Journal Article

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

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

2025

Overview

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. T cell antigen receptor stimulation by the ligand antigen triggers multiple downstream pathways that affect CD4 + T cell function. Here authors show that activation of the downstream WNK1 kinase causes water entry into the cells, which is essential for CD4 + T cell proliferation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/31 / 13/95 / 631/250/1619/554/1898 / 631/250/516 / 631/45/269 / 631/80/641 / 64/60 / Animals / Antibodies / Antibody Formation - immunology / Antigens / Aquaporin 3 / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / CD4-Positive T-Lymphocytes - metabolism / Cell activation / Cell cycle / Cell differentiation / Cell growth / Cell Proliferation / Humanities and Social Sciences / Kinases / Lymphocyte Activation - immunology / Lymphocytes / Lymphocytes T / Mice / Mice, Inbred C57BL / Mice, Knockout / multidisciplinary / Osmoregulation / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Receptors / Receptors, Antigen, T-Cell - immunology / Receptors, Antigen, T-Cell - metabolism / Science / Science (multidisciplinary) / Signal Transduction / T cell receptors / Water - metabolism / WNK Lysine-Deficient Protein Kinase 1 - genetics / WNK Lysine-Deficient Protein Kinase 1 - immunology / WNK Lysine-Deficient Protein Kinase 1 - metabolism