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

Yuman WangDepartment of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaZaiqiao SunState Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, ChinaJieming PingDepartment of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaJianlong TangDepartment of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaBoxiao HeState Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, ChinaTeding ChangHuazhong University of Science and TechnologyQian ZhouDepartment of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaShijie YuanDepartment of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaZhaohui TangDepartment of Traumatic Surgery, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaXin LiMedical Research Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaYan LüDepartment of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaRan HeDepartment of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaXimiao HeDepartment of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaZheng LiuDepartment of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected]Lei YinState Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China. [email protected]Ning WuCell Architecture Research Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected]

2023en

ABI

Annotatsiya

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.

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DOI: 10.1038/s41467-023-42817-y

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