A Clinically Relevant Cationic Adjuvant System Induces Th17 T Cells Involved in Skin and Upper Airway Infections with Streptococcus pyogenes ^†

Streptococcus pyogenes (Group A Streptococcus, StrepA) is a human pathogen responsible for hundreds of millions of infections each year and remains one of the most prevalent bacterial causes of upper respiratory and skin infections worldwide. Despite its global impact, there is no approved vaccine, and the optimal protective immune response is still not fully understood. In particular, the role of Th17 T cells in immunity against StrepA remains to be explored. We have previously shown that Th17 T cells are induced in humans following StrepA infection. In this study, we investigated the role of Th17 T cells during skin and upper airway StrepA infections. To generate StrepA-specific Th17 T cells, we utilized a novel cationic liposomal adjuvant system. We demonstrated that vaccine-induced Th17 T cells are recruited to the skin and upper airways upon StrepA infection. In the airways, Th17 T cells and IgA correlate with protection, whereas Th1 T cells and IgG do not. To further characterize the recruited Th17 T cells, we used an IL-17 fate-reporter mouse model to track Th17 T cells. Our results show that Th17 T cells outnumber bona fide Th1 T cells in both StrepA-infected skin and upper airways. Surprisingly, most Th17 T cells lose expression of IL-17, and do not express TNFα, IFNγ, and IL-2. Initial single-cell sequencing data suggest the existence of multiple Th17 T cell subsets with distinct expression profiles. We discuss the functional relevance of these subsets in the context of a StrepA infection.