Granulocyte-macrophage colony-stimulating factor prevents diabetes development in NOD mice by inducing tolerogenic dendritic cells that sustain the suppressive function of CD4+CD25+ regulatory T cells.
Autoimmune diabetes results from a breakdown of self-tolerance that leads to T cell-mediated beta-cell destruction. Abnormal maturation and other defects of dendritic cells (DCs) have been associated with the development of diabetes. Evidence is accumulating that self-tolerance can be restored and maintained by semimature DCs induced by GM-CSF. We have investigated whether GM-CSF is a valuable strategy to induce semimature DCs, thereby restoring and sustaining tolerance in NOD mice. We found that treatment of prediabetic NOD mice with GM-CSF provided protection against diabetes. The protection was associated with a marked increase in the number of tolerogenic immature splenic DCs and in the number of Foxp3+CD4+CD25+ regulatory T cells (Tregs). Activated DCs from GM-CSF-protected mice expressed lower levels of MHC class II and CD80/CD86 molecules, produced more IL-10 and were less effective in stimulating diabetogenic CD8+ T cells than DCs of PBS-treated NOD mice. Adoptive transfer experiments showed that splenocytes of GM-CSF-protected mice did not transfer diabetes into NOD.SCID recipients. Depletion of CD11c+ DCs before transfer released diabetogenic T cells from the suppressive effect of CD4+CD25+ Tregs, thereby promoting the development of diabetes. These results indicated that semimature DCs were required for the sustained suppressive function of CD4+CD25+ Tregs that were responsible for maintaining tolerance of diabetogenic T cells in NOD mice.
Gaudreau
Simon
S
Department of Pediatric, Immunology Division, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada.
Guindi
Chantal
C
Ménard
Michaël
M
Besin
Gilles
G
Dupuis
Gilles
G
Amrani
Abdelaziz
A
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000502:physiology*; D006131:Growth Inhibitors / Q000008:administration & dosage; D016130:Immunophenotyping; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000502:physiology; D008070:Lipopolysaccharides / Q000008:administration & dosage; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011236:Prediabetic State / Q000276:immunology; D017634:Self Tolerance; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism