Transcription factor Etv3 controls the tolerogenic function of dendritic cells (CITE-seq of Etv3 KO LN and thymus cDCs)

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: scRNA-seq with "hashtagging" according to the CITE-seq protocol was performed on cDCs from the skin-draining lymph nodes (sdLNs) and thymus of control and ETV3-deficient mice.

树突状细胞（Dendritic cell, DC）在机体稳态下可介导免疫耐受的维持。本研究发现，转录因子Etv3在成熟树突状细胞（包括组织来源的迁移性树突状细胞（migratory DC, migDC））中优先表达，并可促进这些细胞的稳态成熟以及依赖CCR7的迁移。全局或树突状细胞特异性敲除Etv3的小鼠，表现出CD25低表达调节性T细胞（regulatory T cell, Treg）扩增、常规T细胞自发性活化以及多器官T细胞浸润的表型。Etv3缺陷会加重Toll样受体7（Toll-like receptor 7, TLR7）介导的系统性红斑狼疮（systemic lupus erythematosus, SLE）样疾病，这支持了已报道的人类ETV3基因与SLE的遗传关联。Etv3缺陷的迁移性树突状细胞会上调包括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调节性T细胞的异常表型。本研究结果证实Etv3是树突状细胞耐受性功能的关键调控因子，并提示其参与人类自身免疫性疾病的调控。实验整体设计：本研究依据CITE-seq（细胞转录组与表位联合测序）实验流程，采用hashtag标记技术，对对照组与ETV3缺陷小鼠的皮肤引流淋巴结（skin-draining lymph node, sdLNs）及胸腺中的经典树突状细胞（classical dendritic cell, cDCs）进行了单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）。