Abstract
Female NOD mice develop autoimmune diabetes spontaneously without extrinsic manipulation. Previously, we have shown that weekly administration of the prediabetic female NOD mice with the histone modifier Trichostatin A (TSA) prevented diabetes onset. Herein we show that T lymphocytes from diabetic mice transferred diabetes into immunodeficient NOD.scid recipients while those isolated from drug-treated mice displayed reduced disease-causing ability. Drug treatment also repressed T cell receptor-mediated IFN-γ transcription. Splenic CD4+ T-cells purified from prediabetic mice could be polarized into IFN-γ -producing Th1 and IL-17A-expressing Th17 subsets ex vivo. Adoptive transfer of these cells into immunocompromised NOD.scid mice caused diabetes comparably. Polarized Th1 cells were devoid of IL-17A-producing cells and did not transdifferentiate into Th17 cells in the spleen of immunodeficient recipients. However, polarized Th17 cell preparation had a few contaminant Th1 cells. Adoptive transfer of polarized Th17 cells into NOD.scid recipients led to IFN-γ transcription in recipient splenocytes. Notably, TSA treatment of prediabetic mice abolished the ability of CD4+ T-cells to differentiate into diabetogenic Th1 and Th17 cells ex vivo. This was accompanied by the absence of Ifng and Il17a transcription in the spleen of NOD.scid recipients receiving cells, respectively cultured under Th1 and Th17 polarizing conditions. Significantly, the histone modifier restored the ability of CD4+ but not CD8+ T-cells to undergo CD3-mediated apoptosis ex vivo in a caspase-dependent manner. These results indicate that the histone modifier bestowed protection against type 1 diabetes via negative regulation of signature lymphokines and restitution of self-tolerance in CD4+ T cells.