Abstract
α7 Nicotinic acetylcholine receptor (α7 nAChR) has been found in several non-neuronal cells and is described as an important regulator of cellular function. Naturally occurring CD4+CD25+ regulatory T cells (Tregs) are essential for the active suppression of autoimmunity. The present study investigated whether naturally occurring Tregs expressed α7 nAChR and investigated the functionary role of this receptor in controlling suppressive activity of these cells. We found that CD4+CD25+ Tregs from naive C57BL/6J mice positively expressed α7 nAChR, and its activation by nicotine enhanced the suppressive capacity of Tregs. Nicotine stimulation up-regulated the expression of cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and forkhead/winged helix transcription factor p3 (Foxp3) on Tregs but had no effect on the production of interleukin (IL)-10 and transforming growth factor-β1 by Tregs. In the supernatants of CD4+CD25+ Tregs/CD4+CD25− T-cell cocultures, we observed a decrease in the concentration of IL-2 in nicotine-stimulated groups, but nicotine stimulation had no effect on the ratio of IL-4/interferon (IFN)-γ, which partially represented T-cell polarization. The above-mentioned effects of nicotine were reversed by a selective α7 nAChR antagonist, α-bungarotoxin. In addition, the ratio of IL-4/IFN-γ was increased by treatment with α-bungarotoxin. We conclude that nicotine might increase Treg-mediated immune suppression of lymphocytes via α7 nAChR. The effect is related to the up-regulation of CTLA-4 as well as Foxp3 expression and decreased IL-2 secretion in CD4+CD25+ Tregs/CD4+CD25− T-cell coculture supernatants. α7 nAChR seems to be a critical regulator for immunosuppressive function of CD4+CD25+ Tregs.
Footnotes
This work was supported, in part, by the National Natural Science Foundation [Grants 30872683, 30971192]; the National Basic Research Program of China [Grant 2005CB522602]; and the National Natural Science Outstanding Youth Foundation of China [Grant 30125020].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.169961.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- Treg
- CD4+CD25+ regulatory T cell
- IL
- interleukin
- CTLA
- cytotoxic T-lymphocyte-associated antigen
- Foxp3
- forkhead/winged helix transcription factor p3
- TCR
- T-cell receptor
- TGF
- transforming growth factor
- α7 nAChR
- α7 nicotinic acetylcholine receptor
- α-BGT
- α-bungarotoxin
- FITC
- fluorescein isothiocyanate
- ELISA
- enzyme-linked immunosorbent assay
- IFN
- interferon
- PE
- phycoerythrin
- FACS
- fluorescence-activated cell sorting
- mAb
- monoclonal antibody
- PCR
- polymerase chain reaction
- bp
- base pair(s)
- PBS
- phosphate-buffered saline
- RT-PCR
- reverse transcription-PCR
- RT−
- RNA reverse-transcribed without the enzyme
- Ab
- antibody
- Th
- T helper
- GTS-21
- 3-[(2,4-dimethoxy)benzylidene]-anabaseine
- ARR17779
- (−)-spiro[1-azabicyclo [2.2.2]octane-3,5′-oxazolidin-2′-one]
- PNU-282987
- N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride.
- Received May 8, 2010.
- Accepted September 14, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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