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- and 
-Anomeric Glycolipids1
* Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232;
Pharmaceutical Research Laboratories, Kirin Brewery Co., Ltd., Gunma, Japan; and
Department of Pathology, University of Chicago, Chicago, IL 60637
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 
-galactosylceramide (-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 -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 -GalCer. Our results show that, contrary to current thinking, 
-anomeric GalCer can induce CD1d-dependent biological activities in mice, albeit at lower potency than -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.
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