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. 1995 Nov;86(3):356–363.

Gangliosides are potent immunosuppressors of IL-2-mediated T-cell proliferation in a low protein environment.

P Lu 1, F J Sharom 1
PMCID: PMC1383937  PMID: 8550071

Abstract

Gangliosides are immunosuppressive to many classes of immune cells, and shedding of these glycosphingolipids by tumour cells may regulate immune responses in cancer, and protect tumours from host immune destruction. One mechanism of immunosuppression by gangliosides in vitro involves competition with interleukin-2 receptors (IL-2R) for binding of IL-2. Previous studies on inhibition of IL-2-mediated events by gangliosides have been conducted in the presence of high levels of fetal bovine serum (FBS). However, gangliosides shed by tumours in vivo will encounter immune cells in the low protein microenvironment of the tissue fluid. In order to better mimic physiological conditions, we have examined immunosuppression by gangliosides towards IL-2-dependent HT-2 cells in a low serum-low protein medium. The ability of gangliosides to inhibit IL-2-stimulated DNA synthesis in HT-2 increased dramatically as the serum concentration in the culture medium was decreased; the 50% inhibitory concentration (IC50) value for GM1 was 13 microM under low serum conditions, 14-fold lower than the value obtained in 10% FBS. Further investigation revealed that the mechanism of immunosuppression by gangliosides in low serum-low protein medium involved interference with the IL-2/IL-2R system. Ganglioside-mediated inhibition was dependent on the continued presence of the glycolipids during the first few hours after IL-2 stimulation, and could be reversed by increasing levels of IL-2. Receptor binding experiments demonstrated that gangliosides blocked the interaction of IL-2 with high-affinity IL-2 receptors on HT-2. Taken together, these results support the view that gangliosides will act as much more potent suppressors of IL-2-dependent processes in vivo in the vicinity of a tumour.

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Selected References

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  1. Ausiello C. M., Adorno D., Graña G., Urbani F., Spagnoli G. C., Sconocchia G., Cococcetta N., Casciani C. U. Inhibitory effects of gangliosides and cyclosporine on lymphocyte activation: analysis of cytokine gene mRNA transcripts. Transplant Proc. 1993 Jun;25(3):2315–2316. [PubMed] [Google Scholar]
  2. Chu J. W., Sharom F. J. Effect of micellar and bilayer gangliosides on proliferation of interleukin-2-dependent lymphocytes. Cell Immunol. 1991 Feb;132(2):319–338. doi: 10.1016/0008-8749(91)90031-6. [DOI] [PubMed] [Google Scholar]
  3. Chu J. W., Sharom F. J. Gangliosides inhibit T-lymphocyte proliferation by preventing the interaction of interleukin-2 with its cell surface receptors. Immunology. 1993 May;79(1):10–17. [PMC free article] [PubMed] [Google Scholar]
  4. Chu J. W., Sharom F. J. Gangliosides interact with interleukin-4 and inhibit interleukin-4-stimulated helper T-cell proliferation. Immunology. 1995 Mar;84(3):396–403. [PMC free article] [PubMed] [Google Scholar]
  5. Chu J. W., Sharom F. J. Glycophorin A interacts with interleukin-2 and inhibits interleukin-2-dependent T-lymphocyte proliferation. Cell Immunol. 1992 Dec;145(2):223–239. doi: 10.1016/0008-8749(92)90327-l. [DOI] [PubMed] [Google Scholar]
  6. Chu J. W., Sharom F. J. Interleukin-2 binds to gangliosides in micelles and lipid bilayers. Biochim Biophys Acta. 1990 Oct 19;1028(3):205–214. doi: 10.1016/0005-2736(90)90168-n. [DOI] [PubMed] [Google Scholar]
  7. Dyatlovitskaya E. V., Bergelson L. D. Glycosphingolipids and antitumor immunity. Biochim Biophys Acta. 1987 Jul 8;907(2):125–143. doi: 10.1016/0304-419x(87)90002-3. [DOI] [PubMed] [Google Scholar]
  8. Floutsis G., Ulsh L., Ladisch S. Immunosuppressive activity of human neuroblastoma tumor gangliosides. Int J Cancer. 1989 Jan 15;43(1):6–9. doi: 10.1002/ijc.2910430103. [DOI] [PubMed] [Google Scholar]
  9. Higashi H., Hirabayashi Y., Hirota M., Matsumoto M., Kato S. Detection of ganglioside GM2 in sera and tumor tissues of hepatoma patients. Jpn J Cancer Res. 1987 Dec;78(12):1309–1313. [PubMed] [Google Scholar]
  10. Hoon D. S., Irie R. F., Cochran A. J. Gangliosides from human melanoma immunomodulate response of T cells to interleukin-2. Cell Immunol. 1988 Feb;111(2):410–419. doi: 10.1016/0008-8749(88)90104-9. [DOI] [PubMed] [Google Scholar]
  11. Ikeda T., Nakakuma H., Shionoya H., Kawaguchi T., Yamatsu K., Takatsuki K. Ganglioside-induced inhibition of in vivo immune response in mice. Life Sci. 1992;51(11):847–851. doi: 10.1016/0024-3205(92)90612-s. [DOI] [PubMed] [Google Scholar]
  12. Ladisch S., Becker H., Ulsh L. Immunosuppression by human gangliosides: I. Relationship of carbohydrate structure to the inhibition of T cell responses. Biochim Biophys Acta. 1992 Apr 23;1125(2):180–188. doi: 10.1016/0005-2760(92)90043-u. [DOI] [PubMed] [Google Scholar]
  13. Ladisch S., Gillard B., Wong C., Ulsh L. Shedding and immunoregulatory activity of YAC-1 lymphoma cell gangliosides. Cancer Res. 1983 Aug;43(8):3808–3813. [PubMed] [Google Scholar]
  14. Ladisch S., Kitada S., Hays E. F. Gangliosides shed by tumor cells enhance tumor formation in mice. J Clin Invest. 1987 Jun;79(6):1879–1882. doi: 10.1172/JCI113031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ladisch S., Wu Z. L., Feig S., Ulsh L., Schwartz E., Floutsis G., Wiley F., Lenarsky C., Seeger R. Shedding of GD2 ganglioside by human neuroblastoma. Int J Cancer. 1987 Jan 15;39(1):73–76. doi: 10.1002/ijc.2910390113. [DOI] [PubMed] [Google Scholar]
  16. Marcus D. M. A review of the immunogenic and immuno-modulatory properties of glycosphingolipids. Mol Immunol. 1984 Nov;21(11):1083–1091. doi: 10.1016/0161-5890(84)90118-4. [DOI] [PubMed] [Google Scholar]
  17. Mikhailenko I. A., Dubrovskaya S. A., Korepanova O. B., Timofeeva N. G., Morozkin A. D., Prokazova N. V., Bergelson L. D. Interaction of low-density lipoproteins with gangliosides. Biochim Biophys Acta. 1991 Oct 1;1085(3):299–305. doi: 10.1016/0005-2760(91)90133-3. [DOI] [PubMed] [Google Scholar]
  18. Minami Y., Kono T., Miyazaki T., Taniguchi T. The IL-2 receptor complex: its structure, function, and target genes. Annu Rev Immunol. 1993;11:245–268. doi: 10.1146/annurev.iy.11.040193.001333. [DOI] [PubMed] [Google Scholar]
  19. Portoukalian J., David M. J., Gain P., Richard M. Shedding of GD2 ganglioside in patients with retinoblastoma. Int J Cancer. 1993 Apr 1;53(6):948–951. doi: 10.1002/ijc.2910530614. [DOI] [PubMed] [Google Scholar]
  20. Portoukalian J., David M. J., Shen X., Richard M., Dubreuil C. Tumor size-dependent elevations of serum gangliosides in patients with head and neck carcinomas. Biochem Int. 1989 Apr;18(4):759–765. [PubMed] [Google Scholar]
  21. Prokazova N. V., Dyatlovitskaya E. V., Bergelson L. D. Sialylated lactosylceramides. Possible inducers of non-specific immunosuppression and atherosclerotic lesions. Eur J Biochem. 1988 Feb 15;172(1):1–6. doi: 10.1111/j.1432-1033.1988.tb13847.x. [DOI] [PubMed] [Google Scholar]
  22. Saha S., Chattopadhyay U. Changes in plasma gangliosides in relation to tumor growth and their tumor-enhancing effect. Int J Cancer. 1988 Mar 15;41(3):432–435. doi: 10.1002/ijc.2910410320. [DOI] [PubMed] [Google Scholar]
  23. Sariola H., Terävä H., Rapola J., Saarinen U. M. Cell-surface ganglioside GD2 in the immunohistochemical detection and differential diagnosis of neuroblastoma. Am J Clin Pathol. 1991 Aug;96(2):248–252. doi: 10.1093/ajcp/96.2.248. [DOI] [PubMed] [Google Scholar]
  24. Sekaly R. P., MacDonald H. R., Nabholz M., Smith K. A., Cerottini J. C. Regulation of the rate of cell cycle progression in quiescent cytolytic T cells by T cell growth factor: analysis by flow microfluorometry. J Cell Physiol. 1984 Oct;121(1):159–166. doi: 10.1002/jcp.1041210120. [DOI] [PubMed] [Google Scholar]
  25. Senn H. J., Orth M., Fitzke E., Wieland H., Gerok W. Gangliosides in normal human serum. Concentration, pattern and transport by lipoproteins. Eur J Biochem. 1989 May 15;181(3):657–662. doi: 10.1111/j.1432-1033.1989.tb14773.x. [DOI] [PubMed] [Google Scholar]
  26. Sharom F. J., Chiu A. L., Chu J. W. Membrane gangliosides modulate interleukin-2-stimulated T-lymphocyte proliferation. Biochim Biophys Acta. 1991 Aug 13;1094(1):35–42. doi: 10.1016/0167-4889(91)90023-q. [DOI] [PubMed] [Google Scholar]
  27. Sharom F. J., Chiu A. L., Ross T. E. Gangliosides and glycophorin inhibit T-lymphocyte activation. Biochem Cell Biol. 1990 Apr;68(4):735–744. doi: 10.1139/o90-106. [DOI] [PubMed] [Google Scholar]
  28. Sharom F. J., Ross T. E. Association of gangliosides with the lymphocyte plasma membrane studied using radiolabels and spin labels. Biochim Biophys Acta. 1986 Jan 29;854(2):287–297. doi: 10.1016/0005-2736(86)90122-7. [DOI] [PubMed] [Google Scholar]
  29. Valentino L. A., Ladisch S. Localization of shed human tumor gangliosides: association with serum lipoproteins. Cancer Res. 1992 Feb 15;52(4):810–814. [PubMed] [Google Scholar]
  30. Valentino L., Moss T., Olson E., Wang H. J., Elashoff R., Ladisch S. Shed tumor gangliosides and progression of human neuroblastoma. Blood. 1990 Apr 1;75(7):1564–1567. [PubMed] [Google Scholar]
  31. Venerando B., Roberti S., Sonnino S., Fiorilli A., Tettamanti G. Interactions of ganglioside GM1 with human and fetal calf sera. Formation of ganglioside-serum albumin complexes. Biochim Biophys Acta. 1982 Oct 22;692(1):18–26. doi: 10.1016/0005-2736(82)90497-7. [DOI] [PubMed] [Google Scholar]

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