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Cell volume controlled by LRRC8A-formed volume-regulated anion channels fine-tunes T cell activation and function

Author

Listed:
  • Yuman Wang

    (Huazhong University of Science and Technology)

  • Zaiqiao Sun

    (Renmin Hospital of Wuhan University, Wuhan University)

  • Jieming Ping

    (Huazhong University of Science and Technology)

  • Jianlong Tang

    (Huazhong University of Science and Technology)

  • Boxiao He

    (Renmin Hospital of Wuhan University, Wuhan University)

  • Teding Chang

    (Huazhong University of Science and Technology)

  • Qian Zhou

    (Huazhong University of Science and Technology)

  • Shijie Yuan

    (Huazhong University of Science and Technology)

  • Zhaohui Tang

    (Huazhong University of Science and Technology)

  • Xin Li

    (Guangdong Academy of Medical Sciences)

  • Yan Lu

    (The Third Affiliated Hospital of Sun Yat-sen University)

  • Ran He

    (Huazhong University of Science and Technology)

  • Ximiao He

    (Huazhong University of Science and Technology)

  • Zheng Liu

    (Huazhong University of Science and Technology)

  • Lei Yin

    (Renmin Hospital of Wuhan University, Wuhan University)

  • Ning Wu

    (Huazhong University of Science and Technology
    Huazhong University of Science and Technology
    Huazhong University of Science and Technology
    The First Affiliated Hospital of Anhui Medical University, Institute of Clinical Immunology, Anhui Medical University)

Abstract

Biosynthesis drives the cell volume increase during T cell activation. However, the contribution of cell volume regulation in TCR signaling during T lymphoblast formation and its underlying mechanisms remain unclear. Here we show that cell volume regulation is required for optimal T cell activation. Inhibition of VRACs (volume-regulated anion channels) and deletion of leucine-rich repeat-containing protein 8A (LRRC8A) channel components impair T cell activation and function, particularly under weak TCR stimulation. Additionally, LRRC8A has distinct influences on mRNA transcriptional profiles, indicating the prominent effects of cell volume regulation for T cell functions. Moreover, cell volume regulation via LRRC8A controls T cell-mediated antiviral immunity and shapes the TCR repertoire in the thymus. Mechanistically, LRRC8A governs stringent cell volume increase via regulated volume decrease (RVD) during T cell blast formation to keep the TCR signaling molecules at an adequate density. Together, our results show a further layer of T cell activation regulation that LRRC8A functions as a cell volume controlling “valve” to facilitate T cell activation.

Suggested Citation

  • Yuman Wang & Zaiqiao Sun & Jieming Ping & Jianlong Tang & Boxiao He & Teding Chang & Qian Zhou & Shijie Yuan & Zhaohui Tang & Xin Li & Yan Lu & Ran He & Ximiao He & Zheng Liu & Lei Yin & Ning Wu, 2023. "Cell volume controlled by LRRC8A-formed volume-regulated anion channels fine-tunes T cell activation and function," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42817-y
    DOI: 10.1038/s41467-023-42817-y
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    References listed on IDEAS

    as
    1. Dawid Deneka & Marta Sawicka & Andy K. M. Lam & Cristina Paulino & Raimund Dutzler, 2018. "Structure of a volume-regulated anion channel of the LRRC8 family," Nature, Nature, vol. 558(7709), pages 254-259, June.
    2. Chen Kang & Litao Xie & Susheel K. Gunasekar & Anil Mishra & Yanhui Zhang & Saachi Pai & Yiwen Gao & Ashutosh Kumar & Andrew W. Norris & Samuel B. Stephens & Rajan Sah, 2018. "SWELL1 is a glucose sensor regulating β-cell excitability and systemic glycaemia," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    3. Hung-Ji Tsai & Anjali R. Nelliat & Mohammad Ikbal Choudhury & Andrei Kucharavy & William D. Bradford & Malcolm E. Cook & Jisoo Kim & Devin B. Mair & Sean X. Sun & Michael C. Schatz & Rong Li, 2019. "Hypo-osmotic-like stress underlies general cellular defects of aneuploidy," Nature, Nature, vol. 570(7759), pages 117-121, June.
    4. John R. James & Ronald D. Vale, 2012. "Biophysical mechanism of T-cell receptor triggering in a reconstituted system," Nature, Nature, vol. 487(7405), pages 64-69, July.
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