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

  • Nat Commun. 2025 Feb 21;16(1):1857. doi: 10.1038/s41467-025-56778-x.
Joshua Biggs O'May  1 ,  Lesley Vanes  1 ,  Leonard L de Boer  1  2  3 ,  David A Lewis  1 ,  Harald Hartweger  1  4 ,  Simone Kunzelmann  1 ,  Darryl Hayward  1  5 ,  Miriam Llorian  1 ,  Robert Köchl  1  6 ,  Victor L J Tybulewicz  7
Affiliations
  • 1. The Francis Crick Institute, London, NW1 1AT, UK.
  • 2. Imperial College, London, W12 0NN, UK.
  • 3. Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institute, Box 1031, SE-171 21, Solna, Sweden.
  • 4. Laboratory of Molecular Immunology, The Rockefeller University, 10065, New York, NY, USA.
  • 5. GSK, Stevenage, SG1 2NY, UK.
  • 6. Kings College London, London, SE1 9RT, UK.
  • 7. The Francis Crick Institute, London, NW1 1AT, UK. [email protected].
PMID: 39984435 DOI: 10.1038/s41467-025-56778-x
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.

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