Skip to main content
PMC home page
Immunology logoLink to Immunology
. 1996 Jan;87(1):1–8.

The molecular mechanism of T-cell control of Chlamydia in mice: role of nitric oxide.

J U Igietseme 1
PMCID: PMC1383960  PMID: 8666420

Abstract

T-cell mediated immunity (CMI) is crucial for protection against genital chlamydial infection in mice. To define the underlying molecular mechanism for this protection, several T-cell clones generated against the Chlamydia trachomatis agent of mouse pneumonitis (MoPn) were analysed in an in vitro model of the mucosal epithelium, the polarized epithelial-lymphocyte co-culture (PELC) system, for immunobiological functions that correlated with chlamydial inhibition. The six clones analysed were classified as protective or non-protective on the basis of their ability to cure genital chlamydial infection in syngeneic mice. The results revealed a direct relationship between the ability of a clone to protect in vivo and to inhibit the multiplication of MoPn in vitro. Also, the protective ability of a clone correlated with its capacity to elaborate relatively high levels of interferon-gamma (IFN-gamma) and to induce nitric oxide (NO) production. Moreover, neutralizing anti-IFN-gamma antibodies used alone at 50 micrograms/ml or in combination with anti-tumour necrosis-factor (TNF-alpha), and the L-arginine analogue and NO synthase inhibitor, NG-monomethyl-L-arginine monoacetate (MLA), could significantly suppress the ability of protective clones to inhibit MoPn in epithelial cells. The results suggested that the IFN-gamma-inducible NO synthease pathway is important for chlamydial control in mice. Furthermore, IFN-gamma could stimulate infected murine epithelial cells (line TM3) to secrete NO, resulting in inhibition of MoPn growth. However, the degree of MoPn inhibition obtained with IFN-gamma alone was less than that observed when T cells were co-cultured with infected epithelial cells. T-cell-derived NO could partly explain the enhanced chlamydial inhibition when T cells were co-cultured with infected epithelial cells. These results are consistent with the hypothesis that, besides T-cell-derived IFN-gamma, other factors associated with lymphoepithelial interactions are likely to contribute an important role in chlamydial control by T cells in mice.

Full text

PDF
1

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ankarcrona M., Dypbukt J. M., Brüne B., Nicotera P. Interleukin-1 beta-induced nitric oxide production activates apoptosis in pancreatic RINm5F cells. Exp Cell Res. 1994 Jul;213(1):172–177. doi: 10.1006/excr.1994.1187. [DOI] [PubMed] [Google Scholar]
  2. Arno J. N., Ricker V. A., Batteiger B. E., Katz B. P., Caine V. A., Jones R. B. Interferon-gamma in endocervical secretions of women infected with Chlamydia trachomatis. J Infect Dis. 1990 Dec;162(6):1385–1389. doi: 10.1093/infdis/162.6.1385. [DOI] [PubMed] [Google Scholar]
  3. Byrne G. I., Krueger D. A. Lymphokine-mediated inhibition of Chlamydia replication in mouse fibroblasts is neutralized by anti-gamma interferon immunoglobulin. Infect Immun. 1983 Dec;42(3):1152–1158. doi: 10.1128/iai.42.3.1152-1158.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Byrne G. I., Lehmann L. K., Landry G. J. Induction of tryptophan catabolism is the mechanism for gamma-interferon-mediated inhibition of intracellular Chlamydia psittaci replication in T24 cells. Infect Immun. 1986 Aug;53(2):347–351. doi: 10.1128/iai.53.2.347-351.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cameron M. L., Granger D. L., Weinberg J. B., Kozumbo W. J., Koren H. S. Human alveolar and peritoneal macrophages mediate fungistasis independently of L-arginine oxidation to nitrite or nitrate. Am Rev Respir Dis. 1990 Dec;142(6 Pt 1):1313–1319. doi: 10.1164/ajrccm/142.6_Pt_1.1313. [DOI] [PubMed] [Google Scholar]
  6. Denis M. Tumor necrosis factor and granulocyte macrophage-colony stimulating factor stimulate human macrophages to restrict growth of virulent Mycobacterium avium and to kill avirulent M. avium: killing effector mechanism depends on the generation of reactive nitrogen intermediates. J Leukoc Biol. 1991 Apr;49(4):380–387. doi: 10.1002/jlb.49.4.380. [DOI] [PubMed] [Google Scholar]
  7. Ding A. H., Nathan C. F., Stuehr D. J. Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J Immunol. 1988 Oct 1;141(7):2407–2412. [PubMed] [Google Scholar]
  8. Drapier J. C., Wietzerbin J., Hibbs J. B., Jr Interferon-gamma and tumor necrosis factor induce the L-arginine-dependent cytotoxic effector mechanism in murine macrophages. Eur J Immunol. 1988 Oct;18(10):1587–1592. doi: 10.1002/eji.1830181018. [DOI] [PubMed] [Google Scholar]
  9. Gupta S. L., Carlin J. M., Pyati P., Dai W., Pfefferkorn E. R., Murphy M. J., Jr Antiparasitic and antiproliferative effects of indoleamine 2,3-dioxygenase enzyme expression in human fibroblasts. Infect Immun. 1994 Jun;62(6):2277–2284. doi: 10.1128/iai.62.6.2277-2284.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. Igietseme J. U., Smith K., Simmons A., Rayford P. L. Effect of gamma-irradiation on the effector function of T lymphocytes in microbial control. Int J Radiat Biol. 1995 May;67(5):557–564. doi: 10.1080/09553009514550671. [DOI] [PubMed] [Google Scholar]
  13. Igietseme J. U., Wyrick P. B., Goyeau D., Rank R. G. An in vitro model for immune control of chlamydial growth in polarized epithelial cells. Infect Immun. 1994 Aug;62(8):3528–3535. doi: 10.1128/iai.62.8.3528-3535.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kirk S. J., Regan M. C., Barbul A. Cloned murine T lymphocytes synthesize a molecule with the biological characteristics of nitric oxide. Biochem Biophys Res Commun. 1990 Dec 14;173(2):660–665. doi: 10.1016/s0006-291x(05)80086-5. [DOI] [PubMed] [Google Scholar]
  15. Knight S. C., Iqball S., Woods C., Stagg A., Ward M. E., Tuffrey M. A peptide of Chlamydia trachomatis shown to be a primary T-cell epitope in vitro induces cell-mediated immunity in vivo. Immunology. 1995 May;85(1):8–15. [PMC free article] [PubMed] [Google Scholar]
  16. Liew F. Y., Millott S., Parkinson C., Palmer R. M., Moncada S. Macrophage killing of Leishmania parasite in vivo is mediated by nitric oxide from L-arginine. J Immunol. 1990 Jun 15;144(12):4794–4797. [PubMed] [Google Scholar]
  17. Mather J. P. Establishment and characterization of two distinct mouse testicular epithelial cell lines. Biol Reprod. 1980 Aug;23(1):243–252. doi: 10.1095/biolreprod23.1.243. [DOI] [PubMed] [Google Scholar]
  18. Murray H. W., Szuro-Sudol A., Wellner D., Oca M. J., Granger A. M., Libby D. M., Rothermel C. D., Rubin B. Y. Role of tryptophan degradation in respiratory burst-independent antimicrobial activity of gamma interferon-stimulated human macrophages. Infect Immun. 1989 Mar;57(3):845–849. doi: 10.1128/iai.57.3.845-849.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Nussler A. K., Billiar T. R. Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol. 1993 Aug;54(2):171–178. [PubMed] [Google Scholar]
  20. Nüssler A., Drapier J. C., Rénia L., Pied S., Miltgen F., Gentilini M., Mazier D. L-arginine-dependent destruction of intrahepatic malaria parasites in response to tumor necrosis factor and/or interleukin 6 stimulation. Eur J Immunol. 1991 Jan;21(1):227–230. doi: 10.1002/eji.1830210134. [DOI] [PubMed] [Google Scholar]
  21. Patton D. L. Immunopathology and histopathology of experimental chlamydial salpingitis. Rev Infect Dis. 1985 Nov-Dec;7(6):746–753. doi: 10.1093/clinids/7.6.746. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Ramsey K. H., Soderberg L. S., Rank R. G. Resolution of chlamydial genital infection in B-cell-deficient mice and immunity to reinfection. Infect Immun. 1988 May;56(5):1320–1325. doi: 10.1128/iai.56.5.1320-1325.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rothermel C. D., Rubin B. Y., Murray H. W. Gamma-interferon is the factor in lymphokine that activates human macrophages to inhibit intracellular Chlamydia psittaci replication. J Immunol. 1983 Nov;131(5):2542–2544. [PubMed] [Google Scholar]
  25. Schachter J. Overview of Chlamydia trachomatis infection and the requirements for a vaccine. Rev Infect Dis. 1985 Nov-Dec;7(6):713–716. doi: 10.1093/clinids/7.6.713. [DOI] [PubMed] [Google Scholar]
  26. Shemer-Avni Y., Wallach D., Sarov I. Reversion of the antichlamydial effect of tumor necrosis factor by tryptophan and antibodies to beta interferon. Infect Immun. 1989 Nov;57(11):3484–3490. doi: 10.1128/iai.57.11.3484-3490.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Shemer Y., Sarov I. Inhibition of growth of Chlamydia trachomatis by human gamma interferon. Infect Immun. 1985 May;48(2):592–596. doi: 10.1128/iai.48.2.592-596.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Springall D. R. Nitric oxide--friend and foe. J Pathol. 1995 Feb;175(2):165–166. doi: 10.1002/path.1711750202. [DOI] [PubMed] [Google Scholar]
  29. Stuehr D. J., Nathan C. F. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med. 1989 May 1;169(5):1543–1555. doi: 10.1084/jem.169.5.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Taylor H. R., Prendergast R. A., Dawson C. R., Schachter J., Silverstein A. M. An animal model for cicatrizing trachoma. Invest Ophthalmol Vis Sci. 1981 Sep;21(3):422–433. [PubMed] [Google Scholar]
  31. Williams D. M., Magee D. M., Bonewald L. F., Smith J. G., Bleicker C. A., Byrne G. I., Schachter J. A role in vivo for tumor necrosis factor alpha in host defense against Chlamydia trachomatis. Infect Immun. 1990 Jun;58(6):1572–1576. doi: 10.1128/iai.58.6.1572-1576.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Woods M. L., 2nd, Mayer J., Evans T. G., Hibbs J. B., Jr Antiparasitic effects of nitric oxide in an in vitro murine model of Chlamydia trachomatis infection and an in vivo murine model of Leishmania major infection. Immunol Ser. 1994;60:179–195. [PubMed] [Google Scholar]
  33. 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]
  34. de la Maza L. M., Peterson E. M., Fennie C. W., Czarniecki C. W. The anti-chlamydial and anti-proliferative activities of recombinant murine interferon-gamma are not dependent on tryptophan concentrations. J Immunol. 1985 Dec;135(6):4198–4200. [PubMed] [Google Scholar]

Articles from Immunology are provided here courtesy of British Society for Immunology

RESOURCES