上皮细胞外泌体调节树突状细胞成熟诱发Th2免疫应答及其机制

An aberrant Th2 immune response plays a central role in the pathogenesis of asthma. Dendritic cells (DCs) are the most important antigen-presenting cells (APCs) priming Th2 cell differentiation. Studies had showed that the airway epithelial cells critically participate in the regulation of DCs maturation in the lung compartmental immune micro-environment. However, the underlying mechanisms, in which DCs response to allergens in vivo, remain to be elucidated. Recently, we found that airway epithelial cells stimulated by ovalbumin (OVA), could release exosomes, which heavily involved in cell-cell communication, as well as cytokines including thymic stromal lymphopoietin (TSLP). We further uncovered that exosomes could induce the expression of multiple molecular markers such as CD40, CD80/86, and MHC II, which indicated that exosomes could induce DCs maturation. Numerous studies had demonstrated TNF receptor-associated factor 6 (TRAF6), a signal transducer in the NF-κB pathway, is critical for the differentiation and function of a DC subset, which appears to be specialized for regulation of Th2 cell responses. Importantly, we observed that the level of TRAF6 mRNA was significantly increased in the DCs following exosome stimulation. Taken together, we suppose that exosomes derived from airway epithelial cells following OVA stimulation, may regulate the expression of TRAF6, subsequently activating NF-κB pathway in adjacent immature DCs, then inducing a Th2-priming DC subset, which is crucial for the initiating Th2 immune responses, leading to allergic airway inflammation. In current study, we aim to investigate the pathogenesis of asthma, thus to provide for a potential immune therapy target for this disease.

Th2型免疫反应异常是哮喘的重要机制。树突状细胞（DCs）是诱发Th2细胞分化的重要抗原递呈细胞（APCs）。研究证实在肺组织区域免疫中，气道上皮细胞调控DCs成熟诱发Th2应答，但DCs是如何应答及其机制目前尚未阐明。课题组前期发现OVA刺激上皮细胞后，除分泌TSLP等细胞因子外，且可释放外泌体。外泌体在细胞通讯中发挥重要作用。我们发现外泌体上调未成熟DCs MHC II、CD40、CD80及CD86表达，提示能诱导DCs成熟。TRAF6对倾向于诱导Th2型细胞的DCs亚型分化和成熟是不可或缺的。我们进一步发现外泌体上调未成熟DCs中NF-κB信号通路上游分子TRAF6 mRNA水平。由此假设OVA入肺组织刺激气道上皮细胞释放外泌体，后者作用于邻近未成熟DCs上调TRAF6、激活NF-κB通路由此分化为倾向于诱导Th2细胞的DCs亚型，以此进一步阐释哮喘发生机制，为临床提供新的治疗靶点。

Th2型免疫反应异常是哮喘的重要机制。树突状细胞（DCs）是诱发Th2细胞分化的重要抗原递呈细胞（APCs）。研究证实在肺组织区域免疫中，气道上皮细胞调控DCs成熟诱发Th2应答，但DCs是如何应答及其机制目前尚未阐明。我们发现上皮细胞外泌体致敏联合HDM激发可模拟嗜酸性粒细胞哮喘模型，提示上皮细胞来源外泌体在哮喘中发挥作用。阻断外泌体分泌减少肺DCs比例，过继回输HDM刺激上皮细胞来源外泌体可上调肺DCs数量。而上皮细胞来源外泌体富含contactin-1（CNTN1），可传递至DCs，且可能通过Notch信号通路调控其增殖及活化。本研究阐明了气道上皮细胞释放外泌体，传递CNTN1并调控DCs进而参与Th2应答，为临床治疗提供了理论基础及潜在靶点。