Conserved human effector Treg cell transcriptomic and epigenetic signature in arthritic joint inflammation
Mijnheer, Gerdien; Lutter, Lisanne; Mokry, Michal; van der Wal, Marlot; Scholman, Rianne; Fleskens, Veerle; Pandit, Aridaman; Tao, Weiyang; Wekking, Mark; Vervoort, Stephin; Roberts, Ceri; Petrelli, Alessandra; Peeters, Janneke G C; Knijff, Marthe; de Roock, Sytze; Vastert, Sebastiaan; Taams, Leonie S; van Loosdregt, Jorg; van Wijk, Femke
(2021) Nature Communications, volume 12, issue 1, pp. 1 - 16
(Article)
Abstract
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
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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.
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Keywords: Adolescent, Arthritis, Juvenile/genetics, Base Sequence, Basic-Leucine Zipper Transcription Factors/genetics, CTLA-4 Antigen/genetics, Case-Control Studies, Cell Differentiation, Child, Child, Preschool, Epigenesis, Genetic, Female, Forkhead Transcription Factors/genetics, Gene Expression Profiling, Gene Regulatory Networks, Glucocorticoid-Induced TNFR-Related Protein/genetics, Histones/genetics, Humans, Joints/immunology, Male, Metabolic Networks and Pathways/genetics, Positive Regulatory Domain I-Binding Factor 1/genetics, Primary Cell Culture, Receptors, Calcitriol/genetics, Receptors, Immunologic/genetics, T-Lymphocytes, Regulatory/immunology, Transcriptome, Young Adult, General Chemistry, General Biochemistry,Genetics and Molecular Biology, General Physics and Astronomy, Journal Article, Research Support, Non-U.S. Gov't
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: We would like to thank J. van Velzen and P. Andriessen van der Burght for technical assistance, and Anoushka Samat for help with qPCR primer design. F. van Wijk is supported by a VIDI grant from ZonMw (91714332). Publisher Copyright: © 2021, The Author(s).
(Peer reviewed)
