NKT cells stimulated by long fatty acyl chain sulfatides significantly reduce the incidence of type 1 diabetes in nonobese diabetic mice [corrected].
Sulfatide-reactive type II NKT cells have been shown to regulate autoimmunity and anti-tumor immunity. Although, two major isoforms of sulfatide, C16:0 and C24:0, are enriched in the pancreas, their relative role in autoimmune diabetes is not known. Here, we report that sulfatide/CD1d-tetramer(+) cells accumulate in the draining pancreatic lymph nodes, and that treatment of NOD mice with sulfatide or C24:0 was more efficient than C16:0 in stimulating the NKT cell-mediated transfer of a delay in onset from T1D into NOD.Scid recipients. Using NOD.CD1d(-/-) mice, we show that this delay of T1D is CD1d-dependent. Interestingly, the latter delay or protection from T1D is associated with the enhanced secretion of IL-10 rather than IFN-g by C24:0-treated CD4(+) T cells and the deviation of the islet-reactive diabetogenic T cell response. Both C16:0 and C24:0 sulfatide isoforms are unable to activate and expand type I iNKT cells. Collectively, these data suggest that C24:0 stimulated type II NKT cells may regulate protection from T1D by activating DCs to secrete IL-10 and suppress the activation and expansion of type I iNKT cells and diabetogenic T cells. Our results raise the possibility that C24:0 may be used therapeutically to delay the onset and protect from T1D in humans.
Laboratory of Autoimmune Diabetes, Robarts Research Institute, Western University, London, Ontario, Canada.
Lakshmimathy
L
Subramanian
Hartley
H
Blumenfeld
Robert
R
Tohn
Dalam
D
Ly
Carlos
C
Aguilera
Igor
I
Maricic
Jan-Eric
JE
Mansson
Karsten
K
Buschard
Vipin
V
Kumar
Terry L
TL
Delovitch
D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005434:Flow Cytometry; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD / Q000378:metabolism*; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology; D013329:Structure-Activity Relationship; D013433:Sulfoglycosphingolipids / Q000494:pharmacology*
D055610:Antigens, CD1d; D007376:Interleukin-2; D013433:Sulfoglycosphingolipids; D016753:Interleukin-10; D015847:Interleukin-4