Institute of Molecular Tumor Biology, University of Münster, Münster, Germany.
MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
J Immunol. 2022 Jan 15;208(2):358-370. doi: 10.4049/jimmunol.2100624. Epub 2021 Dec 13.
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.
树突状细胞（DCs）是参与自身免疫性疾病的异质性免疫调节剂。调节 DC 发育和 DC 亚群多样化的表观基因组机制尚未得到充分理解，但对于出于临床目的调节 DC 命运可能很重要。通过结合全基因组甲基化评估和表达降低 DNA 甲基转移酶 1 水平的小鼠分析，我们表明，不同的 DNA 甲基化水平和模式对于浆细胞样 DC 和常规 DC 亚群的发育是必需的。我们提供了在干细胞水平上建立 DC 谱系的克隆体内证据，并表明高 DNA 甲基化阈值水平对于 Flt3 依赖性 DC 前体的存活至关重要。重要的是，降低甲基化主要消耗浆细胞样 DC 并减轻自身免疫性小鼠模型中的系统性红斑狼疮。这项研究展示了 DNA 甲基化如何调节 DC 亚群的产生，并为使用低甲基化剂靶向自身免疫性疾病提供了潜在的理论依据。
