Chemical Research in Toxicology
Article
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addition, 1b and 1c were potent Th1-biased activators of iNKT
cells. Our new findings may overturn long-held notions about
immune-responsive agonists and inspire people to consider
extending the sphingosine chain, an approach that used to be
ignored. A more complete assessment of the biological
properties of 1b and 1c is warranted.
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ASSOCIATED CONTENT
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guilty: natural killer T cell defects and human disease. Nat. Rev.
Immunol. 11, 131−142.
S
* Supporting Information
Analytical data for compounds 10, 11, and 1a−d. The synthetic
procedures for compounds 5 and 6. The Supporting
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antigen induces long-term natural killer T cell anergy in mice. J. Clin.
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AUTHOR INFORMATION
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Corresponding Authors
(10) Parekh, V. V., Lalani, S., Kim, S., Halder, R., Azuma, M., Yagita,
H., Kumar, V., Wu, L., and Van Kaer, L. (2009) PD-1/PD-L blockade
prevents anergy induction and enhances the anti-tumor activities of
glycolipid-activated invariant NKT cells. J. Immunol. 182, 2816−2826.
(11) Aspeslagh, S., Li, Y., Yu, E. D., Pauwels, N., Trappeniers, M.,
Girardi, E., Decruy, T., Van Beneden, K., Venken, K., Drennan, M.,
Leybaert, L., Wang, J., Franck, R. W., Van Calenbergh, S., Zajonc, D.
M., and Elewaut, D. (2011) Galactose-modified iNKT cell agonists
stabilized by an induced fit of CD1d prevent tumour metastasis.
EMBO J. 30, 2294−2305.
Funding
This study was financed by the National Natural Science
Foundation of China under grant no. 30870553, the Interna-
tional Science & Technology Cooperation Program of China
under grant no. 2010DFA34370, the International S&T
Cooperation Program of Zhejiang under grant no.
2013C14012, and Yunnan High-End Technology Professionals
Introduction Program (2010CI117 to C.X.)
(12) Miyamoto, K., Miyake, S., and Yamamura, T. (2001) A synthetic
glycolipid prevents autoimmune encephalomyelitis by inducing TH2
bias of natural killer T cells. Nature 413, 531−534.
(13) Koch, M., Stronge, V. S., Shepherd, D., Gadola, S. D., Mathew,
B., Ritter, G., Fersht, A. R., Besra, G. S., Schmidt, R. R., Jones, E. Y.,
and Cerundolo, V. (2005) The crystal structure of human CD1d with
and without alpha-galactosylceramide. Nat. Immunol. 6, 819−826.
(14) Borg, N. A., Wun, K. S., Kjer-Nielsen, L., Wilce, M. C. J., Pellicci,
D. G., Koh, R., Besra, G. S., Bharadwaj, M., Godfrey, D. I., McCluskey,
J., and Rossjohn, J. (2007) CD1d-lipid-antigen recognition by the
semi-invariant NKT T-cell receptor. Nature 448, 44−49.
(15) Lacone, V., Hunault, J., Pipelier, M., Blot, V., Lecourt, T.,
Rocher, J., Turcot-Dubois, A. L., Marionneau, S., Douillard, J. Y.,
Clement, M., Le Pendu, J., Bonneville, M., Micouin, L., and Dubreuil,
D. (2009) Focus on the controversial activation of human iNKT cells
by 4-deoxy analogue of KRN7000. J. Med. Chem. 52, 4960−4963.
(16) Dangerfield, E. M., Cheng, J. M. H., Knight, D. A., Weinkove, R.,
Dunbar, P. R., Hermans, I. F., Timmer, M. S. M., and Stocker, B. L.
(2012) Species-specific activity of glycolipid ligands for invariant NKT
cells. ChemBioChem 13, 1349−1356.
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
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α-GalCer, α-galactosylceramide; APTS, p-toluenesulfonic acid;
n-Bu4NI, tetrabutylammonium iodide; δ, chemical shift; dd,
doublet of doublets; CD1d, antigen-presenting molecule;
DCCI, N,N′-dicyclohexylcarbodiimide; DMF, N,N-dimethyl-
formamide; DMSO, dimethyl sulfoxide; FCS, fetal calf serum;
Hz, hertz; HRMS, high-resolution mass spectrometry; IFN,
interferon; iNKT, invariant natural killer; i-Pr2Net, N,N-
diisopropylethylamine; MeOH, methanol; NKT, natural killer
T; J, coupling constant; m, multiple; m/z, mass-to-charge ratio;
mmol, millimole; MS, mass spectrometry; NHS, N-hydrox-
ysuccinimide; NMR, nuclear magnetic resonance; ppm, parts
per million; Rf, rate of flow; t, triple; TCR, T cell receptors;
Th1, proinflammatory cytokines; Th2, immunomodulatory
cytokines; THF, tetrahydrofuran; TLC, thin-layer chromatog-
raphy; TMSCl, trimethylsilyl chloride; TMSI, trimethylsilyl
iodide; pTSA, p-toluenesulfonamide
(17) Rauch, J., Gumperz, J., Robinson, C., Skold, M., Roy, C., Young,
D. C., Lafleur, M., Moody, D. B., Brenner, M. B., Costello, C. E., and
Behar, S. M. (2003) Structural features of the acyl chain determine
self-phospholipid antigen recognition by a CD1d-restricted invariant
NKT (iNKT) cell. J. Biol. Chem. 278, 47508−47515.
(18) Ben-Menachem, G., Kubler-Kielb, J., Coxon, B., Yergey, A., and
Schneerson, R. (2003) A newly discovered cholesteryl galactoside
from Borrelia burgdorferi. Proc. Natl. Acad. Sci. U.S.A. 100, 7913−7918.
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