The transcription factor Zeb1 controls homeostasis and function of type 1 conventional dendritic cells

Yan Wang, Quan Zhang, Tingting He, Yechen Wang, Tianqi Lu, Zengge Wang, Yiyi Wang, Shen Lin, Kang Yang, Xinming Wang, Jun Xie, Ying Zhou, Yazhen Hong, Wen-Hsien Liu, Kairui Mao, Shih-Chin Cheng, Xin Chen, Qiyuan Li () and Nengming Xiao ()
Additional contact information
Yan Wang: Xiamen University
Quan Zhang: Xiamen University
Tingting He: Xiamen University
Yechen Wang: Xiamen University
Tianqi Lu: Xiamen University
Zengge Wang: Xiamen University
Yiyi Wang: Xiamen University
Shen Lin: Xiamen University
Kang Yang: Xiamen University
Xinming Wang: Xiamen University
Jun Xie: Xiamen University
Ying Zhou: Xiamen University
Yazhen Hong: Xiamen University
Wen-Hsien Liu: Xiamen University
Kairui Mao: Xiamen University
Shih-Chin Cheng: Xiamen University
Xin Chen: Xiamen University
Qiyuan Li: Xiamen University
Nengming Xiao: Xiamen University

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-42428-7

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