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WNK1-dependent water influx is required for CD4+ T cell activation and T cell-dependent antibody responses

Author

Listed:
  • Joshua Biggs O’May

    (The Francis Crick Institute)

  • Lesley Vanes

    (The Francis Crick Institute)

  • Leonard L. Boer

    (The Francis Crick Institute
    Imperial College
    Box 1031)

  • David A. Lewis

    (The Francis Crick Institute)

  • Harald Hartweger

    (The Francis Crick Institute
    The Rockefeller University)

  • Simone Kunzelmann

    (The Francis Crick Institute)

  • Darryl Hayward

    (The Francis Crick Institute
    GSK)

  • Miriam Llorian

    (The Francis Crick Institute)

  • Robert Köchl

    (The Francis Crick Institute
    Kings College London)

  • Victor L. J. Tybulewicz

    (The Francis Crick Institute)

Abstract

Signaling from the T cell antigen receptor (TCR) on CD4+ T cells plays a critical role in adaptive immune responses by inducing T cell activation, proliferation, and differentiation. Here we demonstrate that WNK1, a kinase implicated in osmoregulation in the kidney, is required in T cells to support T-dependent antibody responses. We show that the canonical WNK1-OXSR1-STK39 kinase signaling pathway is required for TCR signaling in CD4+ T cells, their subsequent entry into the cell cycle, and suppression of the ATR-mediated G2/M cell cycle checkpoint. We show that the WNK1 pathway regulates ion influx leading to water influx, potentially through AQP3, and that water influx is required for TCR-induced signaling and cell cycle entry. Thus, TCR signaling via WNK1, OXSR1, STK39 and AQP3 leads to water entry that is essential for CD4+ T cell proliferation and hence T cell-dependent antibody responses.

Suggested Citation

  • Joshua Biggs O’May & Lesley Vanes & Leonard L. Boer & David A. Lewis & Harald Hartweger & Simone Kunzelmann & Darryl Hayward & Miriam Llorian & Robert Köchl & Victor L. J. Tybulewicz, 2025. "WNK1-dependent water influx is required for CD4+ T cell activation and T cell-dependent antibody responses," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56778-x
    DOI: 10.1038/s41467-025-56778-x
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    References listed on IDEAS

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    1. William C. Skarnes & Barry Rosen & Anthony P. West & Manousos Koutsourakis & Wendy Bushell & Vivek Iyer & Alejandro O. Mujica & Mark Thomas & Jennifer Harrow & Tony Cox & David Jackson & Jessica Sever, 2011. "A conditional knockout resource for the genome-wide study of mouse gene function," Nature, Nature, vol. 474(7351), pages 337-342, June.
    2. Leonard L. Boer & Lesley Vanes & Serena Melgrati & Joshua Biggs O’May & Darryl Hayward & Paul C. Driscoll & Jason Day & Alexander Griffiths & Renata Magueta & Alexander Morrell & James I. MacRae & Rob, 2023. "T cell migration requires ion and water influx to regulate actin polymerization," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
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