呼吸道上皮细胞和Th17细胞构成的正反馈免疫回路在鞭毛素佐剂增强的黏膜IgA应答中的作用研究

鞭毛素是一种高效增强黏膜IgA应答的鼻腔黏膜佐剂。高表达TLR5的呼吸道上皮细胞(REC)是经鼻免疫过程中最先感知鞭毛素的细胞。我们的早期工作证明了TLR5-REC通过分泌细胞因子介导DC活化并调节黏膜IgA应答，近来又发现鞭毛素可在呼吸道有效诱导抗原特异性Th17应答。文献显示Th17细胞既可促进上皮细胞细胞因子的分泌又可上调IgA转运受体pIgR的表达。这提示我们，TLR5通路活化的REC通过细胞因子的桥梁作用诱导Th17应答，Th17细胞通过分泌细胞因子反作用于REC，二者构成一个正反馈的免疫回路，通过促进IgA的合成与分泌推动黏膜IgA应答。本项目将从REC和Th17细胞的交互作用层面，证明TLR5-REC/Th17回路并阐明其免疫学特征及其在鞭毛素增强的黏膜IgA应答中的作用。本研究不但能深入阐明鞭毛素的免疫调节作用及鼻腔黏膜佐剂机制，更将有助于揭示呼吸道黏膜免疫应答的独特机制。

It is well known that flagellin is an effective intranasal adjuvant which efficiently promotes mucosal IgA production and immune protection. Respiratory epithelial cells (REC), with high expression of TLR5, are the first sensing cells of flagellin in the process of intranasal immunization. Our previous work demonstrated that TLR5 signal pathway activated REC (TLR5-REC) regulates DC activation and IgA enhancement via secretion of cytokines. More importantly, we recently found that flagellin can also induce antigen specific Th17 responses in the respiratory tract. It was reported that Th17 cells not only promotes the secretion of cytokines but also up-regulates the expression of IgA transporter pIgR in epithelial cells. Together, we speculated that TLR5-REC cross-talks with Th17 cells and forms a positive feedback immune loop: TLR5-REC enhances Th17 induction via cytokines while the induced Th17 cells reversely regulate REC also via cytokines. The immune loop promotes the synthesis and secretion of IgA thus enhances mucosal IgA responses. Based on the hypothesis and our previous work, with cell and mouse models, this project intends to certify the existence and analyze the immunological features of the TLR5-REC/Th17 loop. Moreover, the contribution of this loop in regulating mucosal IgA enhancement by intranasal flagellin will be elucidated. This study will further clarify the immune-modulatory effect of flagellin and the mechanism of mucosal adjuvant, and help to reveal the unique mechanism of the local immune response in the respiratory tract.