Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1988 Oct 1;168(4):1403–1417. doi: 10.1084/jem.168.4.1403

Bacterial cell wall-induced immunosuppression. Role of transforming growth factor beta

PMCID: PMC2189072  PMID: 2971758

Abstract

Group A streptococcal cell wall (SCW)-injected rats exhibit a profound immunosuppression that persists for months after the initial intraperitoneal injection of SCW. The goal of this study was to determine the mechanisms for the suppressed T lymphocyte proliferative responses in this experimental model of chronic inflammation. When spleen cell preparations were depleted of adherent cells, restoration of T cell proliferative responses to Con A and PHA occurred, implicating adherent macrophages in the regulation of immunosuppression. Furthermore, macrophages from SCW-treated animals, when cocultured with normal spleen cells in the presence of Con A or PHA, effectively inhibited the proliferative response. Supernatants from suppressed spleen cell cultures were found to inhibit normal T cell mitogenesis. Taken together, these results implicated a soluble macrophage-derived suppressor factor in the down regulation of T cell proliferation after exposure to SCW in vivo. Subsequent in vitro studies to identify this suppressor molecule(s) revealed the activity to be indistinguishable from the polypeptide transforming growth factor beta (TGF-beta). Furthermore, TGF-beta was identified by immunolocalization within the spleens of SCW-injected animals. The cells within the spleen that stained positively for TGF-beta were phagocytic cells that had ingested, and were presumably activated by, the SCW. These studies document that TGF-beta, previously shown to be a potent immunosuppressive agent in vitro, also effectively inhibits immune function in chronic inflammatory lesions in vivo.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

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

  1. Allen J. B., Malone D. G., Wahl S. M., Calandra G. B., Wilder R. L. Role of the thymus in streptococcal cell wall-induced arthritis and hepatic granuloma formation. Comparative studies of pathology and cell wall distribution in athymic and euthymic rats. J Clin Invest. 1985 Sep;76(3):1042–1056. doi: 10.1172/JCI112057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Assoian R. K., Fleurdelys B. E., Stevenson H. C., Miller P. J., Madtes D. K., Raines E. W., Ross R., Sporn M. B. Expression and secretion of type beta transforming growth factor by activated human macrophages. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6020–6024. doi: 10.1073/pnas.84.17.6020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Balavoine J. F., de Rochemonteix B., Williamson K., Seckinger P., Cruchaud A., Dayer J. M. Prostaglandin E2 and collagenase production by fibroblasts and synovial cells is regulated by urine-derived human interleukin 1 and inhibitor(s). J Clin Invest. 1986 Oct;78(4):1120–1124. doi: 10.1172/JCI112669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bullock W. E. Leprosy: a model of immunological perturbation in chronic infection. J Infect Dis. 1978 Mar;137(3):341–354. doi: 10.1093/infdis/137.3.341. [DOI] [PubMed] [Google Scholar]
  5. Cromartie W. J., Craddock J. G., Schwab J. H., Anderle S. K., Yang C. H. Arthritis in rats after systemic injection of streptococcal cells or cell walls. J Exp Med. 1977 Dec 1;146(6):1585–1602. doi: 10.1084/jem.146.6.1585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ellingsworth L. R., Brennan J. E., Fok K., Rosen D. M., Bentz H., Piez K. A., Seyedin S. M. Antibodies to the N-terminal portion of cartilage-inducing factor A and transforming growth factor beta. Immunohistochemical localization and association with differentiating cells. J Biol Chem. 1986 Sep 15;261(26):12362–12367. [PubMed] [Google Scholar]
  7. Ellner J. J. Suppressor adherent cells in human tuberculosis. J Immunol. 1978 Dec;121(6):2573–2579. [PubMed] [Google Scholar]
  8. Goodwin J. S., Bankhurst A. D., Messner R. P. Suppression of human T-cell mitogenesis by prostaglandin. Existence of a prostaglandin-producing suppressor cell. J Exp Med. 1977 Dec 1;146(6):1719–1734. doi: 10.1084/jem.146.6.1719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hunter N., Anderle S. K., Brown R. R., Dalldorf F. G., Clark R. L., Cromartie W. J., Schwab J. H. Cell-mediated immune response during experimental arthritis induced in rats with streptococcal cell walls. Clin Exp Immunol. 1980 Dec;42(3):441–449. [PMC free article] [PubMed] [Google Scholar]
  10. Kehrl J. H., Roberts A. B., Wakefield L. M., Jakowlew S., Sporn M. B., Fauci A. S. Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes. J Immunol. 1986 Dec 15;137(12):3855–3860. [PubMed] [Google Scholar]
  11. Kehrl J. H., Wakefield L. M., Roberts A. B., Jakowlew S., Alvarez-Mon M., Derynck R., Sporn M. B., Fauci A. S. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med. 1986 May 1;163(5):1037–1050. doi: 10.1084/jem.163.5.1037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lotz M., Tsoukas C. D., Robinson C. A., Dinarello C. A., Carson D. A., Vaughan J. H. Basis for defective responses of rheumatoid arthritis synovial fluid lymphocytes to anti-CD3 (T3) antibodies. J Clin Invest. 1986 Sep;78(3):713–721. doi: 10.1172/JCI112631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Metzger Z., Hoffeld J. T., Oppenheim J. J. Macrophage-mediated suppression. I. Evidence for participation of both hdyrogen peroxide and prostaglandins in suppression of murine lymphocyte proliferation. J Immunol. 1980 Feb;124(2):983–988. [PubMed] [Google Scholar]
  14. Mulé J. J., Schwarz S. L., Roberts A. B., Sporn M. B., Rosenberg S. A. Transforming growth factor-beta inhibits the in vitro generation of lymphokine-activated killer cells and cytotoxic T cells. Cancer Immunol Immunother. 1988;26(2):95–100. doi: 10.1007/BF00205600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ohura K., Katona I. M., Wahl L. M., Chenoweth D. E., Wahl S. M. Co-expression of chemotactic ligand receptors on human peripheral blood monocytes. J Immunol. 1987 Apr 15;138(8):2633–2639. [PubMed] [Google Scholar]
  16. Panush R. S. Nonspecific suppressor function in rheumatoid arthritis. J Clin Lab Immunol. 1982 Oct;9(1):59–64. [PubMed] [Google Scholar]
  17. Petit J. C., Richard G., Burghoffer B., Daguet G. L. Suppression of cellular immunity to Listeria monocytogenes by activated macrophages: mediation by prostaglandins. Infect Immun. 1985 Aug;49(2):383–388. doi: 10.1128/iai.49.2.383-388.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Piechaczyk M., Blanchard J. M., Marty L., Dani C., Panabieres F., El Sabouty S., Fort P., Jeanteur P. Post-transcriptional regulation of glyceraldehyde-3-phosphate-dehydrogenase gene expression in rat tissues. Nucleic Acids Res. 1984 Sep 25;12(18):6951–6963. doi: 10.1093/nar/12.18.6951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ranges G. E., Figari I. S., Espevik T., Palladino M. A., Jr Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha. J Exp Med. 1987 Oct 1;166(4):991–998. doi: 10.1084/jem.166.4.991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ridge S. C., Zabriske J. B., Oronsky A. L., Kerwar S. S. Streptococcal cell wall arthritis: studies with nude (athymic) inbred Lewis rats. Cell Immunol. 1985 Nov;96(1):231–234. doi: 10.1016/0008-8749(85)90354-5. [DOI] [PubMed] [Google Scholar]
  21. Ridge S. C., Zabriskie J. B., Osawa H., Diamantstein T., Oronsky A. L., Kerwar S. S. Administration of group A streptococcal cell walls to rats induces an interleukin 2 deficiency. J Exp Med. 1986 Jul 1;164(1):327–332. doi: 10.1084/jem.164.1.327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Roberts A. B., Anzano M. A., Wakefield L. M., Roche N. S., Stern D. F., Sporn M. B. Type beta transforming growth factor: a bifunctional regulator of cellular growth. Proc Natl Acad Sci U S A. 1985 Jan;82(1):119–123. doi: 10.1073/pnas.82.1.119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Roberts N. J., Jr, Prill A. H., Mann T. N. Interleukin 1 and interleukin 1 inhibitor production by human macrophages exposed to influenza virus or respiratory syncytial virus. Respiratory syncytial virus is a potent inducer of inhibitor activity. J Exp Med. 1986 Mar 1;163(3):511–519. doi: 10.1084/jem.163.3.511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Robinson A. P., White T. M., Mason D. W. MRC OX-43: a monoclonal antibody which reacts with all vascular endothelium in the rat except that of brain capillaries. Immunology. 1986 Feb;57(2):231–237. [PMC free article] [PubMed] [Google Scholar]
  25. Rook A. H., Kehrl J. H., Wakefield L. M., Roberts A. B., Sporn M. B., Burlington D. B., Lane H. C., Fauci A. S. Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. J Immunol. 1986 May 15;136(10):3916–3920. [PubMed] [Google Scholar]
  26. Rubens R. D., Hayward J. L., Knight R. K., Bulbrook R. D., Fentiman I. S., Chaudary M., Howell A., Bush H., Crowther D., Sellwood R. A. Controlled trial of adjuvant chemotherapy with melphalan for breast cancer. Lancet. 1983 Apr 16;1(8329):839–843. doi: 10.1016/s0140-6736(83)91385-5. [DOI] [PubMed] [Google Scholar]
  27. Sathish M., Bhutani L. K., Sharma A. K., Nath I. Monocyte-derived soluble suppressor factor(s) in patients with lepromatous leprosy. Infect Immun. 1983 Dec;42(3):890–899. doi: 10.1128/iai.42.3.890-899.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Schachter E. N. Tuberculin negative tuberculosis. Am Rev Respir Dis. 1972 Oct;106(4):587–593. doi: 10.1164/arrd.1972.106.4.587. [DOI] [PubMed] [Google Scholar]
  29. Seitz M., Deimann W., Gram N., Hunstein W., Gemsa D. Characterization of blood mononuclear cells of rheumatoid arthritis patients. I. Depressed lymphocyte proliferation and enhanced prostanoid release from monocytes. Clin Immunol Immunopathol. 1982 Dec;25(3):405–416. doi: 10.1016/0090-1229(82)90205-7. [DOI] [PubMed] [Google Scholar]
  30. Wadee A. A., Gear A. J., Rabson A. R. Production of a suppressor factor by human adherent cells treated with Mycobacterium tuberculosis: absence in systemic lupus erythematosus. Clin Exp Immunol. 1981 Oct;46(1):82–88. [PMC free article] [PubMed] [Google Scholar]
  31. Wahl S. M., Allen J. B., Dougherty S., Evequoz V., Pluznik D. H., Wilder R. L., Hand A. R., Wahl L. M. T lymphocyte-dependent evolution of bacterial cell wall-induced hepatic granulomas. J Immunol. 1986 Oct 1;137(7):2199–2209. [PubMed] [Google Scholar]
  32. Wahl S. M., Hunt D. A., Wakefield L. M., McCartney-Francis N., Wahl L. M., Roberts A. B., Sporn M. B. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5788–5792. doi: 10.1073/pnas.84.16.5788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wahl S. M., Hunt D. A., Wong H. L., Dougherty S., McCartney-Francis N., Wahl L. M., Ellingsworth L., Schmidt J. A., Hall G., Roberts A. B. Transforming growth factor-beta is a potent immunosuppressive agent that inhibits IL-1-dependent lymphocyte proliferation. J Immunol. 1988 May 1;140(9):3026–3032. [PubMed] [Google Scholar]
  34. Wahl S. M., Wilder R. L., Katona I. M., Wahl L. M., Allen J. B., Scher I., Decker J. L. Leukapheresis in rheumatoid arthritis. Association of clinical improvement with reversal of anergy. Arthritis Rheum. 1983 Sep;26(9):1076–1084. doi: 10.1002/art.1780260904. [DOI] [PubMed] [Google Scholar]
  35. Wilder R. L., Allen J. B., Wahl L. M., Calandra G. B., Wahl S. M. The pathogenesis of group A streptococcal cell wall-induced polyarthritis in the rat. Comparative studies in arthritis resistant and susceptible inbred rat strains. Arthritis Rheum. 1983 Dec;26(12):1442–1451. doi: 10.1002/art.1780261205. [DOI] [PubMed] [Google Scholar]
  36. Yocum D. E., Allen J. B., Wahl S. M., Calandra G. B., Wilder R. L. Inhibition by cyclosporin A of streptococcal cell wall-induced arthritis and hepatic granulomas in rats. Arthritis Rheum. 1986 Feb;29(2):262–273. doi: 10.1002/art.1780290215. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES