We have identified that WNK1 kinase is required for both T cell activation and migration. In kidney epithelial cells, in response to hyperosmolarity, WNK1 phosphorylates and activates the OXSR1 and STK39 kinases. These phosphorylate the SLC12A-family of ion transporters, resulting in influx of Na+, K+ and Cl- ions, and subsequent water entry by osmosis.

Unexpectedly, we show that TCR stimulation in CD4+ T cells leads to WNK1 activation and subsequent WNK1 signalling results in water influx through Aquaporin 3 (AQP3). This water influx is required for early TCR signalling in and for entry into cell cycle.

Furthermore, we show that CCR7 chemokine receptor signalling leads to activation of WNK1 at the leading edge of migrating CD4+ T cells, resulting in ion influx and consequent water entry by osmosis through AQP3. This water entry swells the membrane at the leading edge, generating space into which actin filaments can polymerize, thereby facilitating forward movement of the cell. Thus, WNK1-regulated ion and water influx play critical roles in T cell activation and migration. This requirement may extend to many other immune and non-immune cell types.