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IL-21R-STAT3 signalling initiates a differentiation program in uterine tissue-resident NK cells to support pregnancy

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  • Mengwei Han

    (Peking University Health Science Center)

  • Luni Hu

    (Peking University Health Science Center)

  • Di Wu

    (Peking University Health Science Center)

  • Yime Zhang

    (Peking University Health Science Center)

  • Peng Li

    (Peking University Health Science Center)

  • Xingyu Zhao

    (Peking University Health Science Center)

  • Yanyu Zeng

    (Peking University Health Science Center)

  • Guanqun Ren

    (Peking University Health Science Center)

  • Zhiyuan Hou

    (Peking University Health Science Center)

  • Yanli Pang

    (Peking University Third Hospital)

  • Tongbiao Zhao

    (Chinese Academy of Sciences)

  • Chao Zhong

    (Peking University Health Science Center
    Peking University
    Chinese Academy of Medical Sciences)

Abstract

Tissue-resident Natural Killer (trNK) cells are crucial components of local immunity that activate rapidly upon infection. However, under steady state conditions, their responses are tightly controlled to prevent unwanted tissue damage. The mechanisms governing their differentiation and activation are not fully understood. Here, we characterise uterine trNK cells longitudinally during pregnancy by single cell RNA sequencing and find that the combined expression pattern of 4-1BB and CD55 defines their three distinct stages of differentiation in mice. Mechanistically, an IL-21R-STAT3 axis is essential for initiating the trNK cell differentiation. The fully differentiated trNK cells demonstrate enhanced functionality, which is necessary for remodelling spiral arteries in the decidua. We identify an apoptotic program that is specific to the terminal differentiation stage, which may preclude tissue damage by these highly activated trNK cells. In summary, uterine trNK cells become intensely active and effective during pregnancy, but tightly controlled via a differentiation program that also limits potential harm, suggesting an intricate mechanism for harnessing trNK cells in maintaining pregnancy.

Suggested Citation

  • Mengwei Han & Luni Hu & Di Wu & Yime Zhang & Peng Li & Xingyu Zhao & Yanyu Zeng & Guanqun Ren & Zhiyuan Hou & Yanli Pang & Tongbiao Zhao & Chao Zhong, 2023. "IL-21R-STAT3 signalling initiates a differentiation program in uterine tissue-resident NK cells to support pregnancy," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42990-0
    DOI: 10.1038/s41467-023-42990-0
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    1. Issaka Yougbaré & Wei-She Tai & Darko Zdravic & Brigitta Elaine Oswald & Sean Lang & Guangheng Zhu & Howard Leong-Poi & Dawei Qu & Lisa Yu & Caroline Dunk & Jianhong Zhang & John G. Sled & Stephen J. , 2017. "Activated NK cells cause placental dysfunction and miscarriages in fetal alloimmune thrombocytopenia," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    2. Jens Kieckbusch & Louise M. Gaynor & Ashley Moffett & Francesco Colucci, 2014. "MHC-dependent inhibition of uterine NK cells impedes fetal growth and decidual vascular remodelling," Nature Communications, Nature, vol. 5(1), pages 1-13, May.
    3. Roser Vento-Tormo & Mirjana Efremova & Rachel A. Botting & Margherita Y. Turco & Miquel Vento-Tormo & Kerstin B. Meyer & Jong-Eun Park & Emily Stephenson & Krzysztof Polański & Angela Goncalves & Lucy, 2018. "Single-cell reconstruction of the early maternal–fetal interface in humans," Nature, Nature, vol. 563(7731), pages 347-353, November.
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