肺脏γδ T细胞的区域免疫特性及其在抗病毒免疫反应中的功能研究

Many studies have indicated that the lung is an organ with unique regional immune characteristics. Our pilot studies found that lung infiltration of B-1 cells with natural antibody production occurred at early stage of influenza virus infection. Moreover, we identified a γδTCRhiCD3hi T cell population that predominantly produced IL-17A in influenza-infected lungs and promoted plasmacytic differentiation of B-1 cells and natural antibody production. Recently, we successfully established human tissue-resident adult stem cell-derived airway organoids for studying viral infection and immune response. Current studies on pulmonary immune response are mainly focused on the draining mediastinal lymph nodes (MedLN), but littler is known about the regional immunity in the lung tissue and local inducible bronchus-associated lymphoid tissue (iBALT). In this project, we will examine the kinetic changes and functional interactions between γδ T and B cells in the lung tissue of mice infected with influenza virus and lymphocytic choriomeningitis virus (LCMV). Moreover, we will further elucidate the cellular and molecular mechanisms by which lung microenvironment regulates regional immune characteristics and anti-viral functions of γδT cells using various research platforms including human tissue-resident adult stem cell-derived airway organoids, human patient lung biopsy, single cell sequencing, humanized mouse models, and two photon in vivo imaging technology. The proposed studies will provide new insights in understanding the characteristics of lung regional immunity, which may facilitate the development of new therapeutic strategies for infection treatment and vaccine development.

近年的研究提示肺脏具有独特的免疫微环境及区域反应特性。我们的前期研究首次发现B-1细胞在病毒感染早期浸润肺组织并分泌特异性中和抗体，并鉴定出具有CD3hiγδTCRhi IL-17A+ 表型的γδ T细胞参与调节B-1细胞分化和抗体分泌。近期我们成功建立了人类组织驻留成体干细胞来源的呼吸道类器官研究平台。目前对肺组织局部及诱导性支气管相关淋巴样组织中的免疫反应及其区域免疫学特性了解甚少。本项目将运用病毒感染模型、人源化小鼠、人类呼吸道类器官、病人肺组织样本，双光子成像、单细胞测序等技术平台，在分子、细胞、动物模型及临床样本等水平，系统研究肺脏微环境对γδ T细胞区域免疫特性及其对抗病毒免疫反应的调控，解析肺部免疫反应启动阶段“上皮细胞-γδ T细胞-B细胞轴”调控机理。预期研究结果将有助于阐明肺脏区域微环境对γδ T和B细胞亚群分化和功能的调控机制，对肺部病毒感染的预防及治疗具有重要意义。

近年的研究提示肺脏具有独特的免疫微环境及区域反应特性。但目前对肺组织局部及诱导性支气管相关淋巴样组织中的免疫反应及其区域免疫学特性了解甚少。先天免疫通过引发快速抗病毒反应和连接适应性免疫在宿主防御中是十分重要。本课题中，利用流感小鼠模型，我们发现病毒感染的宿主细胞释放的内源性脂质可以激活肺γδ T细胞产生白介素17A (IL-17A)，从而用于早期预防H1N1流感感染。单细胞鉴定出γδ T细胞具有独特的表型。病毒感染期间γδT 细胞通过IRF4 依赖性转录来激活 γδ T 细胞中的 IL-17A 产生。我们的研究确定了肺部免疫反应启动阶段“上皮细胞-γδT细胞-B细胞轴”调控机理。我们的研究结果将有助于阐明肺脏区域微环境对γδ T和B细胞亚群分化和功能的调控机制，对肺部病毒感染的预防及治疗具有重要意义。