Histone/protein deacetylase inhibitor therapy for enhancement of Foxp3+ T-regulatory cell function posttransplantation

Abstract

T-regulatory (Treg) cells are like other cells present throughout the body in being subject to biochemical modifications in response to extracellular signals. An important component of these responses involves changes in posttranslational modifications (PTMs) of histones and many nonhistone proteins, including phosphorylation/dephosphorylation, ubiquitination/deubiquitination, and acetylation/deacetylation. Foxp3, the key transcription factor of Tregs, is constantly being rapidly turned over, and a number of these PTMs determine its level of expression and activity. Of interest in the transplant setting, modulation of the acetylation or deacetylation of key lysine residues in Foxp3 can promote the stability and function, leading to increased Treg production and increased Treg suppressive activity. This mini-review focuses on recent data concerning the roles that histone/protein deacetylases (HDACs) play in control of Treg function, and how small molecule HDAC inhibitors can be used to promote Treg-dependent allograft survival in experimental models. These data are discussed in the light of increasing interest in the identification and clinical evaluation of isoform-selective HDAC inhibitors, and their potential application as tools to modulate Foxp3+ Treg cell numbers and function in transplant recipients.

Regulatory T cells in solid organ transplantation

“…However, these data involved pan‐inhibition of their relevant enzymes and so did not reflect the effects of modulating their numerous isoforms. This is important as divergence in the inhibition of different isoforms and their effects on Treg function is known . The authors also used an HDAC9 KO murine model to demonstrate a boost to the quantity of Treg cells and their function.…”

“…This is important as divergence in the inhibition of different isoforms and their effects on Treg function is known. 61,62 The authors also used an HDAC9 KO murine model to demonstrate a boost to the quantity of Treg cells and their function. Similar effects have also been demonstrated in the studies focussing on inhibition of HDAC3/10/11 either pharmacologically or via enzyme KO or Tregspecific enzyme KO.…”

Sirtuin-1 in immunotherapy: A Janus-headed target

“…Three lysine acetylation sites in murine Foxp3 are susceptible to Sirt1 mediated deacetylation, K31, K262, and K267 . Foxp3 acetylation is not just important for the protein stability of Foxp3, but also for its ability to bind to DNA and exert transcriptional control . In addition to the post‐translational control of Foxp3, deletion or pharmacologic inhibition with EX‐527, a Sirt1 inhibitor, leads to increased Foxp3 mRNA production .…”

“…Furthermore, Sirt1 has been shown to alleviate lipopolysaccharide‐induced injury, and mitigate oxidative stress arising in diabetic nephropathy, all of which would be common exposures in kidney transplant recipients. These broad side effects make Sirt1 targeting for immunosuppression less practical …”

“…Foxp3 protein is post-translationally regulated by lysine acetylation through histone/protein deacetylases (HDACs) and histone acetyl transferases (HATs). 6 Global HDAC inhibition [7][8][9] or deletion of HDAC6, 9, 11 and Sirtuin-1 (Sirt1) [10][11][12][13][14][15][16][17] augments Treg function, whereas deleting HDAC3 or 5, Sirt3, or targeting the HATs p300 or CBP impairs Treg. [18][19][20][21][22] Sirtuins are class III HDACs, and stand out from the other HDAC families by being dependent on NAD as a co-factor ( Fig.…”