Abstract：
Dendritic cell (DC) progenitors adapt their transcriptional program during development, generating different subsets. How chromatin modifications modulate these processes is unclear. Here, we investigate the impact of histone deacetylation on DCs by genetically deleting histone deacetylase 1 (HDAC1) or HDAC2 in hematopoietic progenitors and CD11c-expressing cells. While HDAC2 is not critical for DC development, HDAC1 deletion impairs pro-pDC and mature pDC generation and affects ESAM+cDC2 differentiation from tDCs and pre-cDC2s, whereas cDC1s are unchanged. HDAC1 knockdown in human hematopoietic cells also impairs cDC2 development, highlighting its crucial role across species. Multi-omics analyses reveal that HDAC1 controls expression, chromatin accessibility, and histone acetylation of the transcription factors IRF4, IRF8, and SPIB required for efficient development of cDC2 subsets. Without HDAC1, DCs switch immunologically, enhancing tumor surveillance through increased cDC1 maturation and interleukin-12 production, driving T helper 1-mediated immunity and CD8+ T cell recruitment. Our study reveals the importance of histone acetylation in DC development and anti-tumor immunity, suggesting DC-targeted therapeutic strategies for immuno-oncology.
摘要：
树突状细胞（DC）祖细胞在发育过程中适应其转录程序，生成不同的子集。染色质修饰如何调节这些过程尚不清楚。这里,我们通过基因删除造血祖细胞和CD11c表达细胞中的组蛋白去乙酰化酶1（HDAC1）或HDAC2，研究组蛋白去乙酰化对DCs的影响。虽然HDAC2对DC开发并不重要，HDAC1缺失会损害pro-pDC和成熟pDC的生成，并影响ESAM+cDC2与tDC和pre-cDC2的分化，而cDC1s不变。人类造血细胞中的HDAC1敲低也会损害cDC2的发育，强调它在物种中的关键作用。多组学分析显示HDAC1控制表达，染色质可及性，和cDC2亚群有效发育所需的转录因子IRF4，IRF8和SPIB的组蛋白乙酰化。没有HDAC1，DCs会在免疫上转换，通过增加cDC1成熟和白细胞介素12的产生来加强肿瘤监测，驱动T辅助1介导的免疫和CD8+T细胞募集。我们的研究揭示了组蛋白乙酰化在DC发育和抗肿瘤免疫中的重要性，提示免疫肿瘤学的DC靶向治疗策略。
