clearly, in both humans and rodents T cells, functional GABA-A channels are expressed but the subtypes vary. It is important to bear in mind the interspecies difference when selecting the appropriate animal models to study the physiological role and pharmacological properties of GABA-A channels in CD4⁺ and CD8⁺ T cells and when selecting drugs aimed at modulating the human T cells function.