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. 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.