Inflammatory genital strain of Chlamydia trachomatis elicits a Th17 immune response

In humans, infection with Chlamydia trachomatis can result in chronic infection with severe reproductive consequences. The immune response elicited by natural infection fails to protect against reinfection and can contribute to tissue inflammation and damage. CD4+ T cells are key mediators of protection against C. trachomatis. However, these same cells, together with neutrophils, also contribute to tissue pathology. The identity and effector functions of the CD4+ T cells that contribute to protection, pathology, or both remain poorly defined. Notably, C. trachomatis pathology is serovar specific. Infection with serovar D induces severe tissue inflammation in the female upper genital tract, whereas infection with serovar L2 does not. Using a murine model of genital infection, we found that infection with serovar D selectively drives the polarization of naïve CD4+ T cells into inflammatory Th17 cells through the induction of Th17-polarizing cytokines, such as IL-1β, IL-6, and IL-23, compared with serovar L2 infection. Single-cell RNA sequencing of CD4+ T cells from the uteri of serovar D-infected mice revealed a Th17-skewed response with transcriptional features of an inflammatory phenotype, including upregulation of Bhlhe40 and Il1r1. Th17 cells have been reported to contribute to pathology through secretion of pro-inflammatory cytokines that recruit neutrophils and promote tissue damage. Together, these findings demonstrate that serovar D promotes pro-inflammatory CD4+ T-cell responses that could contribute to immunopathology in C. trachomatis infection, in contrast to the response elicited by serovar L2. They also underscore the importance of developing a vaccine that elicits protective immunity while minimizing harmful inflammatory responses.