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. 1994 May;62(5):1995–2001. doi: 10.1128/iai.62.5.1995-2001.1994

Mitogen- and antigen-specific proliferation of T cells in murine toxoplasmosis is inhibited by reactive nitrogen intermediates.

E Candolfi 1, C A Hunter 1, J S Remington 1
PMCID: PMC186459  PMID: 8168967

Abstract

Acute and chronic infections with Toxoplasma gondii result in a nonspecific suppression of immunologic function in mice and humans. Proliferation of spleen cells in response to concanavalin A (ConA) and toxoplasma lysate antigen (TLA) was studied during the course of infection in mice susceptible (CBA/Ca) and resistant (BALB/c) to development of toxoplasmic encephalitis to determine if reactive nitrogen intermediates (RNI) are involved in the suppression of the proliferative responses. Maximal suppression of proliferation of spleen cells in response to ConA and TLA was observed on days 7 and 14 after infection and correlated with elevated levels of nitrite in spleen cell culture supernatants. By day 68 postinfection in BALB/c mice, proliferative responses returned to normal levels, whereas in CBA/Ca mice, they remained suppressed. The addition of an inhibitor of production of RNI (NG-monomethyl-L-arginine) increased proliferation of spleen cells in response to both ConA and TLA at days 7, 14, and 21 after infection. Depletion of adherent cells from spleen cell preparations obtained from acutely infected mice followed by their repletion with adherent spleen cells from uninfected mice resulted in increased proliferation of spleen cells from infected mice and a significant decrease in nitrite in the cultures. These results indicate that production of RNI by macrophages contributes significantly to the suppression of the spleen cell proliferation observed in the acute stage of toxoplasmosis.

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1995

Selected References

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  1. Adams L. B., Hibbs J. B., Jr, Taintor R. R., Krahenbuhl J. L. Microbiostatic effect of murine-activated macrophages for Toxoplasma gondii. Role for synthesis of inorganic nitrogen oxides from L-arginine. J Immunol. 1990 Apr 1;144(7):2725–2729. [PubMed] [Google Scholar]
  2. Albina J. E., Abate J. A., Henry W. L., Jr Nitric oxide production is required for murine resident peritoneal macrophages to suppress mitogen-stimulated T cell proliferation. Role of IFN-gamma in the induction of the nitric oxide-synthesizing pathway. J Immunol. 1991 Jul 1;147(1):144–148. [PubMed] [Google Scholar]
  3. Brinkmann V., Remington J. S., Sharma S. D. Protective immunity in toxoplasmosis: correlation between antibody response, brain cyst formation, T-cell activation, and survival in normal and B-cell-deficient mice bearing the H-2k haplotype. Infect Immun. 1987 Apr;55(4):990–994. doi: 10.1128/iai.55.4.990-994.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chan J., Siegel J. P., Luft B. J. Demonstration of T-cell dysfunction during acute toxoplasma infection. Cell Immunol. 1986 Apr 1;98(2):422–433. doi: 10.1016/0008-8749(86)90301-1. [DOI] [PubMed] [Google Scholar]
  5. Chardès T., Velge-Roussel F., Mevelec P., Mevelec M. N., Buzoni-Gatel D., Bout D. Mucosal and systemic cellular immune responses induced by Toxoplasma gondii antigens in cyst orally infected mice. Immunology. 1993 Mar;78(3):421–429. [PMC free article] [PubMed] [Google Scholar]
  6. Darji A., Sileghem M., Heremans H., Brys L., De Baetselier P. Inhibition of T-cell responsiveness during experimental infections with Trypanosoma brucei: active involvement of endogenous gamma interferon. Infect Immun. 1993 Jul;61(7):3098–3102. doi: 10.1128/iai.61.7.3098-3102.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ding A., Nathan C. F., Graycar J., Derynck R., Stuehr D. J., Srimal S. Macrophage deactivating factor and transforming growth factors-beta 1 -beta 2 and -beta 3 inhibit induction of macrophage nitrogen oxide synthesis by IFN-gamma. J Immunol. 1990 Aug 1;145(3):940–944. [PubMed] [Google Scholar]
  8. Gazzinelli R. T., Oswald I. P., Hieny S., James S. L., Sher A. The microbicidal activity of interferon-gamma-treated macrophages against Trypanosoma cruzi involves an L-arginine-dependent, nitrogen oxide-mediated mechanism inhibitable by interleukin-10 and transforming growth factor-beta. Eur J Immunol. 1992 Oct;22(10):2501–2506. doi: 10.1002/eji.1830221006. [DOI] [PubMed] [Google Scholar]
  9. Gazzinelli R. T., Oswald I. P., James S. L., Sher A. IL-10 inhibits parasite killing and nitrogen oxide production by IFN-gamma-activated macrophages. J Immunol. 1992 Mar 15;148(6):1792–1796. [PubMed] [Google Scholar]
  10. Goyal M., Ganguly N. K., Mahajan R. C. Lymphocyte functions in acute & chronic murine toxoplasmosis. Indian J Med Res. 1986 May;83:487–494. [PubMed] [Google Scholar]
  11. Green L. C., Wagner D. A., Glogowski J., Skipper P. L., Wishnok J. S., Tannenbaum S. R. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem. 1982 Oct;126(1):131–138. doi: 10.1016/0003-2697(82)90118-x. [DOI] [PubMed] [Google Scholar]
  12. Gregory S. H., Wing E. J., Hoffman R. A., Simmons R. L. Reactive nitrogen intermediates suppress the primary immunologic response to Listeria. J Immunol. 1993 Apr 1;150(7):2901–2909. [PubMed] [Google Scholar]
  13. Hibbs J. B., Jr, Vavrin Z., Taintor R. R. L-arginine is required for expression of the activated macrophage effector mechanism causing selective metabolic inhibition in target cells. J Immunol. 1987 Jan 15;138(2):550–565. [PubMed] [Google Scholar]
  14. Hoffman R. A., Langrehr J. M., Billiar T. R., Curran R. D., Simmons R. L. Alloantigen-induced activation of rat splenocytes is regulated by the oxidative metabolism of L-arginine. J Immunol. 1990 Oct 1;145(7):2220–2226. [PubMed] [Google Scholar]
  15. Huldt G., Gard S., Olovson S. G. Effect of Toxoplasma gondii on the thymus. Nature. 1973 Aug 3;244(5414):301–303. doi: 10.1038/244301a0. [DOI] [PubMed] [Google Scholar]
  16. Julius M. H., Simpson E., Herzenberg L. A. A rapid method for the isolation of functional thymus-derived murine lymphocytes. Eur J Immunol. 1973 Oct;3(10):645–649. doi: 10.1002/eji.1830031011. [DOI] [PubMed] [Google Scholar]
  17. Langrehr J. M., Hoffman R. A., Billiar T. R., Lee K. K., Schraut W. H., Simmons R. L. Nitric oxide synthesis in the in vivo allograft response: a possible regulatory mechanism. Surgery. 1991 Aug;110(2):335–342. [PubMed] [Google Scholar]
  18. Liew F. Y., Li Y., Severn A., Millott S., Schmidt J., Salter M., Moncada S. A possible novel pathway of regulation by murine T helper type-2 (Th2) cells of a Th1 cell activity via the modulation of the induction of nitric oxide synthase on macrophages. Eur J Immunol. 1991 Oct;21(10):2489–2494. doi: 10.1002/eji.1830211027. [DOI] [PubMed] [Google Scholar]
  19. Liew F. Y., Millott S., Li Y., Lelchuk R., Chan W. L., Ziltener H. Macrophage activation by interferon-gamma from host-protective T cells is inhibited by interleukin (IL)3 and IL4 produced by disease-promoting T cells in leishmaniasis. Eur J Immunol. 1989 Jul;19(7):1227–1232. doi: 10.1002/eji.1830190712. [DOI] [PubMed] [Google Scholar]
  20. Luft B. J., Kansas G., Engleman E. G., Remington J. S. Functional and quantitative alterations in T lymphocyte subpopulations in acute toxoplasmosis. J Infect Dis. 1984 Nov;150(5):761–767. doi: 10.1093/infdis/150.5.761. [DOI] [PubMed] [Google Scholar]
  21. McLeod R., Estes R. G., Mack D. G., Cohen H. Immune response of mice to ingested Toxoplasma gondii: a model of toxoplasma infection acquired by ingestion. J Infect Dis. 1984 Feb;149(2):234–244. doi: 10.1093/infdis/149.2.234. [DOI] [PubMed] [Google Scholar]
  22. McLeod R., Estes R. G. Role of lymphocyte blastogenesis to Toxoplasma gondii antigens in containment of chronic, latent T. gondii infection in humans. Clin Exp Immunol. 1985 Oct;62(1):24–30. [PMC free article] [PubMed] [Google Scholar]
  23. McLeod R., Mack D. G., Boyer K., Mets M., Roizen N., Swisher C., Patel D., Beckmann E., Vitullo D., Johnson D. Phenotypes and functions of lymphocytes in congenital toxoplasmosis. J Lab Clin Med. 1990 Nov;116(5):623–635. [PubMed] [Google Scholar]
  24. McLeod R., Van Le L., Remington J. S. Toxoplasma gondii: lymphocyte function during acute infection in mice. Exp Parasitol. 1982 Aug;54(1):55–63. doi: 10.1016/0014-4894(82)90110-2. [DOI] [PubMed] [Google Scholar]
  25. Sharma S. D., Mullenax J., Araujo F. G., Erlich H. A., Remington J. S. Western Blot analysis of the antigens of Toxoplasma gondii recognized by human IgM and IgG antibodies. J Immunol. 1983 Aug;131(2):977–983. [PubMed] [Google Scholar]
  26. Sternberg J., McGuigan F. Nitric oxide mediates suppression of T cell responses in murine Trypanosoma brucei infection. Eur J Immunol. 1992 Oct;22(10):2741–2744. doi: 10.1002/eji.1830221041. [DOI] [PubMed] [Google Scholar]
  27. Strickland G. T., Ahmed A., Sell K. W. Blastogenic response of Toxoplasma-infected mouse spleen cells to T- and B-cell mitogens. Clin Exp Immunol. 1975 Oct;22(1):167–176. [PMC free article] [PubMed] [Google Scholar]
  28. Subauste C. S., Koniaris A. H., Remington J. S. Murine CD8+ cytotoxic T lymphocytes lyse Toxoplasma gondii-infected cells. J Immunol. 1991 Dec 1;147(11):3955–3959. [PubMed] [Google Scholar]
  29. Suzuki Y., Joh K., Kobayashi A. Macrophage-mediated suppression of immune responses in Toxoplasma-infected mice. III. Suppression of antibody responses to parasite itself. Cell Immunol. 1987 Dec;110(2):218–225. doi: 10.1016/0008-8749(87)90117-1. [DOI] [PubMed] [Google Scholar]
  30. Suzuki Y., Kobayashi A. Macrophage-mediated suppression of immune responses in Toxoplasma-infected mice. I. Inhibition of proliferation of lymphocytes in primary antibody responses. Cell Immunol. 1984 May;85(2):417–427. doi: 10.1016/0008-8749(84)90255-7. [DOI] [PubMed] [Google Scholar]
  31. Suzuki Y., Kobayashi A. Macrophage-mediated suppression of immune responses in Toxoplasma-infected mice. II. Both H-2-linked and -nonlinked control of induction of suppressor macrophages. Cell Immunol. 1985 Apr 1;91(2):375–384. doi: 10.1016/0008-8749(85)90235-7. [DOI] [PubMed] [Google Scholar]
  32. Suzuki Y., Kobayashi A. Suppression of unprimed T and B cells in antibody responses by irradiation-resistant and plastic-adherent suppressor cells in Toxoplasma gondii-infected mice. Infect Immun. 1983 Apr;40(1):1–7. doi: 10.1128/iai.40.1.1-7.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Suzuki Y., Kobayashi A. Suppressive effect of secondary Toxoplasma gondii infection on antibody responses in mice. Infect Immun. 1985 Jun;48(3):686–689. doi: 10.1128/iai.48.3.686-689.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Suzuki Y., Orellana M. A., Schreiber R. D., Remington J. S. Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science. 1988 Apr 22;240(4851):516–518. doi: 10.1126/science.3128869. [DOI] [PubMed] [Google Scholar]
  35. Suzuki Y., Orellana M. A., Wong S. Y., Conley F. K., Remington J. S. Susceptibility to chronic infection with Toxoplasma gondii does not correlate with susceptibility to acute infection in mice. Infect Immun. 1993 Jun;61(6):2284–2288. doi: 10.1128/iai.61.6.2284-2288.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Suzuki Y., Watanabe N., Kobayashi A. Nonspecific suppression of primary antibody responses and presence of plastic-adherent suppressor cells in Toxoplasma gondii-infected mice. Infect Immun. 1981 Oct;34(1):30–35. doi: 10.1128/iai.34.1.30-35.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Tsunawaki S., Sporn M., Ding A., Nathan C. Deactivation of macrophages by transforming growth factor-beta. Nature. 1988 Jul 21;334(6179):260–262. doi: 10.1038/334260a0. [DOI] [PubMed] [Google Scholar]
  38. Williams D. M., Grumet F. C., Remington J. S. Genetic control of murine resistance to Toxoplasma gondii. Infect Immun. 1978 Feb;19(2):416–420. doi: 10.1128/iai.19.2.416-420.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wilson C. B., Tsai V., Remington J. S. Failure to trigger the oxidative metabolic burst by normal macrophages: possible mechanism for survival of intracellular pathogens. J Exp Med. 1980 Feb 1;151(2):328–346. doi: 10.1084/jem.151.2.328. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Wing E. J., Remington J. S. Studies on the regulation of lymphocyte reactivity by normal and activated macrophages. Cell Immunol. 1977 Apr;30(1):108–121. doi: 10.1016/0008-8749(77)90052-1. [DOI] [PubMed] [Google Scholar]
  41. al-Ramadi B. K., Meissler J. J., Jr, Huang D., Eisenstein T. K. Immunosuppression induced by nitric oxide and its inhibition by interleukin-4. Eur J Immunol. 1992 Sep;22(9):2249–2254. doi: 10.1002/eji.1830220911. [DOI] [PubMed] [Google Scholar]

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