Quantitative and qualitative differences in the in vivo response of NKT cells to distinct alpha- and beta-anomeric glycolipids.

Parekh VV, Singh AK, Wilson MT, Olivares-Villagómez D, Bezbradica JS, Inazawa H, Ehara H, Sakai T, Serizawa I, Wu L, Wang CR, Joyce S, Van Kaer L
J Immunol. 2004 173 (6): 3693-706

PMID: 15356115 · DOI:10.4049/jimmunol.173.6.3693

NKT cells represent a unique subset of immunoregulatory T cells that recognize glycolipid Ags presented by the MHC class I-like molecule CD1d. Because of their immunoregulatory properties, NKT cells are attractive targets for the development of immunotherapies. The prototypical NKT cell ligand alpha-galactosylceramide (alpha-GalCer), originally isolated from a marine sponge, has potent immunomodulatory activities in mice, demonstrating therapeutic efficacy against metastatic tumors, infections, and autoimmune diseases, but also has a number of adverse side effects. In vivo administration of alpha-GalCer to mice results in the rapid activation of NKT cells, which is characterized by cytokine secretion, surface receptor down-regulation, expansion, and secondary activation of a variety of innate and adaptive immune system cells. In this study, we have evaluated the in vivo immune response of mice to a set of structural analogues of alpha-GalCer. Our results show that, contrary to current thinking, beta-anomeric GalCer can induce CD1d-dependent biological activities in mice, albeit at lower potency than alpha-anomeric GalCer. In addition, we show that the response of NKT cells to distinct GalCer differs not only quantitatively, but also qualitatively. These findings indicate that NKT cells can fine-tune their immune responses to distinct glycolipid Ags in vivo, a property that may be exploited for the development of effective and safe NKT cell-based immunotherapies.

Copyright 2004 The American Association of Immunologists, Inc.

MeSH Terms (24)

Adjuvants, Immunologic Animals B-Lymphocytes Cell Division Cytokines Dendritic Cells Disease Progression Down-Regulation Encephalomyelitis, Autoimmune, Experimental Female Galactosylceramides Glycolipids Immunoglobulin E Injections, Intraperitoneal Killer Cells, Natural Lymphocyte Activation Mice Mice, Inbred C57BL Mice, Knockout Psychosine Receptors, Antigen, T-Cell Spleen T-Lymphocyte Subsets Transcriptional Activation

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