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

D. Ly, R. Tohn, B. Rubin, H. Blumenfeld, G. S. Besra, N. Veerapen, S. A. Porcelli, T. L. Delovitch

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)185-198
Number of pages14
JournalClinical and Experimental Immunology
Volume160
Issue number2
DOIs
StatePublished - May 1 2010

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Keywords

  • Dendritic cells
  • Diabetes
  • Immunotherapy
  • NKT cells
  • Regulatory T cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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