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

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  • Yan Wang

    (Xiamen University)

  • Quan Zhang

    (Xiamen University
    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
    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
    Xiamen University
    The First Affiliated Hospital of Xiamen University)

  • Nengming Xiao

    (Xiamen University)

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.

Suggested Citation

  • 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-Ch, 2023. "The transcription factor Zeb1 controls homeostasis and function of type 1 conventional dendritic cells," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42428-7
    DOI: 10.1038/s41467-023-42428-7
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    References listed on IDEAS

    as
    1. Luis J. Sigal & Shane Crotty & Raul Andino & Kenneth L. Rock, 1999. "Cytotoxic T-cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen," Nature, Nature, vol. 398(6722), pages 77-80, March.
    2. Tian-Tian Liu & Sunkyung Kim & Pritesh Desai & Do-Hyun Kim & Xiao Huang & Stephen T. Ferris & Renee Wu & Feiya Ou & Takeshi Egawa & Steven J. Van Dyken & Michael S. Diamond & Peter F. Johnson & Masato, 2022. "Ablation of cDC2 development by triple mutations within the Zeb2 enhancer," Nature, Nature, vol. 607(7917), pages 142-148, July.
    3. Luis J. Sigal & Shane Crotty & Raul Andino & Kenneth L. Rock, 1999. "Cytotoxic T-cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen," Nature, Nature, vol. 402(6763), pages 25-29, December.
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