An α-galactosylceramide C20:2 N-acyl variant enhances anti-inflammatory and regulatory T cell-independent responses that prevent type 1 diabetes

Authors

  • D. Ly,

    1. Laboratory of Autoimmune Diabetes, Robarts Research Institute, and
    2. Department of Microbiology and Immunology, University of Western Ontario, London, ON, Canada,
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    • 1

      Present address: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

  • R. Tohn,

    1. Laboratory of Autoimmune Diabetes, Robarts Research Institute, and
    2. Department of Microbiology and Immunology, University of Western Ontario, London, ON, Canada,
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  • B. Rubin,

    1. Laboratory of Autoimmune Diabetes, Robarts Research Institute, and
    2. Research Center of Pharmacology and Health, Toulouse, France,
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  • H. Blumenfeld,

    1. Laboratory of Autoimmune Diabetes, Robarts Research Institute, and
    2. Department of Microbiology and Immunology, University of Western Ontario, London, ON, Canada,
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  • G. S. Besra,

    1. School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK, and
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  • N. Veerapen,

    1. School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK, and
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  • S. A. Porcelli,

    1. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
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  • T. L. Delovitch

    Corresponding author
    1. Laboratory of Autoimmune Diabetes, Robarts Research Institute, and
    2. Department of Microbiology and Immunology, University of Western Ontario, London, ON, Canada,
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T. L. Delovitch, Laboratory of Autoimmune Diabetes, Robarts Research Institute, University of Western Ontario, 100 Perth Drive, London, ON, Canada N6A 5K8.
E-mail: del@robarts.ca

Summary

Protection from type 1 diabetes (T1D), a T helper type 1 (Th1)-mediated disease, is achievable in non-obese diabetic (NOD) mice by treatment with α-galactosylceramide (α-GalCer) glycolipids that stimulate CD1d-restricted invariant natural killer T (iNK T) cells. While we have reported previously that the C20:2 N-acyl variant of α-GalCer elicits a Th2-biased cytokine response and protects NOD mice from T1D more effectively than a form of α-GalCer that induces mixed Th1 and Th2 responses, it remained to determine whether this protection is accompanied by heightened anti-inflammatory responses. We show that treatment of NOD mice with C20:2 diminished the activation of ‘inflammatory’ interleukin (IL)-12 producing CD11chighCD8+ myeloid dendritic cells (mDCs) and augmented the function of ‘tolerogenic’ DCs more effectively than treatment with the prototypical iNKT cell activator KRN7000 (α-GalCer C26:0) that induces Th1- and Th2-type responses. These findings correlate with a reduced capacity of C20:2 to sustain the early transactivation of T, B and NK cells. They may also explain our observation that C20:2 activated iNK T cells depend less than KRN7000 activated iNK T cells upon regulation by regulatory T cells for cytokine secretion and protection from T1D. The enhanced anti-inflammatory properties of C20:2 relative to KRN7000 suggest that C20:2 should be evaluated further as a drug to induce iNK T cell-mediated protection from T1D in humans.

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