Epigenetic reprogramming ameliorates type 1 diabetes by decreasing the generation of Th1 and Th17 subsets and restoring self-tolerance in CD4+ T cells

SUMMARY The histone modifier Trichostatin A (TSA) ameliorated diabetes and repressed IFN-γ and IL-17A expression in prediabetic female NOD mice. Purified CD4 + cells could be polarized ex vivo into Th1 and Th17 subsets, which comparably transferred diabetes into NOD. scid mice. Polarized Th1 cells were devoid of IL-17A-producing cells and did not transdifferentiate into Th17 cells in an immunodeficient environment. However, Th17 cells had contaminant Th1 cells, which expressed IFN-γ upon adoptive transfer into lymphopenic recipients. Notably, TSA treatment abrogated the transfer of diabetes by CD4 + T-cells cultured under Th1 or Th17 polarizing conditions accompanied by the absence of Ifng and Il17a expression in NOD. scid recipients. 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. Thus, the histone modifier afforded protection against autoimmune diabetes by negative regulation of signature lymphokines and restitution of self-tolerance in CD4 + T cells.