Histone/protein deacetylase inhibitors increase suppressive functions of human FOXP3+ Tregs.
Histone/protein deacetylases (HDACs) decrease histone and protein acetylation, typically leading to suppression of gene transcription and modulation of various protein functions. We found significant differences in expression of HDAC before and after stimulation of human T regulatory (Treg) and T effector cells, suggesting the potential for future selective targeting of Tregs with HDAC inhibitors (HDACi). Use of various HDACi small molecules enhanced, by up to 4.5-fold (average 2-fold), the suppressive functions of both freshly isolated and expanded human Tregs, consistent with our previous murine data. HDACi use increased Treg expression of CTLA-4, a key negative regulator of immune response, and we found a direct and significant correlation between CTLA-4 expression and Treg suppression. Hence, HDACi compounds are promising pharmacologic tools to increase Treg suppressive functions, and this action may potentially be of use in patients with autoimmunity or post-transplantation.
Akimova
Tatiana
T
Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104-4318, USA.
Ge
Guanghui
G
Golovina
Tatiana
T
Mikheeva
Tatiana
T
Wang
Liqing
L
Riley
James L
JL
Hancock
Wayne W
WW
D015703:Antigens, CD / Q000378:metabolism; D060908:CTLA-4 Antigen; D049109:Cell Proliferation; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D006655:Histone Deacetylases