Enhanced early expansion and maturation of semi-invariant NK T cells inhibited autoimmune pathogenesis in congenic nonobese diabetic mice.
Semi-invariant NK T cell (iNKT) deficiency has long been associated with the pathogenesis of type 1 diabetes (T1D), but the linkage between this the deficiency and T1D susceptibility gene(s) remains unclear. We analyzed NOD mice subcongenic for resistant alleles of Idd9 locus in search for protective mechanisms against T1D, and found that iNKT cell development was significantly enhanced with a more advanced mature phenotype and function in mice containing Idd9.1 sublocus of B10 origin. The enhanced iNKT cell development and function suppressed effector function of diabetogenic T cells. Elimination of iNKT cells by CD1d deficiency almost abolished T1D protection in these mice. Interestingly, although the iNKT cells were responsible for a Th2 orientated cytokine profile that is often regarded as a mechanism of T1D prevention, our data suggests that the Th2 bias played little if any role for the protection. In addition, dendritic cells from the congenic NOD mice showed increased abilities to engage and potentiate iNKT cells, suggesting that a mechanism mediated by dendritic cells or other APCs may be critical for the enhanced development and maturation of iNKT cells. The products of T1D susceptibility gene(s) in Idd9.1 locus may be a key factor for this mechanism.
Ueno
Aito
A
Julia McFarlane Diabetes Research Centre, Department of Biochemistry and Molecular Biology, The University of Calgary, Canada.
Wang
Jianxiong
J
Cheng
Lu
L
Im
Jin S
JS
Shi
Yan
Y
Porcelli
Steven A
SA
Yang
Yang
Y
D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D016688:Mice, Inbred NOD; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D055610:Antigens, CD1d