Histone Deacetylase 6 and Heat Shock Protein 90 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 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.

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ACKNOWLEDGMENTS

This work was supported by research grants from the National Institutes of Health (K08DK080189 to E.F.D. and P01AI073489 to W.W.H.) and CDHNF/CCFA (2712) grants to E.F.D.

We thank Kapil Bhalla for the gift of anti-acetylated HSP90 Ab.