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FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3
Liqing Wang, … , Scott W. Hiebert, Wayne W. Hancock
Liqing Wang, … , Scott W. Hiebert, Wayne W. Hancock
Published February 2, 2015
Citation Information: J Clin Invest. 2015;125(3):1111-1123. https://doi.org/10.1172/JCI77088.
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Research Article

FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

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Abstract

Treg dysfunction is associated with a variety of inflammatory diseases. Treg populations are defined by expression of the oligomeric transcription factor FOXP3 and inability to produce IL-2, a cytokine required for T cell maintenance and survival. FOXP3 activity is regulated post-translationally by histone/protein acetyltransferases and histone/protein deacetylases (HDACs). Here, we determined that HDAC3 mediates both the development and function of the two main Treg subsets, thymus-derived Tregs and induced Tregs (iTregs). We determined that HDAC3 and FOXP3 physically interact and that HDAC3 expression markedly reduces Il2 promoter activity. In murine models, conditional deletion of Hdac3 during thymic Treg development restored Treg production of IL-2 and blocked the suppressive function of Tregs. HDAC3-deficient mice died from autoimmunity by 4–6 weeks of age; however, injection of WT FOXP3+ Tregs prolonged survival. Adoptive transfer of Hdac3-deficient Tregs, unlike WT Tregs, did not control T cell proliferation in naive mice and did not prevent allograft rejection or colitis. HDAC3 also regulated the development of iTregs, as HDAC3-deficient conventional T cells were not converted into iTregs under polarizing conditions and produced large amounts of IL-2, IL-6, and IL-17. We conclude that HDAC3 is essential for the normal development and suppressive functions of thymic and peripheral FOXP3+ Tregs.

Authors

Liqing Wang, Yujie Liu, Rongxiang Han, Ulf H. Beier, Tricia R. Bhatti, Tatiana Akimova, Mark I. Greene, Scott W. Hiebert, Wayne W. Hancock

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Figure 1

HDAC3 is required for suppression of IL-2 production in Tregs.

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HDAC3 is required for suppression of IL-2 production in Tregs.
(A) Co-im...
(A) Co-immunoprecipitation of HDAC3 and FOXP3 proteins from 293T cells transfected with FLAG-tagged HDAC3 and FOXP3 constructs. (B) Colocalization of HDAC3 and FOXP3 within the nuclei of WT Tregs (original magnification, ×400). (C) ChIP assay showing recruitment of HDAC3 to the Il2 promoter. (D) Il2 promoter–driven luciferase activity in 293T cells transfected with empty vector (EV) or vectors for NFAT, FOXP3, and HDAC3, as shown. (E) Il2 gene expression (qPCR) in conventional Teffs and Tregs. In C–E, mean ± SD, n = 4/group, with statistical analysis using Student’s t test for unpaired data in C and E, and Kruskal-Wallis with Dunn’s multiple comparison test for D; *P < 0.05 and **P < 0.01 for the indicated comparisons, and versus WT in E.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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