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DNMT1 deficiency impacts on plasmacytoid dendritic cells in homeostasis and autoimmune disease

Dendritic cells (DCs) are heterogeneous immune regulators involved in autoimmune diseases. Epigenomic mechanisms orchestrating DC development and DC subset diversification remain insufficiently understood but could be important to modulate DC fate for clinical purposes. By combining whole-genome met...

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Main Authors: Czéh, Melinda (Author) , Stäble, Sina (Author) , Krämer, Stephen (Author) , Tepe, Lena (Author) , Talyan, Sweta (Author) , Carrelha, Joana (Author) , Meng, Yiran (Author) , Heitplatz, Barbara (Author) , Schwabenland, Marius (Author) , Milsom, Michael (Author) , Plass, Christoph (Author) , Prinz, Marco (Author) , Schlesner, Matthias (Author) , Andrade-Navarro, Miguel A. (Author) , Nerlov, Claus (Author) , Jacobsen, Sten Eirik W. (Author) , Lipka, Daniel (Author) , Rosenbauer, Frank (Author)
Format: Article (Journal)
Language:English
Published: January 11, 2022
In: The journal of immunology
Year: 2022, Volume: 208, Issue: 2, Pages: 358-370
ISSN:1550-6606
DOI:10.4049/jimmunol.2100624
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.4049/jimmunol.2100624
Verlag, lizenzpflichtig, Volltext: https://www.jimmunol.org/content/208/2/358
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Author Notes:Melinda Czeh, Sina Stäble, Stephen Krämer, Lena Tepe, Sweta Talyan, Joana Carrelha, Yiran Meng, Barbara Heitplatz, Marius Schwabenland, Michael D. Milsom, Christoph Plass, Marco Prinz, Matthias Schlesner, Miguel A. Andrade-Navarro, Claus Nerlov, Sten Eirik W. Jacobsen, Daniel B. Lipka and Frank Rosenbauer

MARC

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520 |a Dendritic cells (DCs) are heterogeneous immune regulators involved in autoimmune diseases. Epigenomic mechanisms orchestrating DC development and DC subset diversification remain insufficiently understood but could be important to modulate DC fate for clinical purposes. By combining whole-genome methylation assessment with the analysis of mice expressing reduced DNA methyltransferase 1 levels, we show that distinct DNA methylation levels and patterns are required for the development of plasmacytoid DC and conventional DC subsets. We provide clonal in vivo evidence for DC lineage establishment at the stem cell level, and we show that a high DNA methylation threshold level is essential for Flt3-dependent survival of DC precursors. Importantly, reducing methylation predominantly depletes plasmacytoid DC and alleviates systemic lupus erythematosus in an autoimmunity mouse model. This study shows how DNA methylation regulates the production of DC subsets and provides a potential rationale for targeting autoimmune disease using hypomethylating agents. 
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