Inhibition of HDAC9 increases T regulatory cell function and prevents colitis in mice.
OBJECTIVE
Foxp3+ T regulatory cells (Tregs) help prevent autoimmunity, and increases in their numbers of functions could decrease the development of inflammatory bowel disease. Like other cells, Foxp3+ Tregs express histone/protein deacetylases (HDACs), which regulate chromatin remodeling and gene expression. We investigated whether disruption of a specific class IIa HDAC, HDAC9, activity in Tregs affects the pathogenesis of colitis in mice.


METHODS
We tested the effects of various HDAC inhibitors (HDACi) in models of colitis using wild-type mice. We also transferred Tregs and non-Treg cells from HDAC9-/- or wild-type mice to immunodeficient mice. HDAC9 contributions to the functions of Tregs were determined during development and progression of colitis.


RESULTS
Pan-HDACi, but not class I-specific HDACi, increased the functions of Foxp3+ Tregs, prevented colitis, and reduced established colitis in mice, indicating the role of class II HDACs in controlling Treg function. The abilities of pan-HDACi to prevent/reduce colitis were associated with increased numbers of Foxp3+ Tregs and their suppressive functions. Colitis was associated with increased local expression of HDAC9; HDAC9-/- mice resistant to development of colitis. HDAC9-/- Tregs expressed increased levels of the heat shock protein (HSP) 70, compared with controls. Immunoprecipitation experiments indicated an interaction between HSP70 and Foxp3. Inhibition of HSP70 reduced the suppressive functions of HDAC9-/- Tregs; Tregs that overexpressed HSP70 had increased suppressive functions.


CONCLUSIONS
Strategies to decrease HDAC9 expression or function in Tregs or to increase expression of HSP70 might be used to treat colitis and other autoimmune disorders.
de Zoeten
Edwin F
EF
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania 19104-4318, USA.
Wang
Liqing
L
Sai
Hong
H
Dillmann
Wolfgang H
WH
Hancock
Wayne W
WW
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D003092:Colitis / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000473:pathology / Q000502:physiology*
D004791:Enzyme Inhibitors; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018840:HSP70 Heat-Shock Proteins; D012097:Repressor Proteins; C486545:Hdac9 protein, mouse; D006655:Histone Deacetylases