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¹ Weatherall Institute of Molecular Medicine, Tumour Immunology Group, John Radcliffe Hospital, Oxford OX3 9DS, England, UK
² Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, England, UK
³ School of Biosciences, University of Birmingham, Birmingham B15 2TT, England, UK

CORRESPONDENCE Vincenzo Cerundolo: vincenzo.cerundolo{at}imm.ox.ac.uk

Glycolipid ligands for invariant natural killer T cells (iNKT cells) are loaded onto CD1d molecules in the late endosome/lysosome. Accumulation of glycosphingolipids (GSLs) in lysosomal storage diseases could potentially influence endogenous and exogenous lipid loading and/or presentation and, thus, affect iNKT cell selection or function. The percentages and frequency of iNKT cells were reduced in multiple mouse models of lysosomal GSL storage disease, irrespective of the specific genetic defect or lipid species stored. Reduced numbers of iNKT cells resulted in the absence of cytokine production in response to -galactosylceramide (-GalCer) and reduced iNKT cell–mediated lysis of wild-type targets loaded with -GalCer. The reduction in iNKT cells did not result from defective expression of CD1d or a lack of antigen-presenting cells. Although H-2 restricted CD4⁺ T cell responses were generally unaffected, processing of a lysosome-dependent analogue of -GalCer was impaired in all the strains of mice tested. These data suggest that GSL storage may result in alterations in thymic selection of iNKT cells caused by impaired presentation of selecting ligands.

Abbreviations used: -GalCer, -galactosylceramide; BMDC, bone marrow–derived DC; Gal(12)GalCer, galactosyl(12) galactosylceramide; GSL, glycosphingolipid; iGb3, isoglobotrihexosylceramide; iNKT cells, invariant natural killer T cells; LOTS, late-onset Tay-Sachs disease; NPC1, Niemann-Pick disease type C1.

S.D. Gadola, J.D. Silk, and A. Jeans contributed equally to this work.

S.D. Gadola's current address is Clinic for Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, CH-3010 Bern, Switzerland.

F.M. Platt and A. Jeans's current address is Dept. of Pharmacology, University of Oxford, Oxford OX1 3QT, England, UK.

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