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. 1995 Dec;63(12):4661–4668. doi: 10.1128/iai.63.12.4661-4668.1995

Gene knockout mice establish a primary protective role for major histocompatibility complex class II-restricted responses in Chlamydia trachomatis genital tract infection.

R P Morrison 1, K Feilzer 1, D B Tumas 1
PMCID: PMC173669  PMID: 7591120

Abstract

Mice with disrupted beta 2-microglobulin (beta 2m-/-), I-A (class II-/-), or CD4 (CD4-/-) genes were examined for their capacity to resolve Chlamydia trachomatis genital tract infection. C57BL/6 and beta 2m-/- mice resolved infection similarly and were culture negative by 4 to 5 weeks following infection. Conversely, major histocompatibility complex (MHC) class II-/- mice failed to resolve infection, and CD4-/- mice showed a significant delay (2 weeks). Secondary challenge of C57BL/6, beta 2m-/-, and CD4-/- mice established that acquired protective immunity, which was characterized by an infection of shortened duration and reduced shedding of infectious organisms, developed. Serological analysis of C57BL/6 and beta 2m-/- mice by enzyme-linked immunosorbent assays revealed no striking differences in the immunoglobulin subclass specificity of the anti-Chlamydia response, although some differences were observed in the magnitude of the immunoglobulin G2a (IgG2a) and IgG2b responses. Class II-/- mice produced lower-titered serum anti-Chlamydia antibodies of all isotypes. The serum antibody responses of CD4-/- mice were similar to those of C57BL/6 mice, except that the anti-Chlamydia IgA response was delayed by approximately 3 weeks. Analysis of vaginal washes for Chlamydia-reactive antibodies revealed the presence of IgG2a, IgG2b, and IgA in C57BL/6 and beta 2m-/- mice and primarily of IgA in CD4-/- mice. Vaginal washes from class II-/- mice were consistently antibody negative. Interestingly, the Chlamydia-specific IgA response in the vaginal washes of CD4-/- mice was delayed, but its appearance coincided with decreased shedding of infectious organisms and resolution of infection. Our results demonstrate that MHC class II-restricted T-cell responses are necessary for the development of protective immunity to Chlamydia genital tract infection and that local (vaginal) anti-Chlamydia IgA antibody coincides with the resolution of infection. A substantive role for MHC class I-restricted T-cell responses in protective immunity to Chlamydia genital tract infection was not confirmed.

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Selected References

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  1. Apasov S., Sitkovsky M. Highly lytic CD8+, alpha beta T-cell receptor cytotoxic T cells with major histocompatibility complex (MHC) class I antigen-directed cytotoxicity in beta 2-microglobulin, MHC class I-deficient mice. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2837–2841. doi: 10.1073/pnas.90.7.2837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Batteiger B. E., Rank R. G. Analysis of the humoral immune response to chlamydial genital infection in guinea pigs. Infect Immun. 1987 Aug;55(8):1767–1773. doi: 10.1128/iai.55.8.1767-1773.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beatty P. R., Stephens R. S. CD8+ T lymphocyte-mediated lysis of Chlamydia-infected L cells using an endogenous antigen pathway. J Immunol. 1994 Nov 15;153(10):4588–4595. [PubMed] [Google Scholar]
  4. Bodmer H., Obert G., Chan S., Benoist C., Mathis D. Environmental modulation of the autonomy of cytotoxic T lymphocytes. Eur J Immunol. 1993 Jul;23(7):1649–1654. doi: 10.1002/eji.1830230738. [DOI] [PubMed] [Google Scholar]
  5. Brunham R. C., Kuo C. C., Cles L., Holmes K. K. Correlation of host immune response with quantitative recovery of Chlamydia trachomatis from the human endocervix. Infect Immun. 1983 Mar;39(3):1491–1494. doi: 10.1128/iai.39.3.1491-1494.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Caldwell H. D., Kromhout J., Schachter J. Purification and partial characterization of the major outer membrane protein of Chlamydia trachomatis. Infect Immun. 1981 Mar;31(3):1161–1176. doi: 10.1128/iai.31.3.1161-1176.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Correa I., Bix M., Liao N. S., Zijlstra M., Jaenisch R., Raulet D. Most gamma delta T cells develop normally in beta 2-microglobulin-deficient mice. Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):653–657. doi: 10.1073/pnas.89.2.653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Eichelberger M., Allan W., Zijlstra M., Jaenisch R., Doherty P. C. Clearance of influenza virus respiratory infection in mice lacking class I major histocompatibility complex-restricted CD8+ T cells. J Exp Med. 1991 Oct 1;174(4):875–880. doi: 10.1084/jem.174.4.875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Flynn J. L., Goldstein M. M., Triebold K. J., Koller B., Bloom B. R. Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12013–12017. doi: 10.1073/pnas.89.24.12013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. GRAYSTON J. T., WOOLRIDGE R. L., WANG S. Trachoma vaccine studies on Taiwan. Ann N Y Acad Sci. 1962 Mar 5;98:352–367. doi: 10.1111/j.1749-6632.1962.tb30558.x. [DOI] [PubMed] [Google Scholar]
  11. Grusby M. J., Johnson R. S., Papaioannou V. E., Glimcher L. H. Depletion of CD4+ T cells in major histocompatibility complex class II-deficient mice. Science. 1991 Sep 20;253(5026):1417–1420. doi: 10.1126/science.1910207. [DOI] [PubMed] [Google Scholar]
  12. Igietseme J. U., Magee D. M., Williams D. M., Rank R. G. Role for CD8+ T cells in antichlamydial immunity defined by Chlamydia-specific T-lymphocyte clones. Infect Immun. 1994 Nov;62(11):5195–5197. doi: 10.1128/iai.62.11.5195-5197.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Igietseme J. U., Ramsey K. H., Magee D. M., Williams D. M., Kincy T. J., Rank R. G. Resolution of murine chlamydial genital infection by the adoptive transfer of a biovar-specific, Th1 lymphocyte clone. Reg Immunol. 1993 Nov-Dec;5(6):317–324. [PubMed] [Google Scholar]
  14. Katz B. P., Batteiger B. E., Jones R. B. Effect of prior sexually transmitted disease on the isolation of Chlamydia trachomatis. Sex Transm Dis. 1987 Jul-Sep;14(3):160–164. doi: 10.1097/00007435-198707000-00008. [DOI] [PubMed] [Google Scholar]
  15. Kaufmann S. H. Immunity to intracellular bacteria. Annu Rev Immunol. 1993;11:129–163. doi: 10.1146/annurev.iy.11.040193.001021. [DOI] [PubMed] [Google Scholar]
  16. Killeen N., Sawada S., Littman D. R. Regulated expression of human CD4 rescues helper T cell development in mice lacking expression of endogenous CD4. EMBO J. 1993 Apr;12(4):1547–1553. doi: 10.1002/j.1460-2075.1993.tb05798.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Koller B. H., Smithies O. Inactivating the beta 2-microglobulin locus in mouse embryonic stem cells by homologous recombination. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8932–8935. doi: 10.1073/pnas.86.22.8932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lammert J. K. Cytotoxic cells induced after Chlamydia psittaci infection in mice. Infect Immun. 1982 Mar;35(3):1011–1017. doi: 10.1128/iai.35.3.1011-1017.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Landers D. V., Erlich K., Sung M., Schachter J. Role of L3T4-bearing T-cell populations in experimental murine chlamydial salpingitis. Infect Immun. 1991 Oct;59(10):3774–3777. doi: 10.1128/iai.59.10.3774-3777.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Magee D. M., Williams D. M., Smith J. G., Bleicker C. A., Grubbs B. G., Schachter J., Rank R. G. Role of CD8 T cells in primary Chlamydia infection. Infect Immun. 1995 Feb;63(2):516–521. doi: 10.1128/iai.63.2.516-521.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mosmann T. R., Schumacher J. H., Street N. F., Budd R., O'Garra A., Fong T. A., Bond M. W., Moore K. W., Sher A., Fiorentino D. F. Diversity of cytokine synthesis and function of mouse CD4+ T cells. Immunol Rev. 1991 Oct;123:209–229. doi: 10.1111/j.1600-065x.1991.tb00612.x. [DOI] [PubMed] [Google Scholar]
  22. Muller D., Koller B. H., Whitton J. L., LaPan K. E., Brigman K. K., Frelinger J. A. LCMV-specific, class II-restricted cytotoxic T cells in beta 2-microglobulin-deficient mice. Science. 1992 Mar 20;255(5051):1576–1578. doi: 10.1126/science.1347959. [DOI] [PubMed] [Google Scholar]
  23. Pavia C. S., Schachter J. Failure to detect cell-mediated cytotoxicity against Chlamydia trachomatis-infected cells. Infect Immun. 1983 Mar;39(3):1271–1274. doi: 10.1128/iai.39.3.1271-1274.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Qvigstad E., Hirschberg H. Lack of cell-mediated cytotoxicity towards Chlamydia trachomatis infected target cells in humans. Acta Pathol Microbiol Immunol Scand C. 1984 Jun;92(3):153–159. doi: 10.1111/j.1699-0463.1984.tb00067.x. [DOI] [PubMed] [Google Scholar]
  25. Ramsey K. H., Newhall W. J., 5th, Rank R. G. Humoral immune response to chlamydial genital infection of mice with the agent of mouse pneumonitis. Infect Immun. 1989 Aug;57(8):2441–2446. doi: 10.1128/iai.57.8.2441-2446.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ramsey K. H., Rank R. G. Resolution of chlamydial genital infection with antigen-specific T-lymphocyte lines. Infect Immun. 1991 Mar;59(3):925–931. doi: 10.1128/iai.59.3.925-931.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rank R. G., Barron A. L. Humoral immune response in acquired immunity to chlamydial genital infection of female guinea pigs. Infect Immun. 1983 Jan;39(1):463–465. doi: 10.1128/iai.39.1.463-465.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rank R. G., Batteiger B. E. Protective role of serum antibody in immunity to chlamydial genital infection. Infect Immun. 1989 Jan;57(1):299–301. doi: 10.1128/iai.57.1.299-301.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rank R. G., Batteiger B. E., Soderberg L. S. Susceptibility to reinfection after a primary chlamydial genital infection. Infect Immun. 1988 Sep;56(9):2243–2249. doi: 10.1128/iai.56.9.2243-2249.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rank R. G., Soderberg L. S., Barron A. L. Chronic chlamydial genital infection in congenitally athymic nude mice. Infect Immun. 1985 Jun;48(3):847–849. doi: 10.1128/iai.48.3.847-849.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rank R. G., White H. J., Barron A. L. Humoral immunity in the resolution of genital infection in female guinea pigs infected with the agent of guinea pig inclusion conjunctivitis. Infect Immun. 1979 Nov;26(2):573–579. doi: 10.1128/iai.26.2.573-579.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Roberts A. D., Ordway D. J., Orme I. M. Listeria monocytogenes infection in beta 2 microglobulin-deficient mice. Infect Immun. 1993 Mar;61(3):1113–1116. doi: 10.1128/iai.61.3.1113-1116.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rothermel C. D., Byrne G. I., Havell E. A. Effect of interferon on the growth of Chlamydia trachomatis in mouse fibroblasts (L cells). Infect Immun. 1983 Jan;39(1):362–370. doi: 10.1128/iai.39.1.362-370.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schachter J., Cles L. D., Ray R. M., Hesse F. E. Is there immunity to chlamydial infections of the human genital tract? Sex Transm Dis. 1983 Jul-Sep;10(3):123–125. doi: 10.1097/00007435-198307000-00004. [DOI] [PubMed] [Google Scholar]
  35. Starnbach M. N., Bevan M. J., Lampe M. F. Protective cytotoxic T lymphocytes are induced during murine infection with Chlamydia trachomatis. J Immunol. 1994 Dec 1;153(11):5183–5189. [PubMed] [Google Scholar]
  36. Su H., Caldwell H. D. Immunogenicity of a synthetic oligopeptide corresponding to antigenically common T-helper and B-cell neutralizing epitopes of the major outer membrane protein of Chlamydia trachomatis. Vaccine. 1993;11(11):1159–1166. doi: 10.1016/0264-410x(93)90080-h. [DOI] [PubMed] [Google Scholar]
  37. Su H., Morrison R. P., Watkins N. G., Caldwell H. D. Identification and characterization of T helper cell epitopes of the major outer membrane protein of Chlamydia trachomatis. J Exp Med. 1990 Jul 1;172(1):203–212. doi: 10.1084/jem.172.1.203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Tuffrey M., Falder P., Taylor-Robinson D. Effect on Chlamydia trachomatis infection of the murine genital tract of adoptive transfer of congenic immune cells or specific antibody. Br J Exp Pathol. 1985 Aug;66(4):427–433. [PMC free article] [PubMed] [Google Scholar]
  39. Tuffrey M., Falder P., Taylor-Robinson D. Genital-tract infection and disease in nude and immunologically competent mice after inoculation of a human strain of Chlamydia trachomatis. Br J Exp Pathol. 1982 Oct;63(5):539–546. [PMC free article] [PubMed] [Google Scholar]
  40. Wang S. P., Grayston J. T., Alexander E. R. Trachoma vaccine studies in monkeys. Am J Ophthalmol. 1967 May;63(5 Suppl):1615–1630. doi: 10.1016/0002-9394(67)94155-4. [DOI] [PubMed] [Google Scholar]
  41. Williams D. M., Byrne G. I., Grubbs B., Marshal T. J., Schachter J. Role in vivo for gamma interferon in control of pneumonia caused by Chlamydia trachomatis in mice. Infect Immun. 1988 Nov;56(11):3004–3006. doi: 10.1128/iai.56.11.3004-3006.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Williams D. M., Schachter J., Weiner M. H., Grubbs B. Antibody in host defense against mouse pneumonitis agent (murine Chlamydia trachomatis). Infect Immun. 1984 Sep;45(3):674–678. doi: 10.1128/iai.45.3.674-678.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Woolridge R. L., Grayston J. T., Chang I. H., Cheng K. H., Yang C. Y., Neave C. Field trial of a monovalent and of a bivalent mineral oil adjuvant trachoma vaccine in Taiwan school children. Am J Ophthalmol. 1967 May;63(5 Suppl):1645–1650. doi: 10.1016/0002-9394(67)94158-x. [DOI] [PubMed] [Google Scholar]
  44. Yuan Y., Lyng K., Zhang Y. X., Rockey D. D., Morrison R. P. Monoclonal antibodies define genus-specific, species-specific, and cross-reactive epitopes of the chlamydial 60-kilodalton heat shock protein (hsp60): specific immunodetection and purification of chlamydial hsp60. Infect Immun. 1992 Jun;60(6):2288–2296. doi: 10.1128/iai.60.6.2288-2296.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Zhong G. M., Peterson E. M., Czarniecki C. W., de la Maza L. M. Recombinant murine gamma interferon inhibits Chlamydia trachomatis serovar L1 in vivo. Infect Immun. 1988 Jan;56(1):283–286. doi: 10.1128/iai.56.1.283-286.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Zijlstra M., Auchincloss H., Jr, Loring J. M., Chase C. M., Russell P. S., Jaenisch R. Skin graft rejection by beta 2-microglobulin-deficient mice. J Exp Med. 1992 Apr 1;175(4):885–893. doi: 10.1084/jem.175.4.885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Zijlstra M., Bix M., Simister N. E., Loring J. M., Raulet D. H., Jaenisch R. Beta 2-microglobulin deficient mice lack CD4-8+ cytolytic T cells. Nature. 1990 Apr 19;344(6268):742–746. doi: 10.1038/344742a0. [DOI] [PubMed] [Google Scholar]

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