Foxp3+ Tregs are key to immune homeostasis, but the contributions of various large, multiprotein complexes that regulate gene expression remain unexplored. We analyzed the role in Tregs of the evolutionarily conserved CoREST complex, consisting of a scaffolding protein, Rcor1 or Rcor2, plus Hdac1 or Hdac2 and Lsd1 enzymes. Rcor1, Rcor2, and Lsd1 were physically associated with Foxp3, and mice with conditional deletion of Rcor1 in Foxp3+ Tregs had decreased proportions of Tregs in peripheral lymphoid tissues and increased Treg expression of IL-2 and IFN-γ compared with what was found in WT cells. Mice with conditional deletion of the gene encoding 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 CoREST complex bivalent inhibitors, which also altered the phenotype of human Tregs and impaired their suppressive function. 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.

中文翻译：

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抑制核心调节因子 CoREST 会损害 Foxp3+ Treg 功能并促进抗肿瘤免疫。

Foxp3+ Tregs 是免疫稳态的关键，但调节基因表达的各种大型多蛋白复合物的贡献仍未被探索。我们分析了进化上保守的 CoREST 复合体在 Tregs 中的作用，该复合体由支架蛋白 Rcor1 或 Rcor2，加上 Hdac1 或 Hdac2 和 Lsd1 酶组成。Rcor1、Rcor2和Lsd1与Foxp3有物理相关性，与WT相比，条件性删除Foxp3+ Tregs中Rcor1的小鼠外周淋巴组织中Treg的比例降低，IL-2和IFN-γ的Treg表达增加细胞。有条件地删除其Treg中编码Rcor1的基因的小鼠，其对稳态增殖的抑制减少，尽管共刺激阻断，但仍无法维持长期同种异体移植物存活，并增强同基因模型中的抗肿瘤免疫力。在用 CoREST 复合物二价抑制剂治疗的 WT 小鼠中也观察到了类似的结果，这也改变了人类 Tregs 的表型并损害了其抑制功能。我们的数据表明通过药理靶向 CoREST 复合物的酶成分来治疗调节 Treg 功能的潜力，并有助于理解 Foxp3 抑制大基因集并维持这一关键免疫细胞的独特性质的生化和分子机制。