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* Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461;
School of Biosciences, University of Birmingham, Birmingham, United Kingdom;
Department of Chemistry, University of Connecticut, Storrs, CT 06269;
Department of Microbiology and Infectious Diseases and Julia McFarlane Diabetes Research Centre, University of Calgary, Calgary, Canada; and
¶ Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461
Activation of CD1d-restricted invariant NKT (iNKT) cells by 
-galactosylceramide (GalCer) significantly suppresses development of diabetes in NOD mice. The mechanisms of this protective effect are complex, involving both Th1 and Th2 cytokines and a network of regulatory cells including tolerogenic dendritic cells. In the current study, we evaluated a newly described synthetic GalCer analog (C20:2) that elicits a Th2-biased cytokine response for its impact on disease progression and immunopathology in NOD mice. Treatment of NOD mice with GalCer C20:2 significantly delayed and reduced the incidence of diabetes. This was associated with significant suppression of the late progression of insulitis, reduced infiltration of islets by autoreactive CD8+ T cells, and prevention of progressive disease-related changes in relative proportions of different subsets of dendritic cells in the draining pancreatic lymph nodes. Multiple favorable effects observed with GalCer C20:2 were significantly more pronounced than those seen in direct comparisons with a closely related analog of GalCer that stimulated a more mixed pattern of Th1 and Th2 cytokine secretion. Unlike a previously reported Th2-skewing murine iNKT cell agonist, the GalCer C20:2 analog was strongly stimulatory for human iNKT cells and thus warrants further examination as a potential immunomodulatory agent for human disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants RO1 AI45889 and RO1 AI064424 (to S.A.P.), RO1 AI064422 and RO1 DK064315 (to T.P.D.), RO1 AI057519 (to A.R.H.), and a Pilot and Feasibility Award (to S.A.P. and T.P.D.) from the Albert Einstein College of Medicine Diabetes Research and Training Center (DK20541). S.A.P. is the recipient of an Irma T. Hirschl Career Scientist Award. C.F. is the recipient of a Human Frontier Science Program long-term fellowship. G.S.B. is a former Lister Institute-Jenner Research Fellow and acknowledges support from the Medical Research Council (United Kingdom), the Wellcome Trust, and from the James Bardrick Research Chair. P.S. is supported by the Canadian Institutes of Health Research, and is a Scientist of the Alberta Heritage Foundation for Medical Research. Flow cytometry studies were supported by the FACS Core Facilities of the Albert Einstein College of Medicine Center for AIDS Research (National Institutes of Health/National Institute of Allergy and Infectious Diseases AI51519) and the Albert Einstein College of Medicine Cancer Center (National Institutes of Health/National Cancer Institute P30 CA13330).
2 C.F. and T.T. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Steven A. Porcelli, Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail address: porcelli{at}aecom.yu.edu
4 Abbreviations used in this paper: iNKT, invariant NKT; GalCer, -galactosylceramide; PLN, pancreatic lymph node; DC, dendritic cell; IGRP, islet-specific glucose-6-phosphatase catalytic subunit-related protein; Treg, regulatory T cell.
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