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

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

Author information

1
Klinikum Rechts der Isar, Department of Experimental Neuroimmunology, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany.
2
Biomedical Center (BMC) and Center for Integrated Protein Science Munich, Faculty of Medicine, LMU Munich, Grosshaderner Str. 9, 82152 Planegg-Martinsried, Germany.
3
The Peter Doherty Institute for Infection and Immunity, University of Melbourne, 792 Elizabeth St., Melbourne Victoria 3000, Australia; The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
4
Experimental Immunology, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
5
Institute of Molecular Oncology and Functional Genomics, TranslaTUM Cancer Center, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany; Klinikum Rechts der Isar, Department of Medicine II, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany.
6
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
7
Klinikum Rechts der Isar, Department of Experimental Neuroimmunology, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Feodor-Lynen-Str. 17, 81377 Munich, Germany.
8
Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 1044 West Walnut St., Indianapolis, IN 46202, USA.
9
Klinikum Rechts der Isar, Department of Experimental Neuroimmunology, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Feodor-Lynen-Str. 17, 81377 Munich, Germany. Electronic address: thomas.korn@tum.de.

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

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