CTH522/CAF01 vaccination elicits clonally related Th17 subsets that mediate IL-17A–dependent protection against Chlamydia trachomatis

Abstract Chlamydia trachomatis is the leading bacterial sexually transmitted pathogen worldwide and a major cause of reproductive tract disease, highlighting the need for an effective vaccine. Defining the immune mechanisms underlying vaccine-induced protection is therefore critical. We previously demonstrated that in mice vaccinated with CTH522/CAF01, genital tract Th17 cells correlated with protection against both infection and pathology. In this study, we further characterized these vaccine-induced Th17 cells in an infected genital tract. Fate-mapping and single-cell transcriptomic analyses revealed that CTH522/CAF01 vaccination generated multiple Th17-derived subsets, including a large memory-like population as well as effector Th17 and Th17-derived Th1-like subsets. These subsets shared common TCR clonotypes, and RNA velocity analyses predicted a unified differentiation trajectory, with one precursor population seeding both effector lineages. Our findings demonstrate a high degree of plasticity within the Th17 population and reveals previously uncharacterized Th17 subsets present during infection with C. trachomatis. Functional studies demonstrated that the Th17 subset that produced IL-17A was essential for early bacterial control, whereas IFN-γ–producing Th1 cells and Th17-derived Th1-like cells were not. Collectively, our findings provide mechanistic insight into Th17 biology and redefine the importance of IL-17A producing Th17 cells in early vaccine-mediated protection against C. trachomatis.