Tumor necrosis factor alpha production from CD8⁺ T cells mediates oviduct pathological sequelae following primary genital Chlamydia muridarum Infection

The immunopathogenesis of Chlamydia trachomatis-induced oviduct pathological sequelae is not well understood. Mice genetically deficient in perforin (perforin^-/- mice) or tumor necrosis factor alpha (TNF-α) production (TNF-α^-/- mice) displayed comparable vaginal chlamydial clearance rates but significantly reduced oviduct pathology (hydrosalpinx) compared to that of wild-type mice. Since both perforin and TNF-α are effector mechanisms of CD8⁺ T cells, we evaluated the role of CD8⁺ T cells during genital Chlamydia muridarum infection and oviduct sequelae. Following vaginal chlamydial challenge, (i) mice deficient in TAP I (and therefore the major histocompatibility complex [MHC] I pathway and CD8⁺ T cells), (ii) wild-type mice depleted of CD8⁺ T cells, and (iii) mice genetically deficient in CD8 (CD8^-/- mice) all displayed similar levels of vaginal chlamydial clearance but significantly reduced hydrosalpinx, compared to those of wild-type C57BL/6 mice, suggesting a role for CD8⁺ T cells in chlamydial pathogenesis. Repletion of CD8^-/- mice with wild-type or perforin^-/-, but not TNF-α^-/-, CD8⁺ T cells at the time of challenge restored hydrosalpinx to levels observed in wild-type C57BL/6 mice, suggesting that TNF-α production from CD8⁺ T cells is important for pathogenesis. Additionally, repletion of TNF-α^-/- mice with TNF-α^+/+ CD8⁺ T cells significantly enhanced the incidence of hydrosalpinx and oviduct dilatation compared to those of TNF-α^-/- mice but not to the levels found in wild-type mice, suggesting that TNF-α production from CD8⁺ T cells and non-CD8⁺ cells cooperates to induce optimal oviduct pathology following genital chlamydial infection. These results provide compelling new evidence supporting the contribution of CD8⁺ T cells and TNF-α production to Chlamydiainduced reproductive tract sequelae.