Skip to main content
PMC home page
Infection and Immunity logoLink to Infection and Immunity
. 1995 Sep;63(9):3442–3447. doi: 10.1128/iai.63.9.3442-3447.1995

A Toxoplasma gondii-derived factor(s) stimulates immune downregulation: an in vitro model.

S Haque 1, A Haque 1, L H Kasper 1
PMCID: PMC173474  PMID: 7642275

Abstract

Suppression of the T-cell lymphoproliferative response and downregulation of interleukin 2 (IL-2) production by Toxoplasma gondii has been observed following in vivo infection. In this study, an experimental in vitro murine system was developed to evaluate the kinetics of these responses. Normal splenocytes from uninfected mice were stimulated with either concanavalin A or an anti-CD3 monoclonal antibody and cocultured with Toxoplasma tachyzoites either directly or separated by a transwell. A progressive decline in the lymphoproliferative response was observed as the concentration of parasites in culture increased. Neither heat-killed nor formaldehyde-fixed parasites stimulated this downregulatory response by the splenocytes. A decline in IL-2 production was associated with the decrease in lymphocyte proliferation. The addition of an antibody to IL-10 or heat-inactivated anti-Toxoplasma sera to the culture supernatant partially neutralized the inhibitory effect on lymphocyte proliferation. Cytokine analysis of the responder splenocytes demonstrated a decrease in the message for IL-2 and IL-2 receptor and an increase in IL-10. Together, these observations suggest that during in vitro culture in a murine system, parasite antigens that stimulate the release of a soluble factor(s), such as IL-10, that inhibits proliferation of mitogen-stimulated T cells are expressed.

Full Text

The Full Text of this article is available as a PDF (233.8 KB).

Selected References

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

  1. Beltz L. A., Kierszenbaum F., Sztein M. B. Selective suppressive effects of Trypanosoma cruzi on activated human lymphocytes. Infect Immun. 1989 Aug;57(8):2301–2305. doi: 10.1128/iai.57.8.2301-2305.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Burke J. M., Roberts C. W., Hunter C. A., Murray M., Alexander J. Temporal differences in the expression of mRNA for IL-10 and IFN-gamma in the brains and spleens of C57BL/10 mice infected with Toxoplasma gondii. Parasite Immunol. 1994 Jun;16(6):305–314. doi: 10.1111/j.1365-3024.1994.tb00353.x. [DOI] [PubMed] [Google Scholar]
  3. Candolfi E., Hunter C. A., Remington J. S. Mitogen- and antigen-specific proliferation of T cells in murine toxoplasmosis is inhibited by reactive nitrogen intermediates. Infect Immun. 1994 May;62(5):1995–2001. doi: 10.1128/iai.62.5.1995-2001.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cesbron-Delauw M. F., Capron A. Excreted/secreted antigens of Toxoplasma gondii--their origin and role in the host-parasite interaction. Res Immunol. 1993 Jan;144(1):41–44. doi: 10.1016/s0923-2494(05)80096-3. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Chizzolini C., Geinoz A., Schrijvers D. Interleukin-2 reverses T cell unresponsiveness to Plasmodium falciparum-antigen in malaria immune subjects. Cell Immunol. 1990 Jun;128(1):1–10. doi: 10.1016/0008-8749(90)90001-8. [DOI] [PubMed] [Google Scholar]
  7. Ding L., Linsley P. S., Huang L. Y., Germain R. N., Shevach E. M. IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up-regulation of B7 expression. J Immunol. 1993 Aug 1;151(3):1224–1234. [PubMed] [Google Scholar]
  8. Ding L., Shevach E. M. IL-10 inhibits mitogen-induced T cell proliferation by selectively inhibiting macrophage costimulatory function. J Immunol. 1992 May 15;148(10):3133–3139. [PubMed] [Google Scholar]
  9. Drapier J. C., Hibbs J. B., Jr Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron-sulfur enzymes in the macrophage effector cells. J Immunol. 1988 Apr 15;140(8):2829–2838. [PubMed] [Google Scholar]
  10. Fiorentino D. F., Zlotnik A., Vieira P., Mosmann T. R., Howard M., Moore K. W., O'Garra A. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol. 1991 May 15;146(10):3444–3451. [PubMed] [Google Scholar]
  11. Gazzinelli R. T., Wysocka M., Hayashi S., Denkers E. Y., Hieny S., Caspar P., Trinchieri G., Sher A. Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol. 1994 Sep 15;153(6):2533–2543. [PubMed] [Google Scholar]
  12. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  13. Haque S., Khan I., Haque A., Kasper L. Impairment of the cellular immune response in acute murine toxoplasmosis: regulation of interleukin 2 production and macrophage-mediated inhibitory effects. Infect Immun. 1994 Jul;62(7):2908–2916. doi: 10.1128/iai.62.7.2908-2916.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Harel-Bellan A., Joskowicz M., Fradelizi D., Eisen H. Modification of T-cell proliferation and interleukin 2 production in mice infected with Trypanosoma cruzi. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3466–3469. doi: 10.1073/pnas.80.11.3466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kasper L. H. Isolation and characterization of a monoclonal anti-P30 antibody resistant mutant of Toxoplasma gondii. Parasite Immunol. 1987 Jul;9(4):433–445. doi: 10.1111/j.1365-3024.1987.tb00521.x. [DOI] [PubMed] [Google Scholar]
  16. Kasper L. H., Khan I. A., Ely K. H., Buelow R., Boothroyd J. C. Antigen-specific (p30) mouse CD8+ T cells are cytotoxic against Toxoplasma gondii-infected peritoneal macrophages. J Immunol. 1992 Mar 1;148(5):1493–1498. [PubMed] [Google Scholar]
  17. Khan I. A., Matsuura T., Kasper L. H. IL-10 mediates immunosuppression following primary infection with Toxoplasma gondii in mice. Parasite Immunol. 1995 Apr;17(4):185–195. doi: 10.1111/j.1365-3024.1995.tb00888.x. [DOI] [PubMed] [Google Scholar]
  18. Lucas B., Smith K., Haque A. Plasmodium yoelii in mice: differential induction of cytokine gene expression during hyporesponsiveness induction and restimulation. Cell Immunol. 1995 Jan;160(1):79–90. doi: 10.1016/0008-8749(95)80012-8. [DOI] [PubMed] [Google Scholar]
  19. Mills C. D. Molecular basis of "suppressor" macrophages. Arginine metabolism via the nitric oxide synthetase pathway. J Immunol. 1991 Apr 15;146(8):2719–2723. [PubMed] [Google Scholar]
  20. Paul W. E., Seder R. A. Lymphocyte responses and cytokines. Cell. 1994 Jan 28;76(2):241–251. doi: 10.1016/0092-8674(94)90332-8. [DOI] [PubMed] [Google Scholar]
  21. Sztein M. B., Cuna W. R., Kierszenbaum F. Trypanosoma cruzi inhibits the expression of CD3, CD4, CD8, and IL-2R by mitogen-activated helper and cytotoxic human lymphocytes. J Immunol. 1990 May 1;144(9):3558–3562. [PubMed] [Google Scholar]
  22. Sztein M. B., Kierszenbaum F. Trypanosoma cruzi suppresses the ability of activated human lymphocytes to enter the cell cycle. J Parasitol. 1991 Jun;77(3):502–505. [PubMed] [Google Scholar]
  23. Taga K., Tosato G. IL-10 inhibits human T cell proliferation and IL-2 production. J Immunol. 1992 Feb 15;148(4):1143–1148. [PubMed] [Google Scholar]
  24. Tamura T., Yanagida T., Nariuchi H. Difference in signal transduction pathway for IL-2 and IL-4 production in T helper 1 and T helper 2 cell clones in response to anti-CD3. J Immunol. 1993 Dec 1;151(11):6051–6061. [PubMed] [Google Scholar]
  25. Tanaka T., Hu-Li J., Seder R. A., Fazekas de St Groth B., Paul W. E. Interleukin 4 suppresses interleukin 2 and interferon gamma production by naive T cells stimulated by accessory cell-dependent receptor engagement. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5914–5918. doi: 10.1073/pnas.90.13.5914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. de Waal Malefyt R., Yssel H., de Vries J. E. Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol. 1993 Jun 1;150(11):4754–4765. [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES