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Invariant natural killer T-cell control of type 1 diabetes: a dendritic cell genetic decision of a silver bullet or Russian roulette. Diabetes 2010 Feb;59(2):423-32

Date

11/12/2009

Pubmed ID

19903740

Pubmed Central ID

PMC2809954

DOI

10.2337/db09-1116

Scopus ID

2-s2.0-77449115674   22 Citations

Abstract

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.

RESEARCH DESIGN AND 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.

Author List

Driver JP, Scheuplein F, Chen YG, Grier AE, Wilson SB, Serreze DV

Author

Yi-Guang Chen PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Autoantibodies
B7-1 Antigen
CD27 Ligand
CD8-Positive T-Lymphocytes
Crosses, Genetic
Dendritic Cells
Diabetes Mellitus, Type 1
Female
Flow Cytometry
Humans
Killer Cells, Natural
Lymphocyte Activation
Major Histocompatibility Complex
Male
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Specific Pathogen-Free Organisms