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Whole transcriptome sequencing of Treg with and without Rcor1 deletion

ABSTRACT: Foxp3+ T-regulatory (Treg) cells have well established roles in maintaining immune homeostasis and tolerance, but the contributions of several large multiprotein complexes that regulate gene expression remain unexplored in Tregs. We analyzed the role in Tregs of the evolutionarily conserved CoREST complex that consists of a scaffolding protein, Rcor1 or Rcor2, plus Hdac1, Hdac2 and Lsd1 enzymes. We found Rcor1, Rcor2 and Lsd1 were physically associated with Foxp3, and that mice with conditional deletion of Rcor1 in Foxp3+ Treg cells had decreased proportions of Tregs in their peripheral lymphoid tissues, and increased Treg expression of IL-2 and IFN-g compared to WT cells. In vivo, compared with WT mice, mice with conditional deletion of Rcor1 in their Tregs had reduced suppression of homeostatic proliferation, inability to maintain long-term allograft survival despite costimulation blockade, and enhanced antitumor immunity in syngeneic models. Comparable findings were seen in WT mice treated with a CoREST inhibitor. Our data point to the potential for therapeutic modulation of Treg functions by pharmacologic targeting of enzymatic components of the CoREST complex, and contribute to an understanding of the biochemical and molecular mechanisms by which Foxp3 represses large gene sets and maintains the unique properties of this key immune cell type.

ORGANISM(S): Mus musculus

PROVIDER: GSE137137 | GEO | 2019/09/10

REPOSITORIES: GEO

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Project description: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. RNA was isolated using RNeasy kits (QIAGEN), and RNA integrity and quantity were analyzed by NanoDrop ND-1000 and Nanochip 2100 Bioanalyzer (Agilent Technologies). Microarray experiments were performed using whole mouse genome oligoarrays (Mouse430a, Affymetrix) and array data analyzed using MAYDAY 2.12 software. Array data were subjected to robust multiarray average (RMA) normalization and analyzed using Student’s t test. Only data with a false discovery rate-adjusted P value of less than 0.05 and at least 2× differential expression were included in the analysis. Data underwent z-score transformation for display.

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Whole transcriptome sequencing of Treg with and without Rcor1 deletion

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