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. We demonstrate that WNK1, a kinase implicated in osmoregulation in the kidney, is required in T cells to support T-dependent antibody responses. WNK1-deficient CD4+ T cells are severely impaired in their ability to proliferate and to generate antigen-specific T follicular helper cells in response to immunization with a T-dependent antigen. We show that WNK1 and its downstream OXSR1 and STK39 kinases are required for TCR signaling in CD4+ T cells and for entry into cell cycle. Additionally, by preventing ATR activation, this pathway is required for T cells to progress from G2 into M phase of the cell cycle. Unexpectedly, we show that this WNK1 pathway regulates water influx, most likely through AQP3, which 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. Given the broad expression of WNK1, WNK1-dependent water influx may be a common feature of mitogenic pathways in many cell types, both within the immune system and beyond. One Sentence SummaryT cell antigen receptor signaling via the WNK1 kinase causes water entry which is essential for CD4+ T cell proliferation.