Editors' ChoiceImmunology

WNK1 inhibits T cell adhesion

Sci. Signal.  30 Aug 2016:
Vol. 9, Issue 443, pp. ec197
DOI: 10.1126/scisignal.aai8874

As they search for antigens, T cells move through the circulatory system and enter lymph nodes through high endothelial venules (HEVs). Chemokine receptors, such as CCR7, stimulate inside-out activation of integrins, such as LFA-1, which leads to adhesion of the T cells to HEVs and their extravasation across the endothelium. Once inside the lymph node, T cells migrate in response to additional chemokine-dependent stimulation to search for and interact with antigen-presenting cells (APCs). The T cells then leave the lymph node through lymphatic vessels to return to the circulation. Köchl et al. performed an RNA interference–based screen with human Jurkat T cells to identify kinases that regulated the LFA-1–dependent adhesion of the T cells to antigen-loaded B cells (the APCs). Knockdown of WNK1, which encodes the serine and threonine kinase WNK1, resulted in a prolonged interaction between the T cells and the APCs. Compared with wild-type mouse CD4+ T cells, WNK1-deficient CD4+ T cells stimulated through CCR7 or the T cell receptor (TCR) showed enhanced binding to plates coated with the LFA-1 ligand ICAM1, as well as more efficient antigen-dependent interactions with APCs. Loss of WNK1 had no effect on the ability of chemokine signaling to mediate activation of LFA-1; however, WNK1-deficient T cells showed increased activation of the GTPase Rap1, which promotes integrin-mediated adhesion. In culture, WNK1-deficient CD4+ T cells migrated more slowly to chemokine than did their wild-type counterparts. Transfer experiments in mice showed that WNK1-deficient T cells exhibited defective trafficking to lymph nodes and the spleen, which was associated with defective transmigration across endothelial cells. The best-characterized pathway of WNK1 signaling is through activation of the kinases OXSR1 and STK39, which then phosphorylate and activate cation cotransporters, such as the sodium, potassium, and chloride cotransporters SLC12A2 and SLC12A1. In primary mouse CD4+ T cells, stimulation of either TCR or CCR7 stimulated the WNK1 kinase–dependent phosphorylation of OXSR1 and STK39; however, activation of OSXR1 required the kinases PI3K and AKT, suggesting that they were also required for WNK1 activation by TCR or CCR7 signaling. Knockdown of SLC12A2 or inactivation of OSXR1 had no effect on the TCR- or CCR7-dependent adhesion of T cells to ICAM1; however, chemokine-induced migration in vitro was impaired. Chemical inhibition of SLC12A2 also resulted in reduced T cell migration in vitro. Together, these data suggest that the kinase WNK1, best characterized for its role in controlling salt reabsorption in the kidney, limits integrin-mediated adhesion of T cells and promotes their migration.

R. Köchl, F. Thelen, L. Vanes, T. F. Brazão, K. Fountain, J. Xie, C.-L. Huang, R. Lyck, J. V. Stein, V. L. J. Tybulewicz, WNK1 kinase balances T cell adhesion versus migration in vivo. Nat. Immunol. 17, 1075–1083 (2016). [PubMed]