Enhanced Early Expansion and Maturation of Semi-Invariant NK T Cells Inhibited Autoimmune Pathogenesis in Congenic Nonobese Diabetic Mice

Abstract

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.

Genetic control of murine invariant natural killer T cells maps to multiple type 1 diabetes regions

“…Previous linkage studies and congenic analyses reported by others and us identified genetic loci on Chr 1, 2, and 4 that reduce iNKT-cell development in NOD mice 22–26, 28, 44 . Compared to the previous linkage studies, the splenic QTL on Chr 1 (peaks at 172.96Mb) identified here overlaps with the Nkt1 locus that contains Slamf1 and Slamf6 genes known to regulate iNKT-cell development 27, 29 .…”

Role of SLAM in NKT Cell Development Revealed by Transgenic Complementation in NOD Mice

“…To date, the best studied example of this association is T1D in NOD mice. Increasing numbers of NKT cells in NOD mice by adoptive transfer (45,46), congenesis (35,36,39,47), transgenic expression of the Va14Ja18 TCR a-chain (48) or CD1d (49), or by stimulating them with a-GalCer (50, 51) all inhibit the onset of T1D. Furthermore, T1D was accelerated in NOD.Cd1d 2/2 mice, which completely lack NKT cells (52)(53)(54).…”

Advances in our understanding of the pathophysiology of Type 1 diabetes: lessons from the NOD mouse

“…Although the genes localized at Idd9.1 are unknown, they are associated with increased B-cell pathogenic activity [23], low numbers of induced iNKT cells [invariant NKT cells (natural killer T-cells)] and reduced T reg cell (regulatory T-cell) development and activity in NOD mice [24,25]. Candidate susceptibility genes at Idd9.2 and Idd9.3 encode CD30, TNFR2 (tumour necrosis factor receptor 2) and CD137 respectively [22].…”