Invariant natural killer T-cell control of type 1 diabetes: a dendritic cell genetic decision of a silver bullet or Russian roulette.
OBJECTIVE
In part, activation of invariant natural killer T (iNKT)-cells with the superagonist alpha-galactosylceramide (alpha-GalCer) inhibits the development of T-cell-mediated autoimmune type 1 diabetes in NOD mice by inducing the downstream differentiation of antigen-presenting dendritic cells (DCs) 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 whether in some circumstances genetic variation would enable activated iNKT-cells to support rather than inhibit type 1 diabetes development.


METHODS
We tested whether iNKT-conditioned DCs in NOD mice and a major histocompatibility complex-matched C57BL/6 (B6) background congenic stock differed in capacity to inhibit type 1 diabetes induced by the adoptive transfer of pathogenic AI4 CD8 T-cells.


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


CONCLUSIONS
This great variability in the interactions between iNKT-cells and DCs in two inbred mouse strains should raise a cautionary note about considering manipulation of this axis as a potential type 1 diabetes prevention therapy in genetically heterogeneous humans.
Driver
John P
JP
The Jackson Laboratory, Bar Harbor, Maine, USA.
Scheuplein
Felix
F
Chen
Yi-Guang
YG
Grier
Alexandra E
AE
Wilson
S Brian
SB
Serreze
David V
DV
D000818:Animals; D001323:Autoantibodies / Q000097:blood; D018122:B7-1 Antigen / Q000276:immunology; D053282:CD27 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D013047:Specific Pathogen-Free Organisms
D001323:Autoantibodies; D018122:B7-1 Antigen; D053282:CD27 Ligand