Journal
CLINICAL AND EXPERIMENTAL IMMUNOLOGY
Volume 164, Issue 1, Pages 26-41Publisher
WILEY
DOI: 10.1111/j.1365-2249.2011.04323.x
Keywords
anergy; apoptosis; cytokines; diabetes; iNK T cells
Categories
Funding
- Juvenile Diabetes Research Foundation International [24-2007-388]
- Canadian Institutes of Health Research [MOP 64386, RO1 AI45889, RO1 AI064424]
- Canada Research Chair in Viral Immunity
- Pathogenesis award
- Schulich Graduate Enhancement Scholarship
- Department of Microbiology and Immunology
- Ontario Graduate Scholarship
- Irma T. Hirschl Cancer Scientist Award
- Mr James Badick, Royal Society Wolfson Research Merit Award
- Listar Institute-Jenner Research Fellowship
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P>We have reported previously that treatment of non-obese diabetic (NOD) mice with the invariant natural killer T (iNK T) cell agonist alpha-galactosylceramide C26:0 (alpha-GalCer) or its T helper type 2 (Th2)-biasing derivative alpha-GalCer C20:2 (C20:2) protects against type 1 diabetes (T1D), with C20:2 yielding greater protection. After an initial response to alpha-GalCer, iNK T cells become anergic upon restimulation. While such anergic iNK T cells can induce tolerogenic dendritic cells (DCs) that mediate protection from T1D, chronic administration of alpha-GalCer also results in long-lasting anergy accompanied by significantly reduced iNK T cell frequencies, which raises concerns about its long-term therapeutic use. In this study, our objective was to understand more clearly the roles of anergy and induction of tolerogenic DCs in iNK T cell-mediated protection from T1D and to circumvent potential complications associated with alpha-GalCer. We demonstrate that NOD iNK T cells activated during multi-dose (MD) treatment in vivo with C20:2 enter into and exit from anergy more rapidly than after activation by alpha-GalCer. Importantly, this shorter duration of iNK T cells in the anergic state promotes the more rapid induction of tolerogenic DCs and reduced iNK T cell death, and enables C20:2 stimulated iNK T cells to elicit enhanced protection from T1D. Our findings further that suggest C20:2 is a more effective therapeutic drug than alpha-GalCer for protection from T1D. Moreover, the characteristics of C20:2 provide a basis of selection of next-generation iNK T cell agonists for the prevention of T1D.
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