Transcription factor Etv3 controls the tolerogenic function of dendritic cells (H3K4me3 CUT&RUN of Etv3 KO GM-DCs)

Dendritic cells (DC) facilitate the maintenance of immunological tolerance in the steady state. We report that transcription factor Etv3 is preferentially expressed in mature DC including tissue-derived migratory DC (migDC), and facilitates their homeostatic maturation and CCR7-dependent migration. Mice with global or DC-specific deletion of Etv3 manifested the expansion of CD25low regulatory T cells (Treg), spontaneous activation of conventional T cells, and multiorgan T cell infiltration. Etv3 deficiency exacerbated TLR7-driven systemic lupus erythematosus (SLE)-like disease, supporting the reported genetic association of human ETV3 with SLE. Etv3-deficient migDC upregulated multiple costimulatory molecules including OX40 ligand (OX40L/TNFSF4), whose blockade partially rescued the Treg abnormalities. These results identify Etv3 as an essential regulator of the tolerogenic function of DC, and implicate it in the regulation of human autoimmunity. Overall design: CUT&RUN for H3K4me3 was performed on DC enriched from GM-BMDC cultures derived from control (WT) and Etv3-deficient (KO) mice (2 replicates per genotype).

树突状细胞（dendritic cells, DC）在生理稳态下参与维持免疫耐受。本研究报道，转录因子Etv3在成熟DC中优先表达，包括组织来源的迁移性DC（migratory DC, migDC），并可促进其稳态成熟及依赖CCR7的迁移过程。全局敲除或DC特异性敲除Etv3的小鼠，会呈现出CD25low调节性T细胞（regulatory T cells, Treg）扩增、常规T细胞自发活化以及多器官T细胞浸润的表型。Etv3缺陷会加重TLR7驱动的系统性红斑狼疮（systemic lupus erythematosus, SLE）样疾病，这也支持了人类ETV3与SLE的已报道遗传关联。Etv3缺陷的迁移性DC会上调包括OX40配体（OX40 ligand, OX40L/TNFSF4）在内的多种共刺激分子，阻断该分子可部分挽救Treg异常表型。上述结果表明Etv3是DC耐受性功能的关键调控因子，并提示其在人类自身免疫病调控中发挥作用。整体实验设计：对来自对照（野生型，WT）和Etv3缺陷型（KO）小鼠的GM-BMDC培养物中富集的DC，进行H3K4me3的CUT&RUN检测，每个基因型设置2个生物学重复。