γ-Aminobutyric Acid Transporter 1 Negatively Regulates T Cell-Mediated Immune Responses and Ameliorates Autoimmune Inflammation in the CNS

Wang, Ying; Feng, Dechun; Liu, Guoxiang; Luo, Qiang; Xu, Yan; Lin, Shuting; Fei, Jian; Xu, Lu

doi:10.4049/jimmunol.181.12.8226

Cited by 45 publications

(49 citation statements)

References 49 publications

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“…Our previous study has demonstrated that after Ag triggered T cell activation, GAT-1 expression is up-regulated (4). In this project, we found that PKC activation in T cells can also promote GAT-1 expression.…”

Section: Discussionsupporting

confidence: 51%

“…Neurotransmitters, together with their receptors and transporters, bridge the activity between nervous system and immune system (1,4). Studies of transgenic mice or of agonist/antagonist administration have established critical functions of neurotransmitters and associated molecules in regulating T cell responses (1,4,23).…”

Section: Discussionmentioning

confidence: 99%

“…We have reported that MNCs from GAT-1 Ϫ/Ϫ mice induced with EAE exhibit more proliferative capability than do MNCs from WT EAE mice (4). In this study, we examine further whether and how GAT-1 deficiency affects T cell proliferation.…”

Section: Proliferation Of Gat-1 ϫ/ϫ T Cellsmentioning

confidence: 94%

“…Our previous study has revealed that GAT-1 deficiency exacerbates experimental autoimmune encephalomyelitis (EAE) through promotion of Ag-specific T cell responses. Interestingly, we found that GAT-1 is expressed on Ag-activated T cells, but not on quiescent T cells, B cells, or macrophages (4). However, the mechanisms by which GAT-1 regulates Ag-specific T cell activation remain unclear.…”

mentioning

confidence: 85%

“…Our previous study has demonstrated that Ag-pulsed T cells can express GAT-1 while Con A seems not to affect GAT-1 expression on T cells (4). We wondered by which mechanisms GAT-1 expression might be regulated in T cell activation.…”

Section: Activated Pkc Is Involved In Regulating Gat-1 Expression In Cd4mentioning

confidence: 99%

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γ-Aminobutyric Acid Transporter 1 Negatively Regulates T Cell Activation and Survival through Protein Kinase C-Dependent Signaling Pathways

Wang

Luo²,

et al. 2009

The Journal of Immunology

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γ-aminobutyric acid transporter 1 (GAT-1), as the major regulator in maintaining a γ-aminobutyric acid reservoir in the CNS, plays negative roles in experimental autoimmune encephalomyelitis pathogenesis. Our previous study has revealed that, besides its wide expression in the CNS, GAT-1 expression can be induced on activated T cells triggered by Ag. However, the function of GAT-1 in T cell activation is unclear. In this study, we show that GAT-1 deficiency induces more vigorous cell cycle entry and less cell apoptosis in T cells, thus leading to enhanced cell proliferation. GAT-1 deficiency promotes T cell division and survival by down-regulating cyclin dependent kinase inhibitor p27kip1, differentially regulating the pro- and anti-apoptotic proteins Bcl-2, Bcl-xl, and Bad and activating transcription factor NF-κB through induction of translocation and phosphorylation of protein kinase C (PKC) θ. In addition, our data reveal that GAT-1 expression on T cells is modulated by PKC activation. Taken together, the data show that GAT-1 negatively regulates T cell activation and survival through PKC-dependent signaling pathways.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Proliferation Of Gat-1 ϫ/ϫ T Cellsmentioning

confidence: 94%

mentioning

confidence: 85%

Section: Activated Pkc Is Involved In Regulating Gat-1 Expression In Cd4mentioning

confidence: 99%

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γ-Aminobutyric Acid Transporter 1 Negatively Regulates T Cell Activation and Survival through Protein Kinase C-Dependent Signaling Pathways

Wang

Luo²,

et al. 2009

The Journal of Immunology

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Microglial expression of GAT‐1 in the cerebral cortex

Fattorini

Melone

Serpe

et al. 2019

Glia

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Microglial cells are the immune cells of the brain that, by sensing the microenvironment, permit a correct brain development and function. They communicate with other glial cells and with neurons, releasing and responding to a number of molecules that exert effects on surrounding cells. Among these, neurotransmitters and, in particular, gamma‐aminobutyric acid (GABA) has recently gained interest in this context. We demonstrated the expression of GABA transporter 1 (GAT‐1) in microglial cells both in soma and cell processes. We show that microglial cell treatment with 1,2,5,6‐tetrahydro‐1‐[2‐[[(diphenylmethylene)amino]oxy]ethyl]‐3‐pyridinecarboxylic acid hydrochloride (NNC‐711), a potent and selective GAT‐1 inhibitor, significantly reduced Na+‐dependent GABA uptake. On the other hand, GABA uptake was significantly increased by cell treatment with (S)‐1‐[2‐[tris(4‐methoxyphenyl)methoxy]ethyl]‐3‐piperidinecarboxylic acid (SNAP‐5114), a GAT‐2/3 inhibitor, and this effect was completely blocked by the botulinum toxin BoNT/C1, that specifically cleaves and inactives syntaxin 1A (STX1A). Overall, these findings show that microglial cells express GAT‐1 and indicate that STX1A plays an important role in the regulation of GAT‐1‐dependent GABA uptake in microglia.

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GABAergic signaling in human and murine NK cells upon challenge withToxoplasma gondii

Bhandage

Friedrich

Kanatani

et al. 2021

Journal of Leukocyte Biology

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Protective cytotoxic and proinflammatory cytokine responses by NK cells impact the outcome of infections by Toxoplasma gondii, a common parasite in humans and other vertebrates. However, T. gondii can also sequester within NK cells and downmodulate their effector functions. Recently, the implication of GABA signaling in infection and inflammation-related responses of mononuclear phagocytes and T cells has become evident. Yet, the role of GABAergic signaling in NK cells has remained unknown. Here, we report that human and murine NK cells synthesize and secrete GABA in response to infection challenge. Parasitized NK cells secreted GABA, whereas activation stimuli, such as IL-12/IL-18 or parasite lysates, failed to induce GABA secretion. GABA secretion by NK cells was associated to a transcriptional up-regulation of GABA synthesis enzymes (glutamate decarboxylases [GAD65/67]) and was abrogated by GAD inhibition. Further, NK cells expressed GABA-A receptor subunits and GABA signaling regulators, with transcriptional modulations taking place upon challenge with T. gondii. Exogenous GABA and GABA-containing supernatants from parasitized dendritic cells (DCs) impacted NK cell function by reducing the degranulation and cytotoxicity of NK cells. Conversely, GABA-containing supernatants from NK cells enhanced the migratory responses of parasitized DCs. This enhanced DC migration was abolished by GABA-A receptor antagonism or GAD inhibition and was reconstituted by exogenous GABA. Jointly, the data show that NK cells are GABAergic cells and that GABA hampers NK cell cytotoxicity in vitro. We hypothesize that GABA secreted by parasitized immune cells modulates the immune responses to T. gondii infection.

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γ-Aminobutyric Acid Transporter 1 Negatively Regulates T Cell-Mediated Immune Responses and Ameliorates Autoimmune Inflammation in the CNS

Cited by 45 publications

References 49 publications

γ-Aminobutyric Acid Transporter 1 Negatively Regulates T Cell Activation and Survival through Protein Kinase C-Dependent Signaling Pathways

γ-Aminobutyric Acid Transporter 1 Negatively Regulates T Cell Activation and Survival through Protein Kinase C-Dependent Signaling Pathways

Microglial expression of GAT‐1 in the cerebral cortex

GABAergic signaling in human and murine NK cells upon challenge withToxoplasma gondii

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