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
Affiliations
Garima Garg
Klinikum Rechts der Isar, Department of Experimental Neuroimmunology, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
Andreas Muschaweckh
Klinikum Rechts der Isar, Department of Experimental Neuroimmunology, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
Helena Moreno
Biomedical Center (BMC) and Center for Integrated Protein Science Munich, Faculty of Medicine, LMU Munich, Grosshaderner Str. 9, 82152 Planegg-Martinsried, Germany
Ajithkumar Vasanthakumar
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
Stefan Floess
Experimental Immunology, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany
Gildas Lepennetier
Klinikum Rechts der Isar, Department of Experimental Neuroimmunology, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
Rupert Oellinger
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
Yifan Zhan
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
Tommy Regen
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
Michael Hiltensperger
Klinikum Rechts der Isar, Department of Experimental Neuroimmunology, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
Christian Peter
Klinikum Rechts der Isar, Department of Experimental Neuroimmunology, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
Lilian Aly
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
Benjamin Knier
Klinikum Rechts der Isar, Department of Experimental Neuroimmunology, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
Lakshmi Reddy Palam
Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 1044 West Walnut St., Indianapolis, IN 46202, USA
Reuben Kapur
Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 1044 West Walnut St., Indianapolis, IN 46202, USA
Mark H. Kaplan
Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 1044 West Walnut St., Indianapolis, IN 46202, USA
Ari Waisman
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
Roland Rad
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
Gunnar Schotta
Biomedical Center (BMC) and Center for Integrated Protein Science Munich, Faculty of Medicine, LMU Munich, Grosshaderner Str. 9, 82152 Planegg-Martinsried, Germany
Jochen Huehn
Experimental Immunology, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany
Axel Kallies
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
Thomas Korn
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; Corresponding author
Summary: 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. : An inflammatory environment threatens the stability of Foxp3+ Treg cells. Garg et al. show that by expressing the transcriptional regulator Blimp1, Treg cells resist the IL-6-driven loss of Foxp3 in inflamed tissues. Blimp1 prevents the methylation and reduced expression of Foxp3 through inhibition of the methyltransferase Dnmt3a. Keywords: regulatory T cells, Blimp1, CNS2, epigenetic regulation, CNS, inflammation, DNA methyltransferases, Foxp3, Interleukin-6
