RT Journal Article
SR Electronic
T1 DNMT1 Deficiency Impacts on Plasmacytoid Dendritic Cells in Homeostasis and Autoimmune Disease
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP 358
OP 370
DO 10.4049/jimmunol.2100624
VO 208
IS 2
A1 Czeh, Melinda
A1 Stäble, Sina
A1 Krämer, Stephen
A1 Tepe, Lena
A1 Talyan, Sweta
A1 Carrelha, Joana
A1 Meng, Yiran
A1 Heitplatz, Barbara
A1 Schwabenland, Marius
A1 Milsom, Michael D.
A1 Plass, Christoph
A1 Prinz, Marco
A1 Schlesner, Matthias
A1 Andrade-Navarro, Miguel A.
A1 Nerlov, Claus
A1 Jacobsen, Sten Eirik W.
A1 Lipka, Daniel B.
A1 Rosenbauer, Frank
YR 2022
UL http://www.jimmunol.org/content/208/2/358.abstract
AB Myeloid-restricted hematopoietic stem cells can replenish pDC and cDC in vivo.DC diversification is associated with differences in genomic methylation levels.Reducing Dnmt1 activity alleviates systemic lupus erythematosus autoimmunity.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.This article is featured in Top Reads, p.