Blimp1 Prevents Methylation of Foxp3 and Loss of Regulatory T Cell Identity at Sites of Inflammation

Cell Rep. 2019 Feb 12;26(7):1854-1868.e5. doi: 10.1016/j.celrep.2019.01.070.

Abstract

Foxp3+ regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. Here, we establish a transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. This pathway is dependent on the transcriptional regulator Blimp1, which prevents downregulation of Foxp3 expression and "toxic" gain-of-function of Treg cells in the inflamed CNS. Blimp1 negatively regulates IL-6- and STAT3-dependent Dnmt3a expression and function restraining methylation of Treg cell-specific conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Consequently, CNS2 is heavily methylated when Blimp1 is ablated, leading to a loss of Foxp3 expression and severe disease. These findings identify a Blimp1-dependent pathway that preserves Treg cell stability in inflamed non-lymphoid tissues.

Keywords: Blimp1; CNS; CNS2; DNA methyltransferases; Foxp3; Interleukin-6; epigenetic regulation; inflammation; regulatory T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
  • DNA (Cytosine-5-)-Methyltransferases / immunology
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation*
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Epigenesis, Genetic
  • Female
  • Forkhead Transcription Factors / biosynthesis
  • Forkhead Transcription Factors / genetics*
  • Forkhead Transcription Factors / immunology
  • Genomic Imprinting
  • Interleukin-6 / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Positive Regulatory Domain I-Binding Factor 1 / genetics*
  • Positive Regulatory Domain I-Binding Factor 1 / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-6
  • Prdm1 protein, mouse
  • interleukin-6, mouse
  • Positive Regulatory Domain I-Binding Factor 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A