Mucosal vaccination with cyclic-di-nucleotide adjuvants induces effective T cell homing and IL-17 dependent protection against <i>M. tuberculosis</i> infection

Abstract The only licensed vaccine for tuberculosis, Mycobacterium bovis Bacille Calmette-Guérin (BCG), is not reliably effective against adult pulmonary tuberculosis. A major hurdle to tuberculosis vaccine development is incomplete understanding of successful immunity against the causative agent Mycobacterium tuberculosis . Recently, we demonstrated that a protein subunit vaccine adjuvanted with STING-activating cyclic-di-nucleotides (CDNs) robustly protects against tuberculosis infection in mice. Here we show mucosal vaccination with this vaccine induces production of T cells that home to lung parenchyma and penetrate lesions in the lung. Protection is partially dependent on IL-17, type I interferon (IFN), and IFN-γ, while the transcription factor STAT-6 is dispensable. Single cell transcriptomics reveals mucosal vaccination with a CDN vaccine increases transcriptional heterogeneity in CD4 cells, including a significant population of non-classical IFN-γ and IL-17 co-expressing Th1-Th17 cells, as well as markers of memory and activation. Th1-Th17 cells in vaccinated mice are enriched for expression of the T cell functional markers Tnfsf8 and Il1r1 relative to more conventional Th1 cells. These data provide critical insight into the immune mediators and diversity of T cell responses that can contribute to vaccine efficacy against M. tuberculosis infection.