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

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 () and Ning Wu ()
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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

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

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42817-y

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