Skip to main content
Log in

Gangliosides in T cell development and function of mice

  • Mini Review
  • Published:
Glycoconjugate Journal Aims and scope Submit manuscript

Abstract

The molecular diversity of glycosphingolipids (GSLs) that arouse during the course of evolution clearly plays an essential role in maintenance of biological homeostasis. Why is such a wide variety of GSLs necessary, and what gave rise to the expression mechanisms that are selective and specific to individual cells, tissues, or organs? What is the biological significance of these mechanisms? The same questions apply to GSLs involved in T cell development and activation. Primary CD4+ T cells and CD8+ T cells preferentially express differing ganglioside series: a-series and o-series, respectively. Conversely, a-series and o-series ganglioside deficiency results respectively in CD4+ and CD8+ T cell dysfunction. Dynamic changes in ganglioside expression occur during T cell development in thymus. Ganglioside GM3 synthase deficiency, which results in lack of a-series gangliosides, ameliorated CD4+ T cell-mediated airway hypersensitivity in a mouse model of allergic asthma. In this review, we summarize findings from these and many studies to illustrate the key roles of gangliosides in T cell differentiation and function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Inokuchi, J., Radin, N.S.: Preparation of the active isomer of 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, inhibitor of murine glucocerebroside synthetase. J. Lipid. Res. 28(5), 565–571 (1987)

    Article  CAS  Google Scholar 

  2. Radin, N.S., Inokuchi, J.: Glucosphingolipids as sites of action in the chemotherapy of cancer. Biochem. Pharmacol. 37(15), 2879–2886 (1988). https://doi.org/10.1016/0006-2952(88)90271-7

    Article  CAS  PubMed  Google Scholar 

  3. Felding-Habermann, B., Igarashi, Y., Fenderson, B.A., Park, L.S., Radin, N.S., Inokuchi, J., Strassmann, G., Handa, K., Hakomori, S.: A ceramide analogue inhibits T cell proliferative response through inhibition of glycosphingolipid synthesis and enhancement of N. N-dimethylsphingosine synthesis. Biochemistry 29(26), 6314–6322 (1990). https://doi.org/10.1021/bi00478a028

    Article  CAS  PubMed  Google Scholar 

  4. Inokuchi, J., Momosaki, K., Shimeno, H., Nagamatsu, A., Radin, N.S.: Effects of D-threo-PDMP, an inhibitor of glucosylceramide synthetase, on expression of cell surface glycolipid antigen and binding to adhesive proteins by B16 melanoma cells. J. Cell Physiol. 141(3), 573–583 (1989). https://doi.org/10.1002/jcp.1041410316

    Article  CAS  PubMed  Google Scholar 

  5. Shukla, G.S., Shukla, A., Inokuchi, J., Radin, N.S.: Rapid kidney changes resulting from glycosphingolipid depletion by treatment with a glucosyltransferase inhibitor. Biochim. Biophys. Acta. 1083(1), 101–108 (1991). https://doi.org/10.1016/0005-2760(91)90130-a

    Article  CAS  PubMed  Google Scholar 

  6. Kyogashima, M., Inoue, M., Seto, A., Inokuchi, J.: Glucosylceramide synthetase inhibitor, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol exhibits a novel decarcinogenic activity against Shope carcinoma cells. Cancer Lett. 101(1), 25–30 (1996). https://doi.org/10.1016/0304-3835(95)04106-0

    Article  CAS  PubMed  Google Scholar 

  7. Mizutani, A., Kuroda, Y., Muramoto, K., Kobayashi, K., Yamagishi, K., Inokuchi, J.: Effects of glucosylceramide synthase inhibitor and ganglioside GQ1b on synchronous oscillations of intracellular Ca2+ in cultured cortical neurons. Biochem. Biophys. Res. Commun. 222(2), 494–498 (1996). https://doi.org/10.1006/bbrc.1996.0772

    Article  CAS  PubMed  Google Scholar 

  8. Mutoh, T., Tokuda, A., Inokuchi, J., Kuriyama, M.: Glucosylceramide synthase inhibitor inhibits the action of nerve growth factor in PC12 cells. J. Biol. Chem. 273(40), 26001–26007 (1998). https://doi.org/10.1074/jbc.273.40.26001

    Article  CAS  PubMed  Google Scholar 

  9. Tagami, S., Inokuchi Ji, J., Kabayama, K., Yoshimura, H., Kitamura, F., Uemura, S., Ogawa, C., Ishii, A., Saito, M., Ohtsuka, Y., Sakaue, S., Igarashi, Y.: Ganglioside GM3 participates in the pathological conditions of insulin resistance. J. Biol. Chem. 277(5), 3085–3092 (2002). https://doi.org/10.1074/jbc.M103705200

    Article  CAS  PubMed  Google Scholar 

  10. Nagafuku, M., Kabayama, K., Oka, D., Kato, A., Tani-ichi, S., Shimada, Y., Ohno-Iwashita, Y., Yamasaki, S., Saito, T., Iwabuchi, K., Hamaoka, T., Inokuchi, J., Kosugi, A.: Reduction of glycosphingolipid levels in lipid rafts affects the expression state and function of glycosylphosphatidylinositol-anchored proteins but does not impair signal transduction via the T cell receptor. J. Biol. Chem. 278(51), 51920–51927 (2003). https://doi.org/10.1074/jbc.M307674200

    Article  CAS  PubMed  Google Scholar 

  11. Sekimoto, J., Kabayama, K., Gohara, K., Inokuchi, J.: Dissociation of the insulin receptor from caveolae during TNFα-induced insulin resistance and its recovery by D-PDMP. FEBS Lett. 586(2), 191–195 (2012). https://doi.org/10.1016/j.febslet.2011.12.019

    Article  CAS  PubMed  Google Scholar 

  12. Ode, T., Podyma-Inoue, K.A., Terasawa, K., Inokuchi, J.I., Kobayashi, T., Watabe, T., Izumi, Y., Hara-Yokoyama, M.: PDMP, a ceramide analogue, acts as an inhibitor of mTORC1 by inducing its translocation from lysosome to endoplasmic reticulum. Exp. Cell Res. 350(1), 103–114 (2017). https://doi.org/10.1016/j.yexcr.2016.11.011

    Article  CAS  PubMed  Google Scholar 

  13. Rothenberg, E.V., Taghon, T.: Molecular genetics of T cell development. Annu. Rev. Immunol. 23, 601–649 (2005). https://doi.org/10.1146/annurev.immunol.23.021704.115737

    Article  CAS  PubMed  Google Scholar 

  14. Fooksman, D.R., Vardhana, S., Vasiliver-Shamis, G., Liese, J., Blair, D.A., Waite, J., Sacristan, C., Victora, G.D., Zanin-Zhorov, A., Dustin, M.L.: Functional anatomy of T cell activation and synapse formation. Annu. Rev. Immunol. 28, 79–105 (2010). https://doi.org/10.1146/annurev-immunol-030409-101308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dykstra, M., Cherukuri, A., Sohn, H.W., Tzeng, S.J., Pierce, S.K.: Location is everything: lipid rafts and immune cell signaling. Annu. Rev. Immunol. 21, 457–481 (2003). https://doi.org/10.1146/annurev.immunol.21.120601.141021

    Article  CAS  PubMed  Google Scholar 

  16. Kovacs, B., Maus, M.V., Riley, J.L., Derimanov, G.S., Koretzky, G.A., June, C.H., Finkel, T.H.: Human CD8+ T cells do not require the polarization of lipid rafts for activation and proliferation. Proc. Natl. Acad. Sci. U S A 99(23), 15006–15011 (2002). https://doi.org/10.1073/pnas.232058599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gómez-Móuton, C., Abad, J.L., Mira, E., Lacalle, R.A., Gallardo, E., Jiménez-Baranda, S., Illa, I., Bernad, A., Mañes, S., Martínez, A.C.: Segregation of leading-edge and uropod components into specific lipid rafts during T cell polarization. Proc. Natl. Acad. Sci. U S A 98(17), 9642–9647 (2001). https://doi.org/10.1073/pnas.171160298

    Article  PubMed  PubMed Central  Google Scholar 

  18. Saito, T., Yokosuka, T.: Immunological synapse and microclusters: the site for recognition and activation of T cells. Curr. Opin. Immunol. 18(3), 305–313 (2006). https://doi.org/10.1016/j.coi.2006.03.014

    Article  CAS  PubMed  Google Scholar 

  19. Dustin, M.L., Depoil, D.: New insights into the T cell synapse from single molecule techniques. Nat. Rev. Immunol. 11(10), 672–684 (2011). https://doi.org/10.1038/nri3066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Harder, T., Rentero, C., Zech, T., Gaus, K.: Plasma membrane segregation during T cell activation: probing the order of domains. Cur. Opin. Immunol. 19(4), 470–475 (2007). https://doi.org/10.1016/j.coi.2007.05.002

    Article  CAS  Google Scholar 

  21. Eissmann, P., Davis, D.M.: Inhibitory and regulatory immune synapses. Curr. Top Microbiol. Immunol. 340, 63–79 (2010). https://doi.org/10.1007/978-3-642-03858-7_4

    Article  CAS  PubMed  Google Scholar 

  22. Marusić, A., Markotić, A., Kovacić, N., Müthing, J.: Expression of glycosphingolipids in lymph nodes of mice lacking TNF receptor 1: biochemical and flow cytometry analysis. Carbohydr. Res. 339(1), 77–86 (2004). https://doi.org/10.1016/j.carres.2003.09.024

    Article  CAS  PubMed  Google Scholar 

  23. Nakamura, K., Suzuki, H., Hirabayashi, Y., Suzuki, A.: IV3 alpha (NeuGc alpha 2–8NeuGc)-Gg4Cer is restricted to CD4+ T cells producing interleukin-2 and a small population of mature thymocytes in mice. J. Biol. Chem. 270(8), 3876–3881 (1995)

    Article  CAS  Google Scholar 

  24. Nagafuku, M., Okuyama, K., Onimaru, Y., Suzuki, A., Odagiri, Y., Yamashita, T., Iwasaki, K., Fujiwara, M., Takayanagi, M., Ohno, I., Inokuchi, J.: CD4 and CD8 T cells require different membrane gangliosides for activation. Proc. Natl. Acad. Sci. U S A 109(6), E336-342 (2012). https://doi.org/10.1073/pnas.1114965109

    Article  PubMed  PubMed Central  Google Scholar 

  25. Blank, N., Schiller, M., Gabler, C., Kalden, J.R., Lorenz, H.M.: Inhibition of sphingolipid synthesis impairs cellular activation, cytokine production and proliferation in human lymphocytes. Biochem. Pharmacol. 71(1–2), 126–135 (2005). https://doi.org/10.1016/j.bcp.2005.10.004

    Article  CAS  PubMed  Google Scholar 

  26. Yoshikawa, M., Go, S., Takasaki, K., Kakazu, Y., Ohashi, M., Nagafuku, M., Kabayama, K., Sekimoto, J., Suzuki, S., Takaiwa, K., Kimitsuki, T., Matsumoto, N., Komune, S., Kamei, D., Saito, M., Fujiwara, M., Iwasaki, K., Inokuchi, J.: Mice lacking ganglioside GM3 synthase exhibit complete hearing loss due to selective degeneration of the organ of Corti. Proc. Natl. Acad. Sci. U S A 106(23), 9483–9488 (2009). https://doi.org/10.1073/pnas.0903279106

    Article  PubMed  PubMed Central  Google Scholar 

  27. Takamiya, K., Yamamoto, A., Furukawa, K., Yamashiro, S., Shin, M., Okada, M., Fukumoto, S., Haraguchi, M., Takeda, N., Fujimura, K., Sakae, M., Kishikawa, M., Shiku, H., Furukawa, K., Aizawa, S.: Mice with disrupted GM2/GD2 synthase gene lack complex gangliosides but exhibit only subtle defects in their nervous system. Proc. Natl. Acad. Sci. U S A 93(20), 10662–10667 (1996). https://doi.org/10.1073/pnas.93.20.10662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. de Mello Coelho, V., Nguyen, D., Giri, B., Bunbury, A., Schaffer, E., Taub, D.D.: Quantitative differences in lipid raft components between murine CD4+ and CD8+ T cells. BMC Immunol. 5, 2 (2004). https://doi.org/10.1186/1471-2172-5-2

    Article  PubMed  PubMed Central  Google Scholar 

  29. Nakamura, K., Suzuki, M., Inagaki, F., Yamakawa, T., Suzuki, A.: A new ganglioside showing choleragenoid-binding activity in mouse spleen. J. Biochem. 101(4), 825–835 (1987). https://doi.org/10.1093/oxfordjournals.jbchem.a121949

    Article  CAS  PubMed  Google Scholar 

  30. Soriani, M., Williams, N.A., Hirst, T.R.: Escherichia coli enterotoxin B subunit triggers apoptosis of CD8(+) T cells by activating transcription factor c-myc. Infect. Immun. 69(8), 4923–4930 (2001). https://doi.org/10.1128/IAI.69.8.4923-4930.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Salmond, R.J., Pitman, R.S., Jimi, E., Soriani, M., Hirst, T.R., Ghosh, S., Rincón, M., Williams, N.A.: CD8+ T cell apoptosis induced by Escherichia coli heat-labile enterotoxin B subunit occurs via a novel pathway involving NF-kappaB-dependent caspase activation. Eur. J. Immunol. 32(6), 1737–1747 (2002). https://doi.org/10.1002/1521-4141(200206)32:6%3c1737::Aid-immu1737%3e3.0.Co;2-j

    Article  CAS  PubMed  Google Scholar 

  32. Salmond, R.J., Williams, R., Hirst, T.R., Williams, N.A.: The B subunit of Escherichia coli heat-labile enterotoxin induces both caspase-dependent and -independent cell death pathways in CD8+ T cells. Infect. Immun. 72(10), 5850–5857 (2004). https://doi.org/10.1128/IAI.72.10.5850-5857.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Balamuth, F., Brogdon, J.L., Bottomly, K.: CD4 raft association and signaling regulate molecular clustering at the immunological synapse site. J. Immunol. 172(10), 5887–5892 (2004). https://doi.org/10.4049/jimmunol.172.10.5887

    Article  CAS  PubMed  Google Scholar 

  34. Pang, D.J., Hayday, A.C., Bijlmakers, M.J.: CD8 Raft localization is induced by its assembly into CD8alpha beta heterodimers, Not CD8alpha alpha homodimers. J. Biol. Chem. 282(18), 13884–13894 (2007). https://doi.org/10.1074/jbc.M701027200

    Article  CAS  PubMed  Google Scholar 

  35. Kroczek, R.A., Mages, H.W., Hutloff, A.: Emerging paradigms of T-cell co-stimulation. Curr. Opin. Immunol. 16(3), 321–327 (2004). https://doi.org/10.1016/j.coi.2004.03.002

    Article  CAS  PubMed  Google Scholar 

  36. Greenwald, R.J., Freeman, G.J., Sharpe, A.H.: The B7 family revisited. Annu. Rev. Immunol. 23, 515–548 (2005). https://doi.org/10.1146/annurev.immunol.23.021704.115611

    Article  CAS  PubMed  Google Scholar 

  37. Bi, K., Tanaka, Y., Coudronniere, N., Sugie, K., Hong, S., van Stipdonk, M.J., Altman, A.: Antigen-induced translocation of PKC-theta to membrane rafts is required for T cell activation. Nat. Immunol. 2(6), 556–563 (2001). https://doi.org/10.1038/88765

    Article  CAS  PubMed  Google Scholar 

  38. O’Keefe, J.P., Blaine, K., Alegre, M.L., Gajewski, T.F.: Formation of a central supramolecular activation cluster is not required for activation of naive CD8+ T cells. Proc. Natl. Acad. Sci. U S A 101(25), 9351–9356 (2004). https://doi.org/10.1073/pnas.0305965101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Popovic, Z.V., Rabionet, M., Jennemann, R., Krunic, D., Sandhoff, R., Gröne, H.J., Porubsky, S.: Glucosylceramide Synthase Is Involved in Development of Invariant Natural Killer T Cells. Front. Immunol. 8, 848 (2017). https://doi.org/10.3389/fimmu.2017.00848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zech, T., Ejsing, C.S., Gaus, K., de Wet, B., Shevchenko, A., Simons, K., Harder, T.: Accumulation of raft lipids in T-cell plasma membrane domains engaged in TCR signalling. EMBO J. 28(5), 466–476 (2009). https://doi.org/10.1038/emboj.2009.6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Toshima, K., Nagafuku, M., Okazaki, T., Kobayashi, T., Inokuchi, J.I.: Plasma membrane sphingomyelin modulates thymocyte development by inhibiting TCR-induced apoptosis. Int. Immunol. 31(4), 211–223 (2019). https://doi.org/10.1093/intimm/dxy082

    Article  CAS  PubMed  Google Scholar 

  42. Inokuchi, J.: Inhibition of ganglioside biosynthesis as a novel therapeutic approach in insulin resistance. Handb. Exp. Pharmacol. (203), 165–178 (2011). https://doi.org/10.1007/978-3-642-17214-4_8

  43. Tani-ichi, S., Maruyama, K., Kondo, N., Nagafuku, M., Kabayama, K., Inokuchi, J., Shimada, Y., Ohno-Iwashita, Y., Yagita, H., Kawano, S., Kosugi, A.: Structure and function of lipid rafts in human activated T cells. Int. Immunol. 17(6), 749–758 (2005). https://doi.org/10.1093/intimm/dxh257

    Article  CAS  PubMed  Google Scholar 

  44. Dong, L., Hu, S., Chen, F., Lei, X., Tu, W., Yu, Y., Yang, L., Sun, W., Yamaguchi, T., Masaki, Y., Umehara, H.: Increased expression of ganglioside GM1 in peripheral CD4+ T cells correlates soluble form of CD30 in Systemic Lupus Erythematosus patients. J. Biomed. Biotechnol. 2010,(2010)

  45. Rahman, A., Isenberg, D.A.: Systemic lupus erythematosus. N. Engl. J. Med. 358(9), 929–939 (2008). https://doi.org/10.1056/NEJMra071297

    Article  CAS  PubMed  Google Scholar 

  46. Tsokos, G.C.: Systemic lupus erythematosus. N. Engl. J. Med. 365(22), 2110–2121 (2011). https://doi.org/10.1056/NEJMra1100359

    Article  CAS  PubMed  Google Scholar 

  47. Jury, E.C., Kabouridis, P.S., Flores-Borja, F., Mageed, R.A., Isenberg, D.A.: Altered lipid raft-associated signaling and ganglioside expression in T lymphocytes from patients with systemic lupus erythematosus. J. Clin. Invest. 113(8), 1176–1187 (2004). https://doi.org/10.1172/jci20345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Krishnan, S., Nambiar, M.P., Warke, V.G., Fisher, C.U., Mitchell, J., Delaney, N., Tsokos, G.C.: Alterations in lipid raft composition and dynamics contribute to abnormal T cell responses in systemic lupus erythematosus. J. Immunol. 172(12), 7821–7831 (2004). https://doi.org/10.4049/jimmunol.172.12.7821

    Article  CAS  PubMed  Google Scholar 

  49. McDonald, G., Deepak, S., Miguel, L., Hall, C.J., Isenberg, D.A., Magee, A.I., Butters, T., Jury, E.C.: Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients. J. Clin. Invest. 124(2), 712–724 (2014). https://doi.org/10.1172/jci69571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kabouridis, P.S., Jury, E.C.: Lipid rafts and T-lymphocyte function: implications for autoimmunity. FEBS Lett. 582(27), 3711–3718 (2008). https://doi.org/10.1016/j.febslet.2008.10.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Degroote, S., Wolthoorn, J., van Meer, G.: The cell biology of glycosphingolipids. Semin. Cell Dev. Biol. 15(4), 375–387 (2004). https://doi.org/10.1016/j.semcdb.2004.03.007

    Article  CAS  PubMed  Google Scholar 

  52. Kidani, Y., Bensinger, S.J.: Lipids rule: resetting lipid metabolism restores T cell function in systemic lupus erythematosus. J. Clin. Invest. 124(2), 482–485 (2014). https://doi.org/10.1172/jci74141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Shalaby, K.H., Martin, J.G.: Overview of asthma; the place of the T cell. Curr. Opin. Pharmacol. 10(3), 218–225 (2010). https://doi.org/10.1016/j.coph.2010.03.004

    Article  CAS  PubMed  Google Scholar 

  54. Lloyd, C.M., Hessel, E.M.: Functions of T cells in asthma: more than just T(H)2 cells. Nat. Rev. Immunol. 10(12), 838–848 (2010). https://doi.org/10.1038/nri2870

    Article  CAS  PubMed  Google Scholar 

  55. Zhu, Y., Gumlaw, N., Karman, J., Zhao, H., Zhang, J., Jiang, J.L., Maniatis, P., Edling, A., Chuang, W.L., Siegel, C., Shayman, J.A., Kaplan, J., Jiang, C., Cheng, S.H.: Lowering glycosphingolipid levels in CD4+ T cells attenuates T cell receptor signaling, cytokine production, and differentiation to the Th17 lineage. J. Biol. Chem. 286(17), 14787–14794 (2011). https://doi.org/10.1074/jbc.M111.218610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tsukuda, Y., Iwasaki, N., Seito, N., Kanayama, M., Fujitani, N., Shinohara, Y., Kasahara, Y., Onodera, T., Suzuki, K., Asano, T., Minami, A., Yamashita, T.: Ganglioside GM3 has an essential role in the pathogenesis and progression of rheumatoid arthritis. PLoS ONE 7(6), e40136 (2012). https://doi.org/10.1371/journal.pone.0040136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are grateful to Dr. S. Anderson for English editing for the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jin-ichi Inokuchi.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article belongs to the Topical Collection: Tribute to Professor Sen-itiroh Hakomori

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Inokuchi, Ji., Nagafuku, M. Gangliosides in T cell development and function of mice. Glycoconj J 39, 229–238 (2022). https://doi.org/10.1007/s10719-021-10037-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10719-021-10037-5

Keywords

Navigation