The Journal of Experimental Medicine
Avanti Polar Lipids, Inc.
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Published online March 26, 2007
doi:10.1084/jem.20061562
The Journal of Experimental Medicine, Vol. 204, No. 4, 841-852
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Schrantz et al.
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ARTICLE

 The Niemann-Pick type C2 protein loads isoglobotrihexosylceramide onto CD1d molecules and contributes to the thymic selection of NKT cells

Nicolas Schrantz1, Yuval Sagiv2, Yang Liu3, Paul B. Savage3, Albert Bendelac2, and Luc Teyton1

1 Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
2 Committee on Immunology, University of Chicago, Chicago, IL 60637
3 Department of Chemistry, Brigham Young University, Provo, UT 84602

CORRESPONDENCE Luc Teyton: lteyton{at}scripps.edu

The Niemann-Pick type C2 (NPC2) protein is a small, soluble, lysosomal protein important for cholesterol and sphingolipid transport in the lysosome. The immunological phenotype of NPC2-deficient mice was limited to an impaired thymic selection of V{alpha}14 natural killer T cells (NKT cells) and a subsequent reduction of NKT cells in the periphery. The remaining NKT cells failed to produce measurable quantities of interferon-{gamma} in vivo and in vitro after activation with {alpha}-galactosylceramide. In addition, thymocytes and splenocytes from NPC2-deficient mice were poor presenters of endogenous and exogenous lipids to CD1d-restricted V{alpha}14 hybridoma cells.

Importantly, we determined that similar to saposins, recombinant NPC2 was able to unload lipids from and load lipids into CD1d. This transfer activity was associated with a dimeric form of NPC2, suggesting a unique mechanism of glycosphingolipid transfer by NPC2. Similar to saposin B, NPC2 dimers were able to load isoglobotrihexosylceramide (iGb3), the natural selecting ligand of NKT cells in the thymus, into CD1d. These observations strongly suggested that the phenotype observed in NPC2-deficient animals was directly linked to the efficiency of the loading of iGb3 into CD1d molecules expressed by thymocytes. This conclusion was supported by the rescue of endogenous and exogenous iGb3 presentation by recombinant NPC2. Thus, the loading of endogenous and exogenous lipids and glycolipids onto CD1d is dependent on various small, soluble lipid transfer proteins present in the lysosome.

Abbreviations used: DHE, dehydroergosterol; GM2a, GM2 activator; iGb3, isoglobotrihexosylceramide; LacCer, lactosylceramide; LTP, lipid transfer protein; NKT cell, NK T cell; NPC1, Niemann-Pick type C1; NPC2, Niemann-Pick type C2; NTA, nitrilotriacetic acid.


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