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Science 306 (5702): 1786-1789

Copyright © 2004 by the American Association for the Advancement of Science

Lysosomal Glycosphingolipid Recognition by NKT Cells

Dapeng Zhou,1* Jochen Mattner,1 Carlos Cantu, III,2 Nicolas Schrantz,2 Ning Yin,3 Ying Gao,3 Yuval Sagiv,1 Kelly Hudspeth,1 Yun-Ping Wu,4 Tadashi Yamashita,4 Susann Teneberg,5 Dacheng Wang,6 Richard L. Proia,4 Steven B Levery,7 Paul B. Savage,3 Luc Teyton,2 Albert Bendelac1*

Abstract: NKT cells represent a distinct lineage of T cells that coexpress a conserved {alpha}ß T cell receptor (TCR) and natural killer (NK) receptors. Although the TCR of NKT cells is characteristically autoreactive to CD1d, a lipid-presenting molecule, endogenous ligands for these cells have not been identified. We show that a lysosomal glycosphingolipid of previously unknown function, isoglobotrihexosylceramide (iGb3), is recognized both by mouse and human NKT cells. Impaired generation of lysosomal iGb3 in mice lacking ß-hexosaminidase b results in severe NKT cell deficiency, suggesting that this lipid also mediates development of NKT cells in the mouse. We suggest that expression of iGb3 in peripheral tissues may be involved in controlling NKT cell responses to infections and malignancy and in autoimmunity.

1 University of Chicago, Department of Pathology, Chicago, IL 60637, USA.
2 The Scripps Research Institute, Department of Immunology, La Jolla, CA 92037, USA.
3 Brigham Young University, Department of Chemistry and Biochemistry, Provo, UT 84602–5700, USA.
4 Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
5 Institute of Medical Biochemistry, Göteborg University, SE 405 30 Göteborg, Sweden.
6 Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
7 Department of Chemistry, University of New Hampshire, Durham, NH 03824–3598, USA.

* To whom correspondence should be addressed. E-mail: dzhou{at}midway.uchicago.edu (D.Z.) and abendela{at}bsd.uchicago.edu (A.B.)


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   Abstract »    Full Text »    PDF »
Role of NKT cells in the digestive system. IV. The role of canonical natural killer T cells in mucosal immunity and inflammation.
G. Wingender and M. Kronenberg (2008)
Am J Physiol Gastrointest Liver Physiol 294, G1-G8
   Abstract »    Full Text »    PDF »
S1P1 receptor expression regulates emergence of NKT cells in peripheral tissues.
M. L. Allende, D. Zhou, D. N. Kalkofen, S. Benhamed, G. Tuymetova, C. Borowski, A. Bendelac, and R. L. Proia (2008)
FASEB J 22, 307-315
   Abstract »    Full Text »    PDF »
Modulation of human natural killer T cell ligands on TLR-mediated antigen-presenting cell activation.
M. Salio, A. O. Speak, D. Shepherd, P. Polzella, P. A. Illarionov, N. Veerapen, G. S. Besra, F. M. Platt, and V. Cerundolo (2007)
PNAS 104, 20490-20495
   Abstract »    Full Text »    PDF »
Critical Role for CXC Chemokine Ligand 16 (SR-PSOX) in Th1 Response Mediated by NKT Cells.
T. Shimaoka, K.-i. Seino, N. Kume, M. Minami, C. Nishime, M. Suematsu, T. Kita, M. Taniguchi, K. Matsushima, and S. Yonehara (2007)
J. Immunol. 179, 8172-8179
   Abstract »    Full Text »    PDF »
Modulation of CD1d-restricted NKT cell responses by CD4.
X. Chen, X. Wang, G. S. Besra, and J. E. Gumperz (2007)
J. Leukoc. Biol. 82, 1455-1465
   Abstract »    Full Text »    PDF »
Role of NKT Cells in the Digestive System. III. Role of NKT cells in intestinal immunity.
S. Zeissig, A. Kaser, S. K. Dougan, E. E. S. Nieuwenhuis, and R. S. Blumberg (2007)
Am J Physiol Gastrointest Liver Physiol 293, G1101-G1105
   Abstract »    Full Text »    PDF »
Non-classical major histocompatibility complex proteins as determinants of tumour immunosurveillance.
A. Q. Gomes, D. V. Correia, and B. Silva-Santos (2007)
EMBO Rep. 8, 1024-1030
   Abstract »    Full Text »    PDF »
Invariant NKT Cells Biased for IL-5 Production Act as Crucial Regulators of Inflammation.
K. Sakuishi, S. Oki, M. Araki, S. A. Porcelli, S. Miyake, and T. Yamamura (2007)
J. Immunol. 179, 3452-3462
   Abstract »    Full Text »    PDF »
A Y Chromosome-Linked Factor Impairs NK T Development.
J. D. Wesley, M. S. Tessmer, C. Paget, F. Trottein, and L. Brossay (2007)
J. Immunol. 179, 3480-3487
   Abstract »    Full Text »    PDF »
A Single Early Activation of Invariant NK T Cells Confers Long-Term Protection against Collagen-Induced Arthritis in a Ligand-Specific Manner.
K. Coppieters, K. Van Beneden, P. Jacques, P. Dewint, A. Vervloet, B. Vander Cruyssen, S. Van Calenbergh, G. Chen, R. W. Franck, G. Verbruggen, et al. (2007)
J. Immunol. 179, 2300-2309
   Abstract »    Full Text »    PDF »
CD4 engagement by CD1d potentiates activation of CD4+ invariant NKT cells.
A. Thedrez, C. de Lalla, S. Allain, L. Zaccagnino, S. Sidobre, C. Garavaglia, G. Borsellino, P. Dellabona, M. Bonneville, E. Scotet, et al. (2007)
Blood 110, 251-258
   Abstract »    Full Text »    PDF »
Distinct Endosomal Trafficking Requirements for Presentation of Autoantigens and Exogenous Lipids by Human CD1d Molecules.
X. Chen, X. Wang, J. M. Keaton, F. Reddington, P. A. Illarionov, G. S. Besra, and J. E. Gumperz (2007)
J. Immunol. 178, 6181-6190
   Abstract »    Full Text »    PDF »
Identification of an IL-17-producing NK1.1neg iNKT cell population involved in airway neutrophilia.
M.-L. Michel, A. C. Keller, C. Paget, M. Fujio, F. Trottein, P. B. Savage, C.-H. Wong, E. Schneider, M. Dy, and M. C. Leite-de-Moraes (2007)
J. Exp. Med. 204, 995-1001
   Abstract »    Full Text »    PDF »

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