Abstract

Objective: In part, activation of invariant natural killer T (iNKT)-cells with the superagonist α-galactosylceramide (α-GalCer) inhibits the development of T-cell-mediated autoimmune type 1 diabetes (T1D) in NOD mice by inducing the downstream differentiation of antigen-presenting dendritic cells (DC) to an immunotolerogenic state. However, in other systems iNKT-cell activation has an adjuvant-like effect that enhances rather than suppresses various immunological responses. Thus, we tested if in some circumstances genetic variation would enable activated iNKT-cells to support rather than inhibit T1D development.

Research Design and Methods: We tested whether iNKT-conditioned DC in NOD mice and a major histocompatibility complex matched C57BL/6 (B6) background congenic stock differed in capacity to inhibit T1D induced by the adoptive transfer of pathogenic AI4 CD8 T-cells.

Results: Unlike those of NOD origin, iNKT-conditioned DC in the B6 background stock matured to a state that actually supported rather than inhibited AI4 T-cell induced T1D. The induction of a differing activity pattern of T-cell co-stimulatory molecules varying in capacity to override programmed death-ligand-1 (PD-L1) inhibitory effects contributes to the respective ability of iNKT-conditioned DC in NOD and B6 background mice to inhibit or support T1D development. Genetic differences inherent to both iNKT-cells and DC contribute to their varying interactions in NOD and B6.H2^g7 mice.

Conclusion: This great variability in the interactions between iNKT-cells and DC in two inbred mouse strains should raise a cautionary note about considering manipulation of this axis as a potential T1D prevention therapy in genetically heterogeneous humans.