Circulating Chlamydia trachomatis -specific T Cell Immunity Reflects Widespread Exposure in South African Adolescents and Young Women

Chlamydia trachomatis remains the most prevalent bacterial sexually transmitted infection worldwide, with adolescent girls and young women (AGYW) disproportionately affected. Despite this, vaccine development is hindered by our limited understanding of protective immunity, particularly in the context of recurrent infections and immune-mediated pathology. Here, we characterised 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 anti- C. trachomatis IgG levels. Cervicovaginal cytokines were quantified from menstrual cup secretions, and cervical and peripheral blood T cell activation assessed by flow cytometry. CD4+ T cell responses to recombinant MOMP were measured in a subset of 46 women who were NAAT-positive and/or seropositive. Untreated or recurrent C. trachomatis infection (NAAT+/IgG+) was associated with increased cervical T cell activation. All women with untreated or recurrent infections had detectable circulating C. trachomatis -specific CD4+ T cells in blood; however, response magnitude was 2.4-fold lower than in women with cleared or primary infections. Women with cleared infection had the highest proportions of C. trachomatis -specific multifunctional CD4+ T cells, while those with untreated or recurrent infections had almost none. Notably, systemic C. trachomatis -specific Th1 responses were inversely correlated with genital tract concentrations of inflammatory cytokines including IL-1β, TNF, and IL-17. These findings demonstrate that 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, which has important implications for vaccine strategies and evaluation in high-risk populations.