Histone Deacetylases 6 and 9 and Sirtuin-1 Control Foxp3+ Regulatory T Cell Function Through Shared and Isoform-specific Mechanisms

Therapeutic inhibition of the histone deacetylases HDAC6, HDAC9, or sirtuin-1 (Sirt1) augments the suppressive functions of regulatory T cells (T(regs)) that contain the transcription factor Foxp3 (Forkhead box P3) and is useful in organ transplant patients or patients with autoimmune diseases. However, it is unclear whether distinct mechanisms are involved for each HDAC or whether combined inhibition of HDACs would be more effective. We compared the suppressive functions of T(regs) from wild-type C57BL/6 mice with those from mice with either complete or cell-specific deletion of various HDACs, as well as with those of T(regs) treated with isoform-selective HDAC inhibitors. The improvement of T(reg) suppressive function mediated by inhibition of HDAC6, but not Sirt1, required an intact heat shock response. Although HDAC6, HDAC9, and Sirt1 all deacetylated Foxp3, each protein had different effects on transcription factors that control expression of the gene encoding Foxp3. For example, loss of HDAC9, but not other HDACs, was associated with stabilization of the acetylated form of signal transducer and activator of transcription 5 (STAT5) and promoted its transcriptional activity. Thus, targeting different HDACs increased T(reg) function through multiple and additive mechanisms, which suggests the therapeutic potential for using combinations of HDAC inhibitors in the management of autoimmunity and organ transplantation.