Histone deacetylase inhibition facilitates GM-CSF-mediated expansion of myeloid-derived suppressor cells in vitro and in vivo.
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(+)F4/80(int)CD115(+)), 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.
University of Pittsburgh School of Medicine, Thomas E. Starzl Transplantation Institute, 200 Lothrop St., Biomedical Science Tower, W1540, Pittsburgh, PA 15213, USA.
Brian R
BR
Rosborough
Antonino
A
Castellaneta
Sudha
S
Natarajan
Angus W
AW
Thomson
Heth R
HR
Turnquist
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism*
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006655:Histone Deacetylases