病毒感染中肺局部的B细胞免疫反应及其调控机制研究

近期的研究提示肺部炎症微环境是B细胞激活、分化及发挥效应功能的重要外源机制。本课题组前期研究发现：流感病毒感染导致具有固有免疫特征的B-1细胞在肺组织浸润，并分泌天然抗体（natural antibody）参与早期抗病毒免疫反应，促进了呼吸道的病毒清除。我们尚发现IL-17A信号缺失导致B-1细胞的抗体分泌受损，提示流感病毒感染诱导的IL-17A调节了B-1细胞的抗病毒反应。为证实这一假说，我们拟进行如下研究：以IL-17A缺失小鼠为模型，通过离体和在体实验探讨IL-17A调控B-1细胞分化及功能的分子机制；以嵌合鼠和抗体介导的细胞清除手段进一步阐明IL-17A分泌型γδT细胞对B-1细胞的功能调节。本研究有助于深入理解B-1细胞在病毒感染中的保护作用及肺局部炎症微环境的调节机理，并为流感病毒感染中靶向B-1细胞的免疫治疗提供新的线索。

B cells perform their important immune function by producing antibodies in anti-viral immunity. Recent studies indicate that pulmonary inflammatory microenvironment contributes critically to the activation、chemotaxis and effector functions of B cells. Our pilot animal studies found that influenza infection induced early pulmonary infiltration of B-1 cells for producing natural antibodies against viral infection. Moreover, B-1 derived natural antibody production in respiratory tract was severely impaired in IL-17A deficient (Il17a-/-) mice,indicating a crtical role of IL-17A in modulating B-1 cell respone. To test this hypothesis, we will use Il17a-/- mice to characterize the function of IL-17A signaling in moduating B-1 cell differentiation and effector functions both in vivo and in vitro. Furthermore,we will generate chimeric mouse models with B-1 cell depletion and antibody-mediated γδT cell depletion to further investigate the role of IL-17A-producing γδT cell in modulating B-1 cell response. Together, this project will illucidate the molecular mechanisms underlying the interactions between pulmonary inflammatory microenvionment and innate response of B-1 cells during influenza infection, which may contribute to the development of potential therapeutic intervention for human influenza disease.