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

Signaling from the T cell antigen receptor (TCR) on CD4<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> T cell proliferation and hence T cell-dependent antibody responses.

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Publication Details

Journal
Nature Communications
Published
2025-02-21
DOI
https://doi.org/10.1038/s41467-025-56778-x
Citations
4
Primary Topic
MicroRNA in disease regulation
Type
article
Field-Weighted Citation Impact
3.75

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article

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

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4 citations
Nature Communications
MicroRNA in disease regulation
3.75
article

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

Miriam Llorian, Harald Hartweger, Darryl Hayward, Leonard L. de Boer, Robert Köchl, Victor L. J. Tybulewicz, Lesley Vanes, Joshua Biggs O’May, Simone Kunzelmann, David Lewis
article en
4 citations

Abstract

Signaling from the T cell antigen receptor (TCR) on CD4<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> T cell proliferation and hence T cell-dependent antibody responses.

Nature CommunicationsVol. 16(1)
King's College London (GB), Age UK (GB), Science for Life Laboratory (SE), The Francis Crick Institute (GB), Imperial College London (GB), Rockefeller University (US)
Wellcome, Wellcome Trust, Francis Crick Institute, UK Research and Innovation, Cancer Research UK, Imperial College London, Directorate for Biological Sciences, Medical Research Council, Biotechnology and Biological Sciences Research Council
Clean water and sanitation
Openalex Percentile: Top 8%
MicroRNA in disease regulation
3.75
DOIOpen Access PDFOpenAlex
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