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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 Cells¹

Department of Pediatric, Immunology Division, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada

Autoimmune diabetes results from a breakdown of self-tolerance that leads to T cell-mediated -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.

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¹ This work was supported by a grant from the Juvenile Diabetes Foundation International. S.G. is recipient of a PhD scholarship from Fonds de la Recherche en Santé du Québec. C.G. and M.M. are recipients of summer studentships from Diabète Québec. G.B. is the holder of a fellowship from Association de Langue Française pour l’étude du Diabète et des maladies Métaboliques (ALFEDIAM). A.A. is Canadian Diabetes Association New Investigator and a recipient of a Chercheur Boursier Junior 1 and Junior 2 fellowship from the Fonds de la Recherche en Santé du Québec.

² C.G. and M.M. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Abdelaziz Amrani, Department of Pediatric, Immunology Division, Faculty of Medicine and Health Sciences, University of Sherbrooke, 3001 12th Avenue North, Sherbrooke, Quebec, Canada J1H 5N4. E-mail address: Abdelaziz.Amrani{at}USherbrooke.ca

⁴ Abbreviations used in this paper: DC, dendritic cell; iDC, immature DC; Treg, regulatory T cell; PLN, pancreatic lymph node.

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