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Activation of GABA(A) receptors inhibits T cell proliferation

Activation of GABA(A) receptors inhibits T cell proliferation
Activation of GABA(A) receptors inhibits T cell proliferation
Background: the major sites for fast synaptic inhibition in the central nervous system (CNS) are ion channels activated by γ-aminobutyric acid (GABA). These receptors are referred as GABA(A) receptors (GABA(A)R). Recent evidence indicates a role of GABA(A)R in modulating the immune response. This work aimed to discern the role of GABA and GABA(A)Rs in human and mouse T cell activity.

Methods: mouse splenocytes or human peripheral blood mononuclear cells (PBMCs) were activated with anti-CD3 antibodies and the proliferation of both CD8+ and CD4+ T cells assessed through flow cytometry. Subsequently, the effects on T cell proliferation of either GABA(A)R modulation by diazepam that is also capable of activating mitochondrial based translocator protein (TSPO), alprazolam and allopregnanolone or inhibition by bicucculine methiodide (BMI) and (1,2,5,6-Tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) were assessed.

Results: positive modulation of GABA(A)Rs either by benzodiazepines or the neurosteroid allopregnanolone inhibits both mouse and human T cell proliferation. GABAergic inhibition of T cell proliferation by benzodiazepines could be rescued by GABA(A)R blocking. Our data suggest that benzodiazepines influence T cell proliferation through both TSPO and GABA(A)Rs activation.

Conclusions: we conclude that activation of GABA(A)Rs provides immunosuppression by inhibiting T cell proliferation.
1932-6203
Beers, Stephen
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
Sparrow, Emma L
ea74d145-eb97-4830-9992-1d5dc3fed288
James, Sonya
764c80e3-5bea-4b34-a871-b43f87ef97b0
Hussain, Khiyam
9468f252-81d0-4251-b800-702433b610f8
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Bogdanov, Yury
0c970999-e191-4f1b-90d9-7bf25a5d5b4b
Beers, Stephen
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
Sparrow, Emma L
ea74d145-eb97-4830-9992-1d5dc3fed288
James, Sonya
764c80e3-5bea-4b34-a871-b43f87ef97b0
Hussain, Khiyam
9468f252-81d0-4251-b800-702433b610f8
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Bogdanov, Yury
0c970999-e191-4f1b-90d9-7bf25a5d5b4b

Beers, Stephen, Sparrow, Emma L, James, Sonya, Hussain, Khiyam, Cragg, Mark and Bogdanov, Yury (2021) Activation of GABA(A) receptors inhibits T cell proliferation. PLoS ONE, 16 (5 May), [e0251632]. (doi:10.1371/journal.pone.0251632).

Record type: Article

Abstract

Background: the major sites for fast synaptic inhibition in the central nervous system (CNS) are ion channels activated by γ-aminobutyric acid (GABA). These receptors are referred as GABA(A) receptors (GABA(A)R). Recent evidence indicates a role of GABA(A)R in modulating the immune response. This work aimed to discern the role of GABA and GABA(A)Rs in human and mouse T cell activity.

Methods: mouse splenocytes or human peripheral blood mononuclear cells (PBMCs) were activated with anti-CD3 antibodies and the proliferation of both CD8+ and CD4+ T cells assessed through flow cytometry. Subsequently, the effects on T cell proliferation of either GABA(A)R modulation by diazepam that is also capable of activating mitochondrial based translocator protein (TSPO), alprazolam and allopregnanolone or inhibition by bicucculine methiodide (BMI) and (1,2,5,6-Tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) were assessed.

Results: positive modulation of GABA(A)Rs either by benzodiazepines or the neurosteroid allopregnanolone inhibits both mouse and human T cell proliferation. GABAergic inhibition of T cell proliferation by benzodiazepines could be rescued by GABA(A)R blocking. Our data suggest that benzodiazepines influence T cell proliferation through both TSPO and GABA(A)Rs activation.

Conclusions: we conclude that activation of GABA(A)Rs provides immunosuppression by inhibiting T cell proliferation.

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e-pub ahead of print date: 20 May 2021

Identifiers

Local EPrints ID: 449625
URI: http://eprints.soton.ac.uk/id/eprint/449625
ISSN: 1932-6203
PURE UUID: fc7c4d5c-30ac-4383-a29c-c89ea46ebb65
ORCID for Stephen Beers: ORCID iD orcid.org/0000-0002-3765-3342
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X
ORCID for Yury Bogdanov: ORCID iD orcid.org/0000-0003-4667-5890

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Date deposited: 09 Jun 2021 16:31
Last modified: 11 Jun 2021 01:45

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Contributors

Author: Stephen Beers ORCID iD
Author: Emma L Sparrow
Author: Sonya James
Author: Khiyam Hussain
Author: Mark Cragg ORCID iD
Author: Yury Bogdanov ORCID iD

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