CD4+ T cell activation in absence of WNK1

Signaling from the T cell antigen receptor (TCR) on CD4+ T cells triggers the adaptive immune response by inducing T cell activation, proliferation, and differentiation. However, TCR signaling pathways are incompletely understood. Unexpectedly, we demonstrate that WNK1, a kinase previously implicated in osmoregulation in the kidney, is required for T-dependent antibody responses. We show that WNK1-OXSR1-STK39-dependent water influx through AQP3 is required for TCR signaling in CD4+ T cells and for entry into cell cycle. Additionally, by preventing ATR activation this signaling pathway is required for T cells to progress through the G2 phase of the cell cycle. 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. Overall design: Mouse CD4+ T cells of either of Wnk1+/- or Wnk1-/- genotype activated in vitro over a 24 hr timecourse