Lymphocytic cholinergic system and its roles in regulation of immune function

乙酰胆碱（Acetylcholine, ACh）是哺乳动物中枢和外周神经系统中的一种神经递质。在淋巴细胞中发现了毒蕈碱和烟碱乙酰胆碱受体（分别为mAChR和nAChR）， mAChR和nAChR激动剂刺激它们会引起各种功能和生化效应。基于这些发现，人们推测副交感神经系统可能在免疫-神经体液串扰中起作用。然而，我们发现淋巴细胞表达胆碱能系统的大部分成分，如machr和nachr的各种亚型，ACh，胆碱乙酰转移酶（ChAT），高亲和力胆碱转运蛋白和乙酰胆碱酯酶。此外，我们观察到ACh和mAChR激动剂可能通过M_3和M_5 mAChR诱导细胞内Ca^<2+>信号，上调T和B细胞内c-fos表达和一氧化氮合成。乙酰胆碱或尼古丁刺激nAChR，可能通过α7 nAChR亚基介导的途径，在T细胞和B细胞中引起快速和短暂的Ca^<2+>信号转导。植物血凝素或抗原通过细胞表面分子诱导T细胞活化。（T细胞受体/CD3复合物）通过上调ChAT和M_5 mAChR表达增强淋巴细胞胆碱能传递，提示局部淋巴细胞胆碱能系统参与调节免疫功能。这一观点得到了研究结果的支持，即淋巴细胞胆碱能活性在动物模型中发生改变，表现出免疫异常。此外，在细胞表面分子介导的相互作用中，T细胞可能通过ACh与胸腺上皮细胞和血管内皮细胞进行交流，这些细胞也表达ChAT和nachr或machr。总的来说，我们获得的数据提供了一个令人信服的画面，淋巴细胞构成一个独立于胆碱能神经的胆碱能系统，并参与免疫功能的调节。

Acetylcholine(ACh) is well known as a neurotransmitter in the central and peripheral nervous systems in mammalian species. Both muscarinic and nicotinic ACh receptors(mAChRs and nAChRs, respectively) have been identified in lymphocytes, and their stimulation by mAChR and nAChR agonists elicits a variety of functional and biochemical effects. On the basis of these findings, it has been postulated that the parasympathetic nervous system may play a role in immune-neurohumoral crosstalk. However, we discovered that lymphocytes express most components of the cholinergic system, such as various subtypes of mAChRs and nAChRs, ACh, choline acetyltransferase(ChAT), high affinity choline transporter and acetylcholinesterase. Furthermore, we have observed that ACh and mAChR agonists elicit intracellular Ca^<2+> signaling, up-regulation of c-fos expression and nitric oxide synthesis within T and B cells, probably via M_3 and M_5 mAChRs. Stimulation of nAChRs with ACh or nicotine caused rapid and transient Ca^<2+> signaling in T and B cells, probably via α7 nAChR subunit-mediated pathways. Phytohemagglutinin- or antigen-induced T cell activation via cell surface molecules(e.g., T cell receptor/CD3 complexes) enhances lymphocytic cholinergic transmission by up-regulating ChAT and M_5 mAChR expression, suggesting that a local lymphocytic cholinergic system is involved in regulating immune function. This idea is supported by the findings that lymphocytic cholinergic activity is altered in animal models exhibiting immunological abnormalities. In addition, it appears likely that during interactions mediated by cell surface molecules T cells communicate via ACh with thymic epithelial cells and vascular endothelial cells, which also express ChAT and nAChRs or mAChRs. Collectively, the data we obtained provide a compelling picture in which lymphocytes constitute a cholinergic system that is independent of cholinergic nerves, and which is involved in the regulation of immune function.