Histone deacetylase inhibition facilitates GM-CSF-mediated expansion of myeloid-derived suppressor cells in vitro and in vivo

Open Access
Publisher Website
Google Scholar
Abstract
Chromatin‐modifying HDACi exhibit anti‐inflammatory properties that reflect their ability to suppress DC function and enhance regulatory T cells. The influence of HDACi on MDSCs, an emerging regulatory leukocyte population that potently inhibits T cell proliferation, has not been examined. Exposure of GM‐CSF‐stimulated murine BM cells to HDACi led to a robust expansion of monocytic MDSC (CD11b+Ly6C+F4/80intCD115+), which suppressed allogeneic T cell proliferation in a NOS‐ and HO‐1‐dependent manner with similar potency to control MDSCs. The increased yield of MDSCs correlated with blocked differentiation of BM cells and an overall increase in HSPCs (Lin–Sca‐1+c‐Kit+). In vivo, TSA enhanced the mobilization of splenic HSPCs following GM‐CSF administration and increased the number of CD11b+Gr1+ cells in BM and spleen. Increased numbers of Gr1+ cells, which suppressed T cell proliferation, were recovered from spleens of TSA‐treated mice. Overall, HDACi enhance MDSC expansion in vitro and in vivo, suggesting that acetylation regulates myeloid cell differentiation. These findings establish a clinically applicable approach to augment this rare and potent suppressive immune cell population and support a novel mechanism underlying the anti‐inflammatory action of HDACi.
Funding Information
  • NIH (R01 AI60994, P01 AI81678)
  • NIH Institutional Training (T32 AI74490)
  • American Heart Association (11PRE7070020)
  • American Society of Transplantation
  • American Liver Foundation
  • Starzl Transplantation Institute (T32 AI74490)
  • NIH Pathway-to-Independence Career Development (K99/R00 HL97155)