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Lysosomal Glycosphingolipid Recognition by NKT Cells
Dapeng Zhou,1*Jochen Mattner,1Carlos Cantu, III,2Nicolas Schrantz,2Ning Yin,3Ying Gao,3Yuval Sagiv,1Kelly Hudspeth,1Yun-Ping Wu,4Tadashi Yamashita,4Susann Teneberg,5Dacheng Wang,6Richard L. Proia,4Steven B Levery,7Paul B. Savage,3Luc Teyton,2Albert Bendelac1*
NKT cells represent a distinct lineage of T cells that coexpressa conserved ß T cell receptor (TCR) and natural killer(NK) receptors. Although the TCR of NKT cells is characteristicallyautoreactive to CD1d, a lipid-presenting molecule, endogenousligands for these cells have not been identified. We show thata lysosomal glycosphingolipid of previously unknown function,isoglobotrihexosylceramide (iGb3), is recognized both by mouseand human NKT cells. Impaired generation of lysosomal iGb3 inmice lacking ß-hexosaminidase b results in severeNKT cell deficiency, suggesting that this lipid also mediatesdevelopment of NKT cells in the mouse. We suggest that expressionof iGb3 in peripheral tissues may be involved in controllingNKT 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 »
T-cell recognition of glycolipids presented by CD1 proteins.
The Complementarity Determining Region 2 of BV8S2 (Vbeta8.2) Contributes to Antigen Recognition by Rat Invariant NKT Cell TCR..
E. Pyz, O. Naidenko, S. Miyake, T. Yamamura, I. Berberich, S. Cardell, M. Kronenberg, and T. Herrmann (2006)
J. Immunol.
176, 7447-7455
|Abstract »|Full Text »|PDF »
A unique lymphotoxin {alpha}beta-dependent pathway regulates thymic emigration of V{alpha}14 invariant natural killer T cells.
A. S. Franki, K. Van Beneden, P. Dewint, K. J. L. Hammond, S. Lambrecht, G. Leclercq, M. Kronenberg, D. Deforce, and D. Elewaut (2006)
PNAS
103, 9160-9165
|Abstract »|Full Text »|PDF »
Mechanisms imposing the V{beta} bias of V{alpha}14 natural killer T cells and consequences for microbial glycolipid recognition.
D. G. Wei, S. A. Curran, P. B. Savage, L. Teyton, and A. Bendelac (2006)
J. Exp. Med.
203, 1197-1207
|Abstract »|Full Text »|PDF »
Immature Human Dendritic Cells Infected with Leishmania infantum Are Resistant to NK-Mediated Cytolysis but Are Efficiently Recognized by NKT Cells.
Y. Campos-Martin, M. Colmenares, B. Gozalbo-Lopez, M. Lopez-Nunez, P. B. Savage, and E. Martinez-Naves (2006)
J. Immunol.
176, 6172-6179
|Abstract »|Full Text »|PDF »
Oral nickel tolerance: fas ligand-expressing invariant NK T cells promote tolerance induction by eliciting apoptotic death of antigen-carrying, effete B cells..
M. Nowak, F. Kopp, K. Roelofs-Haarhuis, X. Wu, and E. Gleichmann (2006)
J. Immunol.
176, 4581-4589
|Abstract »|Full Text »|PDF »
DOCK2 Is Required in T Cell Precursors for Development of V{alpha}14 NK T Cells..
Y. Kunisaki, Y. Tanaka, T. Sanui, A. Inayoshi, M. Noda, T. Nakayama, M. Harada, M. Taniguchi, T. Sasazuki, and Y. Fukui (2006)
J. Immunol.
176, 4640-4645
|Abstract »|Full Text »|PDF »
Quantitative PCR on 5 genes reliably identifies CTCL patients with 5% to 99% circulating tumor cells with 90% accuracy.
M. Nebozhyn, A. Loboda, L. Kari, A. H. Rook, E. C. Vonderheid, S. Lessin, C. Berger, R. Edelson, C. Nichols, M. Yousef, et al. (2006)
Blood
107, 3189-3196
|Abstract »|Full Text »|PDF »
Genetic and Functional Analysis of the Nkt1 Locus Using Congenic NOD Mice: Improved V{alpha}14-NKT Cell Performance but Failure to Protect Against Type 1 Diabetes..
A.-C. Rocha-Campos, R. Melki, R. Zhu, N. Deruytter, D. Damotte, M. Dy, A. Herbelin, and H.-J. Garchon (2006)
Diabetes
55, 1163-1170
|Abstract »|Full Text »|PDF »
Long-Term Retention of Mature NK1.1+ NKT Cells in the Thymus.
S. P. Berzins, F. W. McNab, C. M. Jones, M. J. Smyth, and D. I. Godfrey (2006)
J. Immunol.
176, 4059-4065
|Abstract »|Full Text »|PDF »
Gestation stage-dependent mechanisms of invariant natural killer T cell-mediated pregnancy loss.
J. E. Boyson, N. Nagarkatti, L. Nizam, M. A. Exley, and J. L. Strominger (2006)
PNAS
103, 4580-4585
|Abstract »|Full Text »|PDF »
A structural basis for selection and cross-species reactivity of the semi-invariant NKT cell receptor in CD1d/glycolipid recognition.
L. Kjer-Nielsen, N. A. Borg, D. G. Pellicci, T. Beddoe, L. Kostenko, C. S. Clements, N. A. Williamson, M. J. Smyth, G. S. Besra, H. H. Reid, et al. (2006)
J. Exp. Med.
203, 661-673
|Abstract »|Full Text »|PDF »
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. 
