title: Tumor necrosis factor alpha production from CD8+ T cells mediates oviduct pathological sequelae following primary genital Chlamydia muridarum infection.
abstract: 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 Chlamydia-induced reproductive tract sequelae.
authors.affiliation: South Texas Center for Emerging Infectious Diseases, Department of Biology, University of Texas at San Antonio, San Antonio, Texas 78249, USA. Ashlesh.murthy@utsa.edu
authors.forename: Ashlesh K
authors.initials: AK
authors.lastname: Murthy
authors.forename: Weidang
authors.initials: W
authors.lastname: Li
authors.forename: Bharat K R
authors.initials: BK
authors.lastname: Chaganty
authors.forename: Sangamithra
authors.initials: S
authors.lastname: Kamalakaran
authors.forename: M Neal
authors.initials: MN
authors.lastname: Guentzel
authors.forename: J
authors.initials: J
authors.lastname: Seshu
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Forsthuber
authors.forename: Guangming
authors.initials: G
authors.lastname: Zhong
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Arulanandam
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002690:Chlamydia Infections / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D023502:Chlamydia muridarum; D005187:Fallopian Tubes / Q000382:microbiology / Q000473:pathology*; D005260:Female; D005831:Genital Diseases, Female / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D014621:Vagina / Q000382:microbiology
chemical_list: D014409:Tumor Necrosis Factor-alpha; D054353:Perforin