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

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

Research output: Contribution to journalArticle

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 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 effects. We show, using HDAC6-deficient mice and wild-type (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 major histocompatibility complex (MHC)-incompatible cardiac allograft rejection. Many of the beneficial effects of HDAC6 targeting are also achieved by inhibition of the HDAC6-regulated protein heat shock protein 90 (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.

Original languageEnglish (US)
Pages (from-to)2066-2078
Number of pages13
JournalMolecular and cellular biology
Volume31
Issue number10
DOIs
StatePublished - May 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    de Zoeten, E. F., Wang, L., Butler, K., Beier, U. H., Akimova, T., Sai, H., Bradner, J. E., Mazitschek, R., Kozikowski, A. P., Matthias, P., & Hancock, W. W. (2011). Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3+ T-regulatory cells. Molecular and cellular biology, 31(10), 2066-2078. https://doi.org/10.1128/MCB.05155-11