期刊
JOURNAL OF IMMUNOLOGY
卷 179, 期 6, 页码 3638-3647出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.179.6.3638
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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 center dot 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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