State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
National Institute for Data Science in Health and Medicine, Xiamen University, Fujian, 361102, China.
Nat Commun. 2023 Oct 20;14(1):6639. doi: 10.1038/s41467-023-42428-7.
Type 1 conventional dendritic cells (cDC1) are the most efficient cross-presenting cells that induce protective cytotoxic T cell response. However, the regulation of their homeostasis and function is incompletely understood. Here we observe a selective reduction of splenic cDC1 accompanied by excessive cell death in mice with Zeb1 deficiency in dendritic cells, rendering the mice more resistant to Listeria infection. Additionally, cDC1 from other sources of Zeb1-deficient mice display impaired cross-presentation of exogenous antigens, compromising antitumor CD8 T cell responses. Mechanistically, Zeb1 represses the expression of microRNA-96/182 that target Cybb mRNA of NADPH oxidase Nox2, and consequently facilitates reactive-oxygen-species-dependent rupture of phagosomal membrane to allow antigen export to the cytosol. Cybb re-expression in Zeb1-deficient cDC1 fully restores the defective cross-presentation while microRNA-96/182 overexpression in Zeb1-sufficient cDC1 inhibits cross-presentation. Therefore, our results identify a Zeb1-microRNA-96/182-Cybb pathway that controls cross-presentation in cDC1 and uncover an essential role of Zeb1 in cDC1 homeostasis.
1 型传统树突状细胞（cDC1）是诱导保护性细胞毒性 T 细胞反应的最有效交叉呈递细胞。然而，其稳态和功能的调节机制尚不完全清楚。本研究观察到在树突细胞中 Zeb1 缺陷的小鼠中，脾脏 cDC1 选择性减少伴随过度细胞死亡，使小鼠对李斯特菌感染更具抵抗力。此外，来自其他来源的 Zeb1 缺陷小鼠的 cDC1 显示对外源抗原的交叉呈递受损，从而损害抗肿瘤 CD8 T 细胞反应。在机制上，Zeb1 抑制 microRNA-96/182 的表达，其靶向 NADPH 氧化酶 Nox2 的 Cybb mRNA，从而促进活性氧依赖性吞噬体膜破裂，允许抗原输出到细胞质。在 Zeb1 缺陷型 cDC1 中重新表达 Cybb 可完全恢复缺陷型的交叉呈递，而在 Zeb1 充足的 cDC1 中 microRNA-96/182 的过表达则抑制交叉呈递。因此，我们的研究结果确定了一个 Zeb1-miRNA-96/182-Cybb 通路，该通路控制 cDC1 中的交叉呈递，并揭示了 Zeb1 在 cDC1 稳态中的重要作用。
