Th细胞亚群比例及分化异常与病毒性心肌炎（VMC）的发生发展密切相关。我们前期研究发现，交感神经系统和迷走神经相关的胆碱能抗炎通路（CAP）在VMC中分别介导促炎和抗炎作用，因此提出了自主神经-免疫调节系统失衡参与VMC发生发展的新观点。然而，CAP能否通过影响Th细胞亚群分化来抑制VMC炎症尚未见报道。申请者发现CAP兴奋后可抑制VMC小鼠Th1和Th17细胞相关炎症因子的表达，而且CD4+T细胞表面表达α7nAChR，这些启示我们CAP很可能通过影响Th分化来抑制VMC的炎症反应。本项目以VMC小鼠及其脾脏CD4+T细胞为研究对象，从兴奋/阻滞α7nAChR及切断颈部迷走神经着手，通过在体和离体两方面观察激活及阻断CAP对Th细胞亚群分化的影响，解析CAP调控VMC小鼠Th细胞亚群分化的机制。本项目最大的特色是将VMC的机制研究深入神经免疫学领域，从而为VMC的治疗提供一个崭新的思路。

CD4+ helper T cell types 1, 2, 17 and Treg have been implicated in the pathogenesis of myocarditis after viral infection. Recently, we have found that excessive sympathetic activation in viral myocarditis aggravates inflammatory lesions, and vagus nerve stimulation and activation of cholinergic antiinflammatory pathway attenuate inflammation in viral myocarditis through α7 nicotinic acetylcholine receptor (α7-nAChR). Therefore, the results provide us a novel insight about the mechanisms involved in the pathogenesis of viral myocarditis and suggest that dysfunctional autonomic neural-immune circuit (sympathetic activation and vagal withdrawal) is associated with the development of viral myocarditis. However, the effects of cholinergic antiinflammatory pathway on CD4+ T cell responses in viral myocarditis are unknown. Our previous studies have demonstrated that activation of cholinergic antiinflammatory pathway via α7-nAChR downregulates the mRNA expression of Th1 and Th17 cytokines, and α7-nAChR is expressed by CD4+ T cells. Hence, we postulate that activation of cholinergic antiinflammatory pathway could ameliorate the severity of myocarditis by regulating the differentiation of Th cell subsets through CD4+ T cell α7-nAChR. In the present study, we will investigate the effects of cholinergic antiinflammatory pathway on CD4+ T cell responses in a coxsackievirus B3 murine myocarditis model. In addition, CD4+ T cells were isolated from murine splenocytes by immunomagnetic beads and cultured in vitro. The agonist and antagonist of α7-nAChR will be administered, and the right cervical vagus nerve will be cut off in the infected mice. The proportion of the Th cell subsets, levels of CD4+ T cell α7-nAChR, inflammatory cytokines, NF-κB, pJAK and pSTAT protein expression within the myocardium will be determined. The most novel insight of the study is that the nervous system may modulate the inflammatory response in viral myocaditis. The study will help elucidate the novel mechanism involved in the pathogenesis of viral myocarditis, and open new possibilities in the therapeutic management of viral myocarditis.