Plasticity of the murine spleen T-cell cholinergic receptors and their role in in vitro differentiation of naïve CD4 T cells toward the Th1, Th2 and Th17 lineages

Abstract

Acetylcholine (ACh) regulates vital functions of T cells by acting on the nicotinic and muscarinic classes of cholinergic receptors, nAChR and mAChRs, respectively. This study was performed in murine splenic T cells. In freshly isolated CD4 and CD8 T cells, we detected mRNAs encoding a5, a9, a10, b1, b2, b4 nAChR subunits and M 1 , M 3 , M 4 and M 5 mAChR subtypes, whereas a2 was detected only in CD8 T cells. In vitro activation of CD4 T cells through T-cell receptor (TCR)/CD3 cross-linking was associated with the appearance of a4 and a7, upregulation of a5, a10, b4, M 1 and M 5 and downregulation of a9 and b2, whereas in vitro activation of CD8 T cells also featured the appearance of a4 and a7, as well as upregulation of a2, a5, b4, M 1 and M 4 , and downregulation of a10, b1, b2 and M 3 . In vitro polarization toward T helper (Th) 1 lineage was associated with a decrease of b2, b4 and M 3 expression; that toward Th2 cells with downregulation of a9 and M 3 , and upregulation of M 1 and M 5 ; and that toward Th17 phenotype with downregulation of a9, a10, b2 and M 3 mAChR. Polarized T cells also expressed a4, but not a1, a2, a3, a6, b3 or M 2 . To determine the role of cholinergic receptors in mediating the immunoregulatory action of autocrine/paracrine ACh, we analyzed the effects of nicotinic and muscarinic agonists ± antagonists on cytokine production in the CD4 þ CD62L þ T cells co-stimulated via TCR/CD3 cross-linking. The nicotinergic stimulation upregulated interferon-g (IFN-g) and downregulated interleukin (IL)-17 secretion, whereas the muscarinic stimulation enhanced IL-10 and IL-17 and inhibited INF-g secretion. These results demonstrated plasticity of the T-cell cholinergic system.

Expression and Functional Role of α7 Nicotinic Receptor in Human Cytokine-stimulated Natural Killer (NK) Cells

“…Such a difference in ␣7 nAChR expression between these two species has also been shown in lymphocytes (8,30,32,39,40), and may underlie a different neuroimmunomodulatory potential of lymphoid cells in them. In mouse, nicotine exposure impairs the ability of NK cells to kill target cells and release cytokines through ␤2-containing nAChRs (29).…”

Effect of Desiccating Environmental Stress Versus Systemic Muscarinic AChR Blockade on Dry Eye Immunopathogenesis

“…These results differed somewhat from the findings of Qian et al regarding the muscarinic cholinergic regulation of CD4 þ T-cell differentiation. 25 They reported that in vitro stimulation of CD4 þ T-cells with the mAChR agonist muscarine increases IL-17 production and decreases IFN-c secretion without affecting IL-4 levels, and these effects are abolished with the administration of the mAChR antagonist atropine. These in vitro results and our in vivo results demonstrate that mAChR blockade leads to Th17 inhibition; however, the findings regarding Th1 and Th2 responses are not consistent between the two studies.…”

Non-neuronal cholinergic system in regulation of immune function with a focus on α7 nAChRs

“…Because of a wide variety of nAChR subtypes, details of nAChR subtype expression in each immune cell type are not yet known. However, most immune cells express mRNAs for neuronal type nAChR subunits, though the patterns of nAChR subunit expression vary among animal species and immune cells, and even between developmental stages within a cell [57]. Gene expression for the α3, α5, α7, α9 and α10 nAChR subunits has been commonly detected in human T and B cells [49].…”