Abstract
Experimental autoimmune encephalomyelitis (EAE) is a prototype autoimmune disease mediated by type 1 helper T (TH1) cells and under the control of regulatory cells1,2,3. Here we report that a synthetic glycolipid ligand for CD1d-restricted natural killer T (NKT) cells expressing the semi-invariant T-cell receptor (Vα14+) is preventive against EAE. The ligand is an analogue of α-galactosylceramide (α-GC), a prototype NKT cell ligand, with a truncated sphingosine chain. α-GC causes NKT cells to produce both interferon (IFN)-γ and interleukin (IL)-4 (refs 4, 5). However, this new ligand can induce a predominant production of IL-4 by the NKT cells. A single injection of this glycolipid, but not of α-GC, consistently induced TH2 bias of autoimmune T cells by causing NKT cells to produce IL-4, leading to suppression of EAE. The lack of polymorphism of CD1d and cross-reactive response of mouse and human NKT cells to the same ligand6 indicates that targeting NKT cells with this ligand may be an attractive means for intervening in human autoimmune diseases such as multiple sclerosis.
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References
Nicholson, L. B. & Kuchroo, V. K. Manipulation of the Th1/Th2 balance in autoimmune disease. Curr. Opin. Immunol. 8, 837–842 (1996).
Kumar, V., Aziz, F., Sercarz, E. & Miller, A. Regulatory T cells specific for the same framework 3 region of the Vβ8.2 chain are involved in the control of collagen II-induced arthritis and experimental autoimmune encephalomyelitis. J. Exp. Med. 185, 1725–1733 (1997).
Zhang, B-n., Yamamura, T., Kondo, T., Fujiwara, M. & Tabira, T. Regulation of experimental autoimmune encephalomyelitis by natural killer (NK) cells. J. Exp. Med. 186, 1677–1687 (1997).
Kawano, T. et al. CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science 278, 1626–1629 (1997).
Spada, F. M., Koezuka, Y. & Porcelli, S. A. CD1d-restricted recognition of synthetic glycolipid antigens by human natural killer T cells. J. Exp. Med. 188, 1529–1534 (1998).
Brossay, L. et al. CD1d-mediated recognition of α-galactosylceramide by natural killer T cells is highly conserved through mammalian evolution. J. Exp. Med. 188, 1521–1528 (1998).
Bix, M. & Locksley, R. M. Natural T cells. Cells that co-express NKRP-1 and TCR. J. Immunol. 155, 1020–1022 (1995).
Bendelac, A., Rivera, M. N., Park, S. & Roark, J. H. Mouse CD1-specific NK1 T cells: development, specificity and function. Annu. Rev. Immunol. 15, 535–562 (1997).
Godfrey, D. I., Hammond, K. J., Poulton, L. D., Smyth, M. J. & Baxter, A. G. NKT cells: Facts, functions and fallacies. Immunol. Today 21, 573–583 (2000).
Matsuda, J. L. et al. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramer. J. Exp. Med. 192, 741–754 (2000).
Moody, D. B., Besra, G. S., Wilson, I. A. & Porcelli, S. A. The molecular basis of CD1-mediated presentation of lipid antigens. Immunol. Rev. 172, 285–296 (1999).
Mieza, M. A. et al. Selective reduction of Vα14+NK T cells associated with disease development in autoimmune-prone mice. J. Immunol. 156, 4035–4040 (1996).
Kirsten, 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).
Sumida, T. et al. Selective reduction of T cells bearing invariant Vα24JαQ antigen receptor in patients with systemic sclerosis. J. Exp. Med. 182, 1163–1168 (1995).
Wilson, S. B. et al. Extreme Th1 bias of invariant Vα24JαQ T cells in type 1 diabetes. Nature 391, 177–181 (1998).
Illés, Zs. et al. Differential expression of natural killer T cell Vα24JαQ invariant TCR chain in the lesions of multiple sclerosis and chronic inflammatory demyelinating polyneuropathy. J. Immunol. 164, 4375–4381 (2000).
Pál, E. et al. Costimulation-dependent modulation of experimental autoimmune encephalomyelitis by ligand stimulation of Vα14 NK T cells. J. Immunol. 166, 662–668 (2001).
Sloan-Lancaster, J. & Allen, P. M. Altered peptide ligand-induced partial T cell activation: molecular mechanisms and role in T cell biology. Annu. Rev. Immunol. 14, 1–27 (1996).
Kappos, L. et al. Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial. Nature Med. 6, 1176–1182 (2000).
Pedotti, R. et al. An unexpected version of horror autotoxicus: Anaphylactic shock to a self-peptide. Nature Immunol. 2, 216–222 (2001).
Morita, M. et al. Synthesis of α-, β-monoglycosylceramides and four diastereomers of an α-galactosylceramide. Bioorg. Med. Chem. Lett. 5, 699–704 (1995).
Acknowledgements
We thank M. Taniguchi for supplying TCR Jα281-/- mice. This work was supported by a Research on Brain Science grant from the Ministry of Health, Labor and Welfare in Japan.
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Miyamoto, K., Miyake, S. & Yamamura, T. A synthetic glycolipid prevents autoimmune encephalomyelitis by inducing TH2 bias of natural killer T cells. Nature 413, 531–534 (2001). https://doi.org/10.1038/35097097
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DOI: https://doi.org/10.1038/35097097
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