GABAA receptors mediate inhibition of T cell responses
Introduction
Many of the cells of the immune system express receptors for neuroactive molecules which modulate immune system function, creating a link between the nervous and immune systems (Nio et al., 1993; Torcia et al., 1996). γ-Aminobutyric acid (GABA) is a ubiquitous inhibitory neurotransmitter in the central nervous system (CNS) (reviewed in Erdo and Wolff, 1990; Olsen and Tobin, 1990; Kaufman and Tobin, 1993; Macdonald and Olsen, 1994; Luddens et al., 1995). GABA is synthesized from glutamic acid by the enzyme glutamate decarboxylase (GAD) (reviewed in Erlander et al., 1991). Outside of the brain, GAD and GABA receptors have been reported in the pancreatic islets, the gastrointestinal tract, ovaries and adrenal medulla (Erdo and Wolff, 1990). Interestingly, the administration of GABA or its agonists peripherally inhibits antibody production and modulates macrophage phagocytosis in vivo (Ratnikov et al., 1982; Frangulyan et al., 1986), suggesting a role for GABA in the regulation of immune system function. Since GABA is unable to pass through the blood brain barrier, this immuno-regulation is likely to be mediated through peripheral rather than central GABA receptors. However, GABA receptors have not yet been described on immunocompetent cells.
There are at least two types of neuronal GABA receptors, GABAA and GABAB. GABAA receptors are ligand-gated ion channels which respond to GABA by opening their integral Cl− channel (Olsen and Tobin, 1990; Macdonald and Olsen, 1994; Luddens et al., 1995). Pharmacologically, muscimol acts as an agonist for GABAA receptors and anxiolytic benzodiazepines as well as anesthetic agents (such as pentobarbital) potentiate the opening of the GABAA–Cl− channel. Bicuculline and RU5315 antagonize GABAA receptor function and picrotoxin blocks the GABAA receptor Cl− channel (Macdonald and Olsen, 1994; Luddens et al., 1995). In contrast, GABAB receptors are coupled to Ca2+ or K+ channels via GTP-binding proteins and are selectively activated by baclofen (Bowery, 1993). GABAB receptors are insensitive to bicuculline and picrotoxin.
A peripheral benzodiazepine receptor also exists which, unlike the central GABAA receptor–Cl− channel complex, is located within mitochondria, modulates Ca2+ release, does not bind GABA and shows no sequence homology with central GABA receptors (Parola et al., 1993). These peripheral benzodiazepine receptors have been shown to modulate immune responses (Ramseier et al., 1993; Schlumpf et al., 1993). Since the immunomodulatory activity of the peripheral benzodiazepine receptor is not modulated by GABA, or GABAA receptor antagonists (picrotoxin and bicuculline), this activity is thought to be independent of GABA receptors.
Here we show that murine T cells express functional GABAA receptors. Through these GABAA receptors, GABA can inhibit T cell responses to antigen both in vitro and in vivo, mostly likely by interfering with the TCR/CD3-gated signal pathway.
Section snippets
Chemicals
γ-Amino-n-butyric acid (GABA), β-alanine, l-glutamic acid, strychnine, picrotoxin, baclofen, bicuculline, nipecotic acid, muscimol, pentobarbital, phorbol 12-myristate 13-acetate (PMA) and ionomycin (A23187) were purchased from Sigma (St. Louis). γ-Vinyl-GABA (vigabatrin) and amidine 3-α-hydroxy-16-imino-5-β-17-azandrostan-11-one (RU5135) were generously provided by Drs. A. Tobin and R. Olsen (UCLA).
Animals
Six–eight-week old NOD (Taconic Farms), Balb/c and AKR (Jackson Laboratory) mice of either sex
GABA inhibits anti-CD3 stimulated T cell proliferation
When naive T cells recognize a peptide/MHC complex via their T cell TCR/CD3 complex, they activate and differentiate into effector cells and proliferate, expanding the antigen-reactive T cell pool (Janeway and Bottomly, 1994). Anti-CD3 can mimic this interaction and polyclonally activate T cells. As an initial screen for an immunoregulatory action by GABA, we assayed anti-CD3 induced T cell proliferation in the presence of GABA. Splenic mononuclear cells from naive BALB/c mice which were
Discussion
We have shown with several different strains of mice, that GABA inhibits T cell proliferative responses to anti-CD3, as well as foreign and self-antigen challenges, in a dose-dependent manner in vitro. The inhibitory effect of GABA on T cell proliferation was associated with greatly reduced IL-2 production by antigen-primed T cells. Furthermore, GABA inhibited the ability of mice to mount DTH responses to antigen. Thus, GABA down-regulated T cell functions both in vitro and in vivo. As
Note added in proof
GABA was recently found to affect T cell cytotoxicity in vitro (Berget et al., 1998).
Acknowledgements
We are especially grateful to Drs. Richard Olsen, Helen Kim and Tim DeLorey for help and advice. This work was supported by grants from the Juvenile Diabetes Foundation International and the National Institutes of Health.
References (35)
- et al.
Regulation of chloride channels in lymphocytes
Current Topics in Membranes
(1994) - et al.
Two genes encode distinct glutamate decarboxylases
Neuron
(1991) - et al.
Local and diffuse synaptic actions of GABA in the hippocampus
Neuron
(1993) - et al.
Transcriptional regulation of the IL-2 gene
Curr. Opin. Immunol.
(1995) - et al.
Signals and signs for lymphocyte responses
Cell
(1994) - et al.
Glutamate decarboxylases and autoimmunity in insulin-dependent diabetes
Trends Pharmacol. Sci.
(1993) - et al.
GABAA/benzodiazepine receptor heterogeneity: neurophysiological implications
Neuropharmacology
(1995) - et al.
Bridging the cleft at GABA synapses in the brain
Trends Neurosci.
(1994) - et al.
Peripheral-type benzodiazepine receptors
Life Sci.
(1993) - et al.
Lymphocyte responses and cytokines
Cell
(1994)
Nerve growth factor is an autocrine survival factor for memory B lymphocytes
Cell
Differential signaling by lymphocyte antigen receptors
Annu. Rev. Immunol.
Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes
J. Clin. Invest.
GABAB receptor pharmacology
Annu. Rev. Pharmacol. Toxicol.
Dose-dependent T cell tolerance to an immunodominant self peptide
Eur. J. Immunol.
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