Lung epithelial signaling mediates early vaccine-induced CD4+ T cell activation and Mtb control

Tuberculosis (TB) is the leading cause of death due to a single infectious agent. The development of a TB vaccine that induces durable and effective immunity to Mycobacterium tuberculosis (Mtb) infection is urgently needed. Complete and early Mtb control can be induced in M. bovis Bacillus Calmette–Guérin (BCG) vaccinated hosts when the innate immune response is targeted to generate effective vaccine-induced immunity. In the present study, we show that the superior and early Mtb control that is mediated by innate activation of DCs is associated with mucosal localization of clonal activated vaccine-induced CD4+ T cells in the lung. Our studies also show that the lung epithelial cell signaling through the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB pathway is critical for the mucosal localization of activated vaccine-induced CD4+ T cells for rapid Mtb control. Thus, our study provides novel insights into the immune mechanisms that can overcome TB vaccine bottlenecks and provide early rapid Mtb control. Overall design: Lung cells were isolated from Mtb-infected unvaccinated mice (Unvac), Mtb-infected BCG vaccinated mice (Vac), and Mtb-infected BCG vaccinated mice that received Z-DC transfer (Vac+Z-DC) and subjected to single cell RNA sequencing (scRNA-Seq) to define immune cell populations driving enhanced vaccine-induced immunity.

结核病（TB）是单一传染性病原体导致死亡的首要病因。研发可诱导针对结核分枝杆菌（Mycobacterium tuberculosis, Mtb）感染产生持久有效免疫的结核疫苗，仍是当前亟需攻克的研发目标。在接种牛分枝杆菌卡介苗（Mycobacterium bovis Bacillus Calmette-Guérin, BCG）的宿主中，若靶向调控固有免疫应答以诱导有效的疫苗介导免疫，即可实现对结核分枝杆菌的完全早期控制。本研究证实，由树突状细胞（Dendritic Cells, DCs）固有激活所介导的优异早期结核分枝杆菌控制效果，与肺内克隆活化的疫苗诱导CD4+ T细胞的黏膜定位密切相关。本研究同时发现，肺上皮细胞通过激活核因子κ轻链增强子（nuclear factor kappa-light-chain-enhancer of activated B cells, NF-κB，即NFKB通路）所介导的信号通路，对于活化的疫苗诱导CD4+ T细胞的黏膜定位以快速控制结核分枝杆菌至关重要。因此，本研究为破解结核疫苗研发瓶颈、实现结核分枝杆菌的早期快速控制提供了全新的免疫机制视角。总体实验设计：从结核分枝杆菌感染的未免疫小鼠（Unvac）、结核分枝杆菌感染的卡介苗免疫小鼠（Vac），以及接受Z-DC转输的结核分枝杆菌感染卡介苗免疫小鼠（Vac+Z-DC）中分离肺脏细胞，通过单细胞RNA测序（single cell RNA sequencing, scRNA-Seq）解析介导增强型疫苗诱导免疫的免疫细胞群特征。