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

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 4

Hdac3 deletion impairs Treg function in vitro and in vivo.

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Hdac3 deletion impairs Treg function in vitro and in vivo. (A–F) In vit...
(A–F) In vitro experiments. (A) Treg suppression assay using pooled Tregs from lymph nodes and spleens of WT and HDAC3–/– mice, with representative data shown in A, along with the percentage of proliferating cells in each panel; pooled data (4 mice/group) are shown in B. Corresponding in vitro Treg assays using purely (C) lymph node Tregs and (D) splenic Tregs. (E) Retroviral transduction of Hdac3 significantly improved Hdac3–/– Treg function compared with empty vector transduction. (F) Treg suppression assay using Tregs from mice with mutations of DADs in both NCoR1 and SMRT/NCoR2. (G and H) In vivo experiments. (G) Contrasting effects of WT and Hdac3–/– Tregs on the extent of homeostatic proliferation at 7 days after adoptive transfer of WT Teffs injected into Rag1–/– mice. (H) Contrasting survival of BALB/c hearts transplanted into C57BL/6 Rag1–/– mice and adoptively transferred with 1 × 106 C57BL/6 Teffs and 0.5 × 106 WT or Hdac3–/– C57BL/6 Tregs (Kaplan-Meier plots, 6 allo­grafts/group). Each experiment in A–G was run in triplicate and repeated at least 3 times, and results of 1 representative experiment are shown; mean ± SD, 1-way ANOVA with corresponding Tukey’s multiple comparison test; *P < 0.05 and **P < 0.01 vs. WT control.