Key Points
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.
Abstract
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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Footnotes
This work was supported by a fellowship from Cancer Research UK (A24872) and an institutional grant from the University of Münster medical faculty (IMF, CZ121523) to M.C., by an international recruitment grant from The Swedish Research Council (538-2013-8995) and The Medical Research Council (MC_UU_12009/5) to S.E.W.J., by a Cancer Transitional Research and Exchange Program Ph.D.-to-Postdoctoral Fellowship to S.S., by institutional funds and grants from the Deutsche Krebshilfe (DKH 70112574) to D.B.L., by the Deutsche Forschungsgemeinschaft (DFG) research unit FOR 2674 to M.D.M., C.P., and D.B.L., and by DFG grants (RO 2295/5-1 and RO 2295/5-2) and institutional funds to F.R.
M.C., S.S., J.C., Y.M., and L.T. performed experiments, S.K., S.T., M. Schlesner, and M.A.A.-N. conducted computational data analyses, B.H., M. Schwabenland, and M.P. performed histological analyses, M.D.M., C.P., C.N., S.E.W.J., D.B.L., and F.R. designed the research and analyzed data. M.C., D.B.L., and F.R. wrote the manuscript.
The online version of this article contains supplemental material.
Abbreviations used in this article
- BM
- bone marrow
- cDC
- conventional DC
- CDP
- common DC progenitor
- cMoP
- common monocyte progenitor
- DC
- dendritic cell
- DMR
- differentially methylated region
- DNMT
- DNA methyltransferase
- HSC
- hematopoietic stem cell
- LSK
- CD45.2+Lin−Sca-1+Kit+
- MDP
- macrophage–DC progenitor
- MHCII
- MHC class II
- P
- platelet
- PAS
- periodic acid–Schiff reaction
- PCA
- principal component analysis
- pDC
- plasmacytoid DC
- PEM
- P–erythrocyte–myeloid
- PEM-B
- PEM–B lymphoid
- SLE
- systemic lupus erythematosus
- TWGBS
- tagmentation-based whole-genome bisulfite sequencing
- Received June 25, 2021.
- Accepted October 28, 2021.
- Copyright © 2022 by The American Association of Immunologists, Inc.
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