Abstract
BACKGROUND: Chlamydia trachomatis remains the most prevalent bacterial sexually transmitted infection worldwide, disproportionately affecting adolescent girls and young women (AGYW). Vaccine development is hindered by a limited understanding of protective immunity, particularly in the context of multiple exposures and immunopathology. METHODS: We characterized mucosal inflammation and systemic immune responses to C. trachomatis in South African AGYW (n = 145), stratified by exposure history based on nucleic acid amplification testing (NAAT) and serology (Ab). Specifically, cervicovaginal cytokines, cervical T cell activation, and C. trachomatis-specific CD4+ T cell responses were assessed. RESULTS: A NAAT+/Ab + status, signifying untreated/recurrent infection, was associated with increased cervical T cell activation. These women all had detectable C. trachomatis-specific CD4+ T cells in blood; however, the magnitude of the response was 2.4-fold lower than in NAAT-/Ab + (cleared infection) or NAAT+/Ab- (primary infection) groups. C. trachomatis-specific multifunctional CD4+ T cells were highest in NAAT-/Ab + women, and nearly absent in those who were NAAT+/Ab +. Notably, systemic C. trachomatis-specific Th1 responses were overall inversely correlated with genital tract concentrations of inflammatory cytokines, including IL-1β, TNF, and IL-17A. CONCLUSIONS: Both the magnitude and quality of the systemic CD4+ T cell responses are critical components of protective immunity to C. trachomatis and may limit mucosal immunopathology, informing vaccine strategies in high-risk populations.