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Impaired selection of invariant natural killer T cells in diverse mouse models of glycosphingolipid lysosomal storage diseases

Impaired selection of invariant natural killer T cells in diverse mouse models of glycosphingolipid lysosomal storage diseases
Impaired selection of invariant natural killer T cells in diverse mouse models of glycosphingolipid lysosomal storage diseases
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 alpha-galactosylceramide (alpha-GalCer) and reduced iNKT cell-mediated lysis of wild-type targets loaded with alpha-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 alpha-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.

0022-1007
2293-2303
Gadola, Stephan D.
ef2fa6cf-2ccc-4fea-a7a5-cc03a9d13ab1
Silk, Jonathan D.
2cce35f9-612c-4bdd-9989-0a7e7612c649
Jeans, Aruna
1720a282-9fe3-425c-b4e7-194c4f813560
Illarionov, Petr A.
9d455f41-82fe-4bcf-ba92-29fc6d674bbc
Salio, Mariolina
f684d870-ca61-49c6-8db5-164404a3852d
Besra, Gurdyal S.
b3523122-c452-4efc-b625-d80744586a47
Dwek, Raymond
98b9ed53-d109-4da2-b7b2-ed5efd655b39
Butters, Terry D.
891552e5-fab9-49f8-9e0a-7fccb5920e35
Platt, Frances M.
3b0d9f95-fba8-4083-91e2-c567c3e77582
Cerundolo, Vincenzo
813bcd4a-ca19-48a3-86e4-71d131e2065a
Gadola, Stephan D.
ef2fa6cf-2ccc-4fea-a7a5-cc03a9d13ab1
Silk, Jonathan D.
2cce35f9-612c-4bdd-9989-0a7e7612c649
Jeans, Aruna
1720a282-9fe3-425c-b4e7-194c4f813560
Illarionov, Petr A.
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Salio, Mariolina
f684d870-ca61-49c6-8db5-164404a3852d
Besra, Gurdyal S.
b3523122-c452-4efc-b625-d80744586a47
Dwek, Raymond
98b9ed53-d109-4da2-b7b2-ed5efd655b39
Butters, Terry D.
891552e5-fab9-49f8-9e0a-7fccb5920e35
Platt, Frances M.
3b0d9f95-fba8-4083-91e2-c567c3e77582
Cerundolo, Vincenzo
813bcd4a-ca19-48a3-86e4-71d131e2065a

Gadola, Stephan D., Silk, Jonathan D., Jeans, Aruna, Illarionov, Petr A., Salio, Mariolina, Besra, Gurdyal S., Dwek, Raymond, Butters, Terry D., Platt, Frances M. and Cerundolo, Vincenzo (2006) Impaired selection of invariant natural killer T cells in diverse mouse models of glycosphingolipid lysosomal storage diseases. The Journal of Experimental Medicine, 203 (10), 2293-2303. (doi:10.1084/jem.20060921).

Record type: Article

Abstract

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 alpha-galactosylceramide (alpha-GalCer) and reduced iNKT cell-mediated lysis of wild-type targets loaded with alpha-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 alpha-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.

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Published date: 2 October 2006

Identifiers

Local EPrints ID: 44287
URI: http://eprints.soton.ac.uk/id/eprint/44287
ISSN: 0022-1007
PURE UUID: b76b6c38-9788-45a5-a4e7-9efbed50fb77

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Date deposited: 22 Feb 2007
Last modified: 15 Mar 2024 09:02

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Contributors

Author: Stephan D. Gadola
Author: Jonathan D. Silk
Author: Aruna Jeans
Author: Petr A. Illarionov
Author: Mariolina Salio
Author: Gurdyal S. Besra
Author: Raymond Dwek
Author: Terry D. Butters
Author: Frances M. Platt
Author: Vincenzo Cerundolo

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