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

Garima Garg; Andreas Muschaweckh; Helena Moreno; Ajithkumar Vasanthakumar; Stefan Floess; Gildas Lepennetier; Rupert Oellinger; Yifan Zhan; Tommy Regen; Michael Hiltensperger; Christian Peter; Lilian Aly; Benjamin Knier; Lakshmi Reddy Palam; Reuben Kapur; Mark H Kaplan; Ari Waisman; Roland Rad; Gunnar Schotta; Jochen Huehn; Axel Kallies; Thomas Korn

doi:10.1016/j.celrep.2019.01.070

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.

Authors

Garima Garg¹, Andreas Muschaweckh¹, Helena Moreno², Ajithkumar Vasanthakumar³, Stefan Floess⁴, Gildas Lepennetier¹, Rupert Oellinger⁵, Yifan Zhan³, Tommy Regen⁶, Michael Hiltensperger¹, Christian Peter¹, Lilian Aly⁷, Benjamin Knier¹, Lakshmi Reddy Palam⁸, Reuben Kapur⁸, Mark H Kaplan⁸, Ari Waisman⁶, Roland Rad⁵, Gunnar Schotta², Jochen Huehn⁴, Axel Kallies³, Thomas Korn⁹

Affiliations

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.

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*
DNA Methyltransferase 3A
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

Dnmt3a protein, mouse
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

Abstract

Publication types

MeSH terms

Substances

Grants and funding