Transcriptomics

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HDAC6 and HSP90 control the functions of Foxp3+ T regulatory cells


ABSTRACT: Foxp3+ T-regulatory cells (Tregs) are key to immune homeostasis such that their diminished numbers or function can cause autoimmunity and allograft rejection. Foxp3+ Tregs express histone/protein deacetylases (HDACs) that regulate chromatin remodeling, gene expression and protein function. Pan-HDAC inhibitors developed for oncology enhance Treg production and suppression but have limited non-oncologic applications given their broad effects. We show, using HDAC6-deficient mice and WT mice treated with HDAC6-specific inhibitors, that HDAC6 inhibition promotes Treg suppressive activity in models of inflammation and autoimmunity, including multiple forms of experimental colitis and fully MHC-incompatible cardiac allograft rejection. Many of the beneficial effects of HDAC6 targeting are also achieved by inhibition of the HDAC6-regulated protein, HSP90. Hence, selective targeting of a single HDAC isoform, HDAC6, or its downstream target, HSP90, can promote Treg-dependent suppression of autoimmunity and transplant rejection. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of HDAC6 knock out, compared to wild type (C57BL6) control

ORGANISM(S): Mus musculus  

SUBMITTER: James E Bradner   Ralph Mazitschek  Hong Sai  Edwin F de Zoeten  Liqing Wang  Wayne W Hancock  Alan P Kozikowski  Ulf H Beier  Kyle Butler  Patrick Matthias 

PROVIDER: E-GEOD-27896 | ArrayExpress | 2011-05-01

SECONDARY ACCESSION(S): GSE27896PRJNA138203

REPOSITORIES: GEO, ArrayExpress

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Publications

Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3(+) T-regulatory cells.

de Zoeten Edwin F EF   Wang Liqing L   Butler Kyle K   Beier Ulf H UH   Akimova Tatiana T   Sai Hong H   Bradner James E JE   Mazitschek Ralph R   Kozikowski Alan P AP   Matthias Patrick P   Hancock Wayne W WW  

Molecular and cellular biology 20110328 10


Foxp3(+) T-regulatory cells (Tregs) are key to immune homeostasis such that their diminished numbers or function can cause autoimmunity and allograft rejection. Foxp3(+) Tregs express multiple histone/protein deacetylases (HDACs) that regulate chromatin remodeling, gene expression, and protein function. Pan-HDAC inhibitors developed for oncologic applications enhance Treg production and Treg suppression function but have limited nononcologic utility given their broad actions and various side eff  ...[more]

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