CD8⁺ T cell responses recognizing immunodominant Chlamydia antigens fail to protect against infection

Chlamydia trachomatis (C.t.) causes the most common bacterial sexually transmitted infection, yet no licensed vaccine exists. CD4⁺ T cells are known to protect, while the role of CD8⁺ T cells is unclear. This study examined whether CD8⁺ T cells targeting five immunodominant C.t. proteins could protect against infection. Using an in silico approach, we identified six novel CD8⁺ T cell epitopes from ArtJ, GroES, IncA, OmpH, and major outer membrane protein (MOMP). These epitopes elicited C.t.-specific CD8⁺ T cells when delivered with the cationic adjuvant formulation 09b (CAF09b) liposomal adjuvant or a lymphocytic choriomeningitis virus (LCMV) vector expressing the MOMP-based CTH522 protein. After C.t. challenge, vaccine-induced CD8⁺ T cells rapidly accumulated in the genital tract, became resident after bacterial clearance, produced effector cytokines, and showed strong cytotoxicity. However, neither single nor combined CD8⁺ T cell responses conferred protection, whereas a CD4⁺ T cell-inducing CTH522-based vaccine did. This implies that vaccine-induced CD8⁺ T cells play a minor or no role in protection against C.t.