Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Activation of natural killer T cells by α-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes

Nature Medicine volume 7, pages 1057–1062 (2001)Cite this article

Abstract

Type 1 diabetes (T1D) in non-obese diabetic (NOD) mice may be favored by immune dysregulation leading to the hyporesponsiveness of regulatory T cells and activation of effector T-helper type 1 (Th1) cells1. The immunoregulatory activity of natural killer T (NKT) cells is well documented2,3, and both interleukin (IL)-4 and IL-10 secreted by NKT cells have important roles in mediating this activity4,5. NKT cells are less frequent and display deficient IL-4 responses in both NOD mice6,7 and individuals at risk for T1D (ref. 8), and this deficiency may lead to T1D (refs. 1,6–9). Thus, given that NKT cells respond to the α-galactosylceramide (α-GalCer) glycolipid in a CD1d-restricted manner by secretion of Th2 cytokines10,11,12, we reasoned that activation of NKT cells by α-GalCer might prevent the onset and/or recurrence of T1D. Here we show that α-GalCer treatment, even when initiated after the onset of insulitis, protects female NOD mice from T1D and prolongs the survival of pancreatic islets transplanted into newly diabetic NOD mice. In addition, when administered after the onset of insulitis, α-GalCer and IL-7 displayed synergistic effects, possibly via the ability of IL-7 to render NKT cells fully responsive to α-GalCer. Protection from T1D by α-GalCer was associated with the suppression of both T- and B-cell autoimmunity to islet β cells and with a polarized Th2-like response in spleen and pancreas of these mice. These findings raise the possibility thatα-GalCer treatment might be used therapeutically to prevent the onset and recurrence of human T1D.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: α-GalCer stimulates IL-4 and IFN-γ production by NKT cells and prevents T1D in NOD mice.
Figure 2: α-GalCer treatment protects female NOD mice from CY-accelerated T1D and recurrent T1D in recipients in a CD1d-dependent manner.
Figure 3: α-GalCer–mediated protection from CY-induced T1D is associated with a Th2-enriched environment in spleen and pancreas and an increased frequency of NKT cells in spleen and PLN.
Figure 4: α-GalCer inhibits the diabetogenic activity of spleen T cells, suppresses β-cell specific autoimmunity and promotes a Th2 response against autoantigens. Female NOD mice were treated at 3–5 wk of age every day (2 μg/mouse/day).

Similar content being viewed by others

References

  1. Delovitch, T.L. & Singh, B. The nonobese diabetic mouse as a model of autoimmune diabetes: Immune dysregulation gets the NOD. Immunity 7, 727–738 (1997).

    Article  PubMed  Google Scholar 

  2. Sonoda, K.H., Exley, M., Snapper, S., Balk, S.P. & Stein-Streilein, J. CD1-reactive natural killer T cells are required for development of systemic tolerance through an immune-privileged site. J. Exp. Med. 190, 1215–1226 (1999).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Godfrey, D.I., Hammond, K.J., Poulton, L.D., Smyth, M.J. & Baxter, A.G. NKT cells: facts, functions and fallacies. Immunol. Today 21, 573–83 (2000).

    Article  PubMed  Google Scholar 

  4. Yoshimoto, T. & Paul, W.E. CD4pos, NK1.1pos T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3. J. Exp. Med. 179, 1285–1295 (1994).

    Article  PubMed  Google Scholar 

  5. Sonoda K.H. et al. NK T cell-derived IL-10 is essential for the differentiation of antigen-specific T regulatory cells in systemic tolerance. J. Immunol. 166, 42–50 (2001).

    Article  PubMed  Google Scholar 

  6. Baxter, A.G., Kinder, S.J., Hammond, K.J., Scollay, R. & Godfrey, D.I. Association between αbetaTCR+CD4−CD8− T-cell deficiency and IDDM in NOD/Lt mice. Diabetes 46, 572–582 (1997).

    Article  PubMed  Google Scholar 

  7. Gombert, J.M. et al. Early quantitative and functional deficiency of NK1+-like thymocytes in the NOD mouse. Eur. J. Immunol. 26, 2989–2998 (1996).

    Article  PubMed  Google Scholar 

  8. Wilson, S.B. et al. Extreme Th1 bias of invariant Vα24JαQ T cells in type 1 diabetes. Nature 391, 177–181 (1998).

    Article  PubMed  Google Scholar 

  9. Lehuen, A. et al. Overexpression of natural killer T cells protects Vα14- Jα281 transgenic nonobese diabetic mice against diabetes. J. Exp. Med. 188, 1831–1839 (1998).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kawano, T. et al. CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science 278, 1626–1629 (1997).

    Article  PubMed  Google Scholar 

  11. Burdin, N., Brossay, L. & Kronenberg, M. Immunization with α-galactosylceramide polarizes CD1-reactive NK T cells towards Th2 cytokine synthesis. Eur. J. Immunol. 29, 2014–2025 (1999).

    Article  PubMed  Google Scholar 

  12. Singh, N. et al. Activation of NK T cells by CD1d and α-galactosylceramide directs conventional T cells to the acquisition of a Th2 phenotype. J. Immunol. 163, 2373–2377 (1999).

    PubMed  Google Scholar 

  13. Hammond, K.J.L. et al. α/β-T cell receptor (TCR)+CD4−CD8− (NKT) thymocytes prevent insulin-dependent diabetes mellitus in nonobese diabetic (NOD)/Lt mice by the influence of interleukin (IL)-4 and/or IL-10. J. Exp. Med. 187, 1047–1056 (1998).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bendelac, A., Rivera M.N., Park S.H. & Roark J.H. Mouse CD1-specific NK1T cells: development, specificity, and function. Annu. Rev. Immunol. 15, 535–562 (1997).

    Article  PubMed  Google Scholar 

  15. Shevach, E.M. Regulatory T cells in autoimmunity. Annu. Rev. Immunol. 18, 423–449 (2000).

    Article  PubMed  Google Scholar 

  16. Brossay, L. et al. CD1d-mediated recognition of an α-galactosylceramide by natural killer T cells is highly conserved through mammalian evolution. J. Exp. Med. 188, 1521–1528 (1998).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Hameg, A. et al. A subset of NKT cells that lacks the NK1.1 marker, expresses CD1d molecules, and autopresents the α-galactosylceramide antigen. J. Immunol. 165, 4917–26 (2000).

    Article  PubMed  Google Scholar 

  18. Gombert, J.M. et al. IL-7 reverses NK1+ T cell-defective IL-4 production in the non-obese diabetic mice. Int. Immunol. 8, 1751–1758 (1996).

    Article  PubMed  Google Scholar 

  19. Vicari, A. et al. NK1.1+ T cells from IL-7-deficient mice have a normal distribution and selection but exhibit impaired cytokine production. Int. Immunol. 8, 1759–1766 (1996).

    Article  PubMed  Google Scholar 

  20. Yasunami, R. & Bach, J.F. Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice. Eur. J. Immunol. 18, 481–484 (1988).

    Article  PubMed  Google Scholar 

  21. Ikehara, Y. et al. CD4(+) Vα14 natural killer T cells are essential for acceptance of rat islet xenografts in mice. J. Clin. Invest. 105, 1761–1767 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Seino Ki, K. et al. Requirement for natural killer T (NKT) cells in the induction of allograft tolerance. Proc. Natl. Acad. Sci. USA 98, 2577–2581 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tori, M. et al. Proliferation of donor-derived NKR-P1+TCR α β+ (NKT) cells in the nonrecurrent spontaneous diabetic BB rats transplanted with pancreatic duodenal grafts of Wistar-Furth donors. Transplant. Proc. 31, 2741–2742 (1999).

    Article  PubMed  Google Scholar 

  24. Rabinovitch, A.O. Suarez-Pinzon, W.L. Sorensen, O. Rajotte, R.V. & Power, R.F. Combination therapy with cyclosporine and interleukin-4 or interleukin-10 prolongs survival of synergeneic pancreatic islet grafts in nonobese diabetic mice: islet graft survival does notcorrelate with mRNA levels of type 1 or type 2 cytokines, or transforming growth factor-beta in the islet grafts. Transplantation 64, 1525–1531 (1997).

    Article  PubMed  Google Scholar 

  25. Matsuda, J.L. et al. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J. Exp. Med. 192, 741–754 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lepault, F., Gagnerault, M.C., Faveeuw, C., Bazin, H. & Boitard, C. Lack of L-selectin expression by cells transferring diabetes in NOD mice: Insights into the mechanisms involved in diabetes prevention by Mel-14 antibody treatment. Eur. J. Immunol. 25, 1502–1507 (1995).

    Article  PubMed  Google Scholar 

  27. Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431–440 (2000).

    Article  PubMed  Google Scholar 

  28. Herbelin, A., Gombert, J.M., Lepault, F., Bach, J.F. & Chatenoud, L. Mature mainstream TCRαβ+CD4+ thymocytes expressing L-selectin mediate “active tolerance” in the nonobese diabetic mouse. J. Immunol. 161, 2620–2628 (1998).

    PubMed  Google Scholar 

  29. Lepault, F. & Gagnerault, M.C. Characterization of peripheral regulatory CD4+ T cells that prevent diabetes onset in nonobese diabetic mice. J. Immunol. 164, 240–247 (2000).

    Article  PubMed  Google Scholar 

  30. Hong, S. et al. The natural killer T-cell ligand α-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice. Nature Med. 7, 1052–1056 (2001).

    Article  PubMed  Google Scholar 

  31. Osman, Y. et al. Activation of hepatic NKT cells and subsequent liver injury following administration of α-galactosylceramide. Eur. J. Immunol. 30, 1919–1928 (2000).

    Article  PubMed  Google Scholar 

  32. Van Der Vliet, H.J. et al. Effects of α-galactosylceramide (KRN7000), interleukin-12 and interleukin-7 on phenotype and cytokine profile of human Vα24+Vαβ11+ T cells. Immunology 98, 557–563 (1999).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Laloux, V., Beaudoin, L., Jeske, D., Carnaud, C. & Lehuen, A. NKT cell-induced protection against diabetes in Vα14-Jα281 transgenic NOD mice is associated with a Th2 shift circumscribed regionally to the islets and functionally to islet auto-antigen. J. Immunol. 166, 749–3756 (2001).

    Article  Google Scholar 

Download references

Acknowledgements

We thank L. Van Kaer for sharing his findings before publication and for providing mutant CD1d-deficient mice; S. Chakrabarti and K. Mukerjee for their assistance with pancreas histology analyses; O. Babin and M.C. Gagnerault for technical assistance; E. Schneider for critical reading of the manuscript; all members of our laboratories for advice and encouragement; O. Lantz and D. Mouton for advice on kinetic PCR and OVA immunization, respectively; and the Sanofi Co. and A. Bendelac for providing human rIL-7 and antibody against CD1d, respectively. This work was supported by grants from the Juvenile Diabetes Research Foundation International, Canadian Institutes of Health Research and London Health Sciences Center Multi-Organ Transplant Program (to T.L.D.), a postdoctoral fellowship from the Canadian Diabetes Association (to S.S.) and a grant from the Fondation pour la Recherche Medicale (to A.H.).

Author information

Author notes

  1. Jean-Marc Gombert

    Present address: Laboratoire d'Immunologie, Centre Hospitalier Universitaire de Poitiers-FRE, Poitiers, 86000, France

  2. Shayan Sharif, Guillermo A. Arreaza, Peter Zucker, Qing-Sheng Mi, Jitin Sondhi, Olga V. Naidenko, Mitchell Kronenberg, Yasuhiko Koezuka, Terry L. Delovitch, Jean-Marc Gombert, Maria Leite-de-Moraes, Christine Gouarin, Ren Zhu, Agathe Hameg, Toshinori Nakayama, Masaru Taniguchi, Françoise Lepault, Agnès Lehuen, Jean-François Bach and André Herbelin: These two groups contributed equally to this study.

Authors and Affiliations

  1. Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada

    Shayan Sharif, Guillermo A. Arreaza, Peter Zucker, Qing-Sheng Mi, Jitin Sondhi & Terry L. Delovitch

  2. La Jolla Institute for Allergy and Immunology, San Diego, California, USA

    Olga V. Naidenko & Mitchell Kronenberg

  3. Pharmaceutical Research Laboratory, Kirin Brewery Co, Ltd., Gunma, Japan

    Yasuhiko Koezuka

  4. Departments of Microbiology and Immunology, and Medicine, University of Western Ontario, London, Ontario, Canada

    Terry L. Delovitch

  5. Institut National de la Santé et de la Recherche Médicale (INSERM), U 25 et Centre de l'Association Claude Bernard, Hôpital Necker, Paris, France

    Jean-Marc Gombert, Christine Gouarin, Ren Zhu, Agathe Hameg, Agnès Lehuen, Jean-François Bach & André Herbelin

  6. Centre National de la Recherche Scientifique (CNRS), UMR 8603, Hôpital Necker, Paris, France

    Maria Leite-de-Moraes & Françoise Lepault

  7. Core Research for Evolutional Science and Technology, Chiba University, Chiba, Japan

    Toshinori Nakayama & Masaru Taniguchi

Authors
  1. Shayan Sharif
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guillermo A. Arreaza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter Zucker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qing-Sheng Mi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jitin Sondhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Olga V. Naidenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mitchell Kronenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yasuhiko Koezuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Terry L. Delovitch
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jean-Marc Gombert
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Maria Leite-de-Moraes
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Christine Gouarin
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ren Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Agathe Hameg
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Toshinori Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Masaru Taniguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Françoise Lepault
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Agnès Lehuen
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Jean-François Bach
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. André Herbelin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Terry L. Delovitch or Jean-François Bach.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sharif, S., Arreaza, G., Zucker, P. et al. Activation of natural killer T cells by α-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes. Nat Med 7, 1057–1062 (2001). https://doi.org/10.1038/nm0901-1057

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0901-1057

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing