HISTONE DEACETYLASE INHIBITORS (HDACI) ENHANCE FOXP3+ REGULATORY T CELL (TREG) FUNCTIONS AND SUPPRESS INFLAMMATORY BOWEL DISEASE (IBD)

IBD involves dysregulation of mucosal T cells and increased cellular immune responses to gut antigens. Naturally occurring CD4+CD25+ Tregs expressing the transcription factor, Foxp3, regulate inflammation in many diseases. We have found that use of HDACi, e.g. Trichostatin A (TsA) or valproic acid (VPA), enhances Tregs functions, leading us to test HDACi in the dextran sodium sulfate (DSS)-induced murine model of IBD. C57BL/6 mice received 3% DSS in their drinking water and were treated for 14 d with TsA (1 mg/kg/d) in DMSO or DMSO alone (n = 10/group). In marked contrast to DMSO-treated controls, mice given TsA maintained their weight (P < 0.01), stool consistency (P < 0.01), lacked bloody diarrhea (P < 0.01), and showed no evidence of colitis by histology. Lower doses of TsA decreased the severity but did not prevent disease. Real-time PCR showed control and TsA-treated Tregs had similar expression of CD25, IL-4, IFN-γ and TGF-β, but TsA therapy increased Treg expression of Foxp3, CTLA-4, PD-1, GITR and IL-10. In the absence of Tregs, T effector cells from TsA-treated or control mice proliferated similarly, demonstrating TsA treatment does not affect proliferative capacity of naive T cells. In contrast, Tregs of TsA-treated mice had significantly enhanced suppressive function compared to WT Tregs. Finally, mice underwent thymectomy and a course of CD25 mAb to deplete CD25+ Tregs before DSS exposure and therapy with TsA or DMSO control. Mice depleted of CD25+ Tregs developed robust colitis, regardless of HDACi therapy. Comparable beneficial effects of HDACi on colitis were also observed using VPA, indicating the therapeutic potential was not confined to a single class of HDACi. In summary, HDACi enhance Tregs suppressive functions and regulate the development of colitis in a dose-dependent and Treg-dependent manner, indicating the potential for pharmacologic manipulation in IBD of this key immunoregulatory T cell subset.