An alpha-galactosylceramide C20:2 N-acyl variant enhances anti-inflammatory and regulatory T cell-independent responses that prevent type 1 diabetes.
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 alpha-galactosylceramide (alpha-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 alpha-GalCer elicits a Th2-biased cytokine response and protects NOD mice from T1D more effectively than a form of alpha-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 CD11c(high)CD8+ myeloid dendritic cells (mDCs) and augmented the function of 'tolerogenic' DCs more effectively than treatment with the prototypical iNKT cell activator KRN7000 (alpha-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.
Ly
D
D
Laboratory of Autoimmune Diabetes, Robarts Research Institute, University of Western Ontario, London, ON, Canada.
Tohn
R
R
Rubin
B
B
Blumenfeld
H
H
Besra
G S
GS
Veerapen
N
N
Porcelli
S A
SA
Delovitch
T L
TL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017951:Antigen Presentation / Q000187:drug effects; D024201:Bystander Effect / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005699:Galactosylceramides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D018664:Interleukin-12 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D013329:Structure-Activity Relationship; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D005699:Galactosylceramides; D007004:Hypoglycemic Agents; D007155:Immunologic Factors; D018664:Interleukin-12; C103873:KRN 7000