Center for Translational Immunology, Pediatric Immunology & Rheumatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Regenerative Medicine Center Utrecht, Department of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands.
Nat Commun. 2021 May 11;12(1):2710. doi: 10.1038/s41467-021-22975-7.
Treg cells are critical regulators of immune homeostasis, and environment-driven Treg cell differentiation into effector (e)Treg cells is crucial for optimal functioning. However, human Treg cell programming in inflammation is unclear. Here, we combine transcriptional and epigenetic profiling to identify a human eTreg cell signature. Inflammation-derived functional Treg cells have a transcriptional profile characterized by upregulation of both a core Treg cell (FOXP3, CTLA4, TIGIT) and effector program (GITR, BLIMP-1, BATF). We identify a specific human eTreg cell signature that includes the vitamin D receptor (VDR) as a predicted regulator in eTreg cell differentiation. H3K27ac/H3K4me1 occupancy indicates an altered (super-)enhancer landscape, including enrichment of the VDR and BATF binding motifs. The Treg cell profile has striking overlap with tumor-infiltrating Treg cells. Our data demonstrate that human inflammation-derived Treg cells acquire a conserved and specific eTreg cell profile guided by epigenetic changes, and fine-tuned by environment-specific adaptations.
调节性 T 细胞（Treg 细胞）是免疫稳态的关键调节因子，环境驱动的 Treg 细胞向效应性（e）Treg 细胞分化对于其最佳功能至关重要。然而，人类 Treg 细胞在炎症中的编程尚不清楚。在这里，我们结合转录组和表观遗传组学分析，鉴定出一个人类 eTreg 细胞特征。炎症来源的功能性 Treg 细胞具有以下转录特征：FOXP3、CTLA4 和 TIGIT 等核心 Treg 细胞基因以及 GITR、BLIMP-1 和 BATF 等效应基因的上调。我们鉴定出一个特定的人类 eTreg 细胞特征，包括维生素 D 受体（VDR）作为 eTreg 细胞分化的预测调节因子。H3K27ac/H3K4me1 占有率表明改变的（超级）增强子景观，包括 VDR 和 BATF 结合基序的富集。Treg 细胞特征与肿瘤浸润性 Treg 细胞有显著重叠。我们的数据表明，人类炎症来源的 Treg 细胞通过表观遗传变化获得保守和特定的 eTreg 细胞特征，并通过特定环境的适应性进行微调。
