Present address: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
An α-galactosylceramide C20:2 N-acyl variant enhances anti-inflammatory and regulatory T cell-independent responses that prevent type 1 diabetes
Article first published online: 15 DEC 2009
© 2009 British Society for Immunology
Clinical & Experimental Immunology
Volume 160, Issue 2, pages 185–198, May 2010
How to Cite
Ly, D., Tohn, R., Rubin, B., Blumenfeld, H., Besra, G. S., Veerapen, N., Porcelli, S. A. and Delovitch, T. L. (2010), An α-galactosylceramide C20:2 N-acyl variant enhances anti-inflammatory and regulatory T cell-independent responses that prevent type 1 diabetes. Clinical & Experimental Immunology, 160: 185–198. doi: 10.1111/j.1365-2249.2009.04074.x
- Issue published online: 8 APR 2010
- Article first published online: 15 DEC 2009
- Accepted for publication 10 November 2009
- dendritic cells;
- NKT cells;
- regulatory T cells
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.