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Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function

ABSTRACT: Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An alternate strategy of pharmacologic modulation of Treg function using histone/protein deacetylase inhibitors (HDACi) may allow more titrable and longer-term dosing. However, the effects of broadly acting HDACi vary, such that HDAC isoform-selective targeting is likely required. We report data from mice with constitutive or conditional deletion of HDAC11 within Foxp3+ Treg cells, and their use, along with small molecule HDAC11 inhibitors, in allograft models. Global HDAC11 deletion had no effect on health or development, and compared to WT controls, Foxp3+ Tregs lacking HDAC11 showed increased suppressive function, and increased expression of Foxp3 and TGF-beta. Likewise, compared to WT recipients, conditional deletion of HDAC11 within Tregs led to long-term survival of fully MHC-mismatched cardiac allografts, and prevented development of transplant arteriosclerosis in an MHC class II-mismatched allograft model. The translational significance of HDAC11 targeting was shown by the ability of an HDAC11i to promote long-term allograft allografts in fully MHC-disparate strains. These data are powerful stimuli for the further development and testing of HDAC11-selective pharmacologic inhibitors, and may ultimately provide new therapies for transplantation and autoimmune diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE95316 | GEO | 2017/02/24

SECONDARY ACCESSION(S): PRJNA376611

REPOSITORIES: GEO

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Sirt1 targeting promotes Treg function

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2011-01-05 | E-GEOD-26425 | biostudies-arrayexpress

Sirt1 targeting promotes Treg function

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

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2011-05-01 | E-GEOD-27896 | biostudies-arrayexpress

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

2011-05-01 | GSE27896 | GEO

RNA-seq analysis for characterization of the TCR repertoire

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2019-07-03 | GSE132691 | GEO

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2012-06-20 | E-GEOD-36095 | biostudies-arrayexpress

Histone/Protein Deacetylase-6, -9, and Sirtuin-1 Control Foxp3+ Treg Through Shared and Isotype-Specific Mechanisms

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2014-10-21 | GSE52164 | GEO

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