Conserved human effector Treg cell transcriptomic and epigenetic signature in arthritic joint inflammation

Nat Commun. 2021 May 11;12(1):2710. doi: 10.1038/s41467-021-22975-7.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Arthritis, Juvenile / genetics*
  • Arthritis, Juvenile / immunology
  • Arthritis, Juvenile / pathology
  • Base Sequence
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / immunology
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / immunology
  • Case-Control Studies
  • Cell Differentiation
  • Child
  • Child, Preschool
  • Epigenesis, Genetic*
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Glucocorticoid-Induced TNFR-Related Protein / genetics
  • Glucocorticoid-Induced TNFR-Related Protein / immunology
  • Histones / genetics
  • Histones / immunology
  • Humans
  • Joints / immunology
  • Joints / pathology
  • Male
  • Metabolic Networks and Pathways / genetics
  • Metabolic Networks and Pathways / immunology
  • Positive Regulatory Domain I-Binding Factor 1 / genetics
  • Positive Regulatory Domain I-Binding Factor 1 / immunology
  • Primary Cell Culture
  • Receptors, Calcitriol / genetics*
  • Receptors, Calcitriol / immunology
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • Transcriptome*
  • Young Adult

Substances

  • BATF protein, human
  • Basic-Leucine Zipper Transcription Factors
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Glucocorticoid-Induced TNFR-Related Protein
  • Histones
  • Receptors, Calcitriol
  • Receptors, Immunologic
  • TIGIT protein, human
  • TNFRSF18 protein, human
  • VDR protein, human
  • PRDM1 protein, human
  • Positive Regulatory Domain I-Binding Factor 1