Expression and Function of Nicotinic Acetylcholine Receptors in Induced Regulatory T Cells

Abstract

A contribution of the cholinergic system to immune cell function has been suggested, though the role of nicotine and its receptors in T cells, especially regulatory T (Treg) cells, is unclear. We herein investigated the expression and function of nicotinic acetylcholine receptors (nAChRs) in murine-induced Treg (iTreg) cells. Upon differentiation of naive BALB/c T cells into iTreg cells and other T-cell subsets, the effect of nicotine on cytokine production and proliferation of iTreg cells was examined. The expression of nAChRs and its regulatory mechanisms were comparatively analyzed among T-cell subsets. Stimulation-induced transforming growth factor-β1 (TGF-β1) production of iTreg cells was suppressed by nicotine, whereas interleukin (IL)-10 production and proliferation was not affected. α2-, α5-, α9-, and β2-nAChRs were differentially expressed in naive, Th1, Th2, Th9, Th17, and iTreg cells. Among these cell types, the α9-nAChR was particularly upregulated in iTreg cells via its gene promoter, but not through tri-methylation at the 4th lysine residue of the histone H3-dependent mechanisms. We conclude that the immunoregulatory role of Treg cells is modified by the cholinergic system, probably through the characteristic expression of nAChRs.

RgIA4 Prevention of Acute Oxaliplatin-Induced Cold Allodynia Requires α9-Containing Nicotinic Acetylcholine Receptors and CD3+ T-Cells

“…Non-canonical signaling is implicated, in part, due to the lack of measurable nAChR-mediated ionic currents in these cells. [ 28 ] Although the signaling of α9-containing nAChRs in lymphocytes remains under investigation, the expression of chrna9 has been shown to be downregulated upon transition of naïve T-cells to T h 1 and T h 2 helper T-cells and upregulated after transition to T h 17 and regulatory T-cells [ 30 ]. In monocytic cell lines, RgIA4 was posited to affect the release of cytokines via modulation of P2 × 7 purinergic receptors and inflammasome assembly.…”

“…Identification of CD3 + T-cells as a necessary population for RgIA4 efficacy adds further insight into the role of α9-containing nAChR mechanisms in providing pain relief and neuronal protection. The chrna9 gene is upregulated within several distinct developmental stages of T-cells, including early double-positive (CD4 + CD8 + ) thymocytes in the thymus and late-induced regulatory T-cells [ 29 , 30 ]. The presence of both chrna9 and chrna10 transcripts was also observed in mature T- and B-cells [ 28 ].…”

“…Transcripts for α9 and α10 subunits have been found in purified T-cells, B-cells, and immortalized T-cell lines (CEM, Jurkat, and MT2) [ 28 ]. The α9-encoding gene, chrna9 , is upregulated in CD4 + CD8 + double-positive (DP) thymocytes, as well as late-stage induced regulatory T-cells (iT regs ) [ 29 , 30 ]. However, acetylcholine-elicited ionic responses have not been observed from α9-containing nAChRs in T-cells, suggesting a possible non-canonical role of these receptors in modulating immune responses.…”

α7- and α9-Containing Nicotinic Acetylcholine Receptors in the Functioning of Immune System and in Pain

“…At the same time, these effects were stopped by the selective α7 nAChR antagonist, α-bungarotoxin [ 124 ]. The treatment of mouse Treg cells with nicotine resulted in the suppression of TGF-β1 production but did not affect cell proliferation and IL-10 release, being mediated by α9 nAChR [ 125 ].…”

Catestatin: Antimicrobial Functions and Potential Therapeutics

“…CST increases insulin sensitivity by decreasing infiltration of macrophages in the liver and the consequent inflammation [44], inhibiting hepatic glucose production [44], decreasing endoplasmic reticulum stress [45], and inducing glycogen production [46]. Although it is known that neurotransmitters released from parasympathetic (e.g., acetylcholine) and sympathetic nerve ending (e.g., norepinephrine) can bind with the acetylcholine receptors [47][48][49][50][51] and adrenergic receptors [52][53][54][55][56], respectively present on innate immune cells, the homeostatic regulation between these two systems is complex. CST, being an intrinsic regulator of neuroendocrine secretory system, can have both direct and indirect effects on the host-pathogen interactions.…”