Distinct and overlapping functions of TEC kinase and BTK in B cell receptor signaling
The Tec tyrosine kinase is expressed in many cell types, including hematopoietic cells, and is a member of the Tec kinase family that also includes Btk. Although the role of Btk in B cells has been extensively studied, the role of Tec kinase in B cells remains largely unclear. It was previously shown that Tec kinase has the ability to partly compensate for loss of Btk activity in B cell differentiation, although the underlying mechanism is unknown. In this study, we confirm that Tec kinase is not essential for normal B cell development when Btk is present, but we also found that Tec-deficient mature B cells showed increased activation, proliferation, and survival upon BCR stimulation, even in the presence of Btk. Whereas Tec deficiency did not affect phosphorylation of phospholipase Cg or Ca2+ influx, it was associated with significantly increased activation of the intracellular Akt/S6 kinase signaling pathway upon BCR and CD40 stimulation. The increased S6 kinase phosphorylation in Tec-deficient B cells was dependent on Btk kinase activity, as ibrutinib treatment restored pS6 to wild-type levels, although Btk protein and phosphorylation levels were comparable to controls. In Tec-deficient mice in vivo, B cell responses to model Ags and humoral immunity upon influenza infection were enhanced. Moreover, aged mice lacking Tec kinase developed a mild autoimmune phenotype. Taken together, these data indicate that in mature B cells, Tec and Btk may compete for activation of the Akt signaling pathway, whereby the activating capacity of Btk is limited by the presence of Tec kinase.
|Persistent URL||dx.doi.org/10.4049/jimmunol.1601285, hdl.handle.net/1765/99123|
|Journal||Journal of Immunology|
|Note||This work was supported in part by Dutch Arthritis Foundation (Reumafonds) Grants 09-1-302 and 13-2-301 and by Dutch Cancer Society Grant 2014-6564.|
de Bruijn, M.J.W, Rip, J, van der Ploeg, E.K, van Greuningen, L.W, Ta, V.T.B, Kil, L-P, … Corneth, O.B.J. (2017). Distinct and overlapping functions of TEC kinase and BTK in B cell receptor signaling. Journal of Immunology, 198(8), 3058–3068. doi:10.4049/jimmunol.1601285