Invariant and Diverse NKT Cells Regulate Bacterial Clearance and Pathology in Chlamydial Genital Tract Infection in Mice

<i>Chlamydia trachomatis</i> infection causes pelvic inflammatory disease and infertility, but how host immune factors control pathogen clearance or pathology is not fully understood. Using a mouse model of genital tract infection with <i>Chlamydia muridarum</i>, we examined the role of CD1d-restricted Natural killer T (NKT) cells. Invariant NKT cell-deficient mice (Jα18^-/-) showed prolonged vaginal shedding of infectious elementary bodies (EBs), delayed clearance, and decreased early cytokine production compared to wild-type (WT) controls. Conversely, CD1d^-/- mice, which lack both invariant and diverse NKT cells, did not show significant differences in vaginal shedding compared to WT mice. Surprisingly, both NKT-deficient mice (Jα18^-/- and CD1d^-/-) produced higher levels of inflammatory cytokines in the oviduct at day 35 post-infection (p.i.) and experienced more frequent upper genital tract pathology (hydrosalpinx) at day 80 p.i. However, no infectious EBs were recovered from the oviducts or uterine horns of NKT-deficient mice after day 35 p.i. Cortisone acetate reactivated infectious shedding in chronically infected NKT-deficient mice at day 100 p.i. These findings highlight distinct roles for NKT cell subsets: invariant NKT cells promote early clearance via rapid cytokine production, while the broader NKT population helps limit tissue damage. Targeting NKT pathways could help prevent chronic infection and infertility.