Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells

Abstract

Classical zinc-dependent histone deacetylases (HDACs) catalyse the removal of acetyl groups from histone tails and also from many non-histone proteins, including the transcription factor FOXP3, a key regulator of the development and function of regulatory T cells. Many HDAC inhibitors are in cancer clinical trials, but a subset of HDAC inhibitors has important anti-inflammatory or immunosuppressive effects that might be of therapeutic benefit in immuno-inflammatory disorders or post-transplantation. At least some of these effects result from the ability of HDAC inhibitors to enhance the production and suppressive functions of FOXP3 + regulatory T cells. Understanding which HDACs contribute to the regulation of the functions of regulatory T cells may further stimulate the development of new class-or subclass-specific HDAC inhibitors with applications beyond oncology.Control of autoimmunity and other undesired immune responses through manipulation of endogenous regulatory mechanisms has long been a dream of physicians and scientists. Recent insights into the role of epigenetics in the regulation of gene expression and cell function suggest new therapeutic opportunities, including regulation of chromatin remodelling and gene transcription by inhibition of histone deacetylases (HDACs) and DNA methyltransferases 1-4 . Moreover, although deacetylation of ε-acetyl-lysine residues in the amino-terminal tail of core histones is a key function of several HDACs, HDACs also deacetylate many non-histone proteins 1-5 , including the forkhead transcription factor FOXP3, which is important in the development and regulation of regulatory T cells (T regs ) 6,7 . Protein acetylation can affect DNA binding, either positively or negatively, protein-protein interactions and enhance protein

Histone Deacetylase 9 Is a Negative Regulator of Adipogenic Differentiation

“…We propose that the elevated HDAC9 levels in preadipocytes function to maintain the undifferentiated state; upon exposure to appropriate adipogenic stimuli, HDAC9 down-regulation removes this block to allow the adipogenic differentiation process to occur. A similar negative regulatory role for HDAC9 in suppressing differentiation of myocytes and Treg cells has previously been proposed (26,27).…”

“…HDAC9 was shown previously to suppress myocyte differentiation by physically interacting with and blocking the transcriptional activity of MEF2 transcription factor at the myogenic gene promoter (26). Similarly, HDAC9 blocks Treg cell differentiation through interacting with and inhibiting FoxP3 (Forkhead box P3) transcriptional activity on cytokine gene promoters (27). Down-regulation of HDAC9, in response to appropriate stimuli, de-represses the transcriptional block to activate the gene expression program supporting differentiation of myocytes or Treg cells.…”

SAHA, an HDAC inhibitor, synergizes with tacrolimus to prevent murine cardiac allograft rejection

“…37 Theraputic manipulation of Foxp3 acetylation using HDACis was demonstrated to promote the development and suppressive functions of Treg cells, with beneficial results obtained in models of colitis, 38 arthritis 39 and transplant rejection. 40 The involvement of CD4 1 cells in immune responses of transplant rejection has long been established, 45 of which Th2 polarization is believed to protect allograft from rejection due to the ability of IL-4 for inhibition of Th1 differentiation.…”

Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy

“…Protein acetylation is an important posttranslational modification and controls many crucial cellular processes, including transcription, cell motility, and metabolism (28,39,57). Protein acetylation can also influence cytoplasmic protein activity (58) and assembly of autophagic vacuoles (21). The acetylase and deacetylase activities must remain balanced to preserve proper cell function.…”