Abstract
Notch2 and B cell antigen receptor (BCR) signaling determine whether transitional B cells become marginal zone B (MZB) or follicular B (FoB) cells in the spleen, but it is unknown how these pathways are related. We generated Taok3−/− mice, lacking the serine/threonine kinase Taok3, and found cell-intrinsic defects in the development of MZB but not FoB cells. Type 1 transitional (T1) B cells required Taok3 to rapidly respond to ligation by the Notch ligand Delta-like 1. BCR ligation by endogenous or exogenous ligands induced the surface expression of the metalloproteinase ADAM10 on T1 B cells in a Taok3-dependent manner. T1 B cells expressing surface ADAM10 were committed to becoming MZB cells in vivo, whereas T1 B cells lacking expression of ADAM10 were not. Thus, during positive selection in the spleen, BCR signaling causes immature T1 B cells to become receptive to Notch ligands via Taok3-mediated surface expression of ADAM10.
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Acknowledgements
H.H. is supported by Ghent University Grant (GOA 01G02817). M.V. is supported by a FWO Fellowship (grant 3F023515W). P.P was supported by Marie Curie grant (MC 237581). S.J. is supported by FWO grant G085915N and a University of Ghent grant (MRP-GROUP-ID). M.K. is supported by the Swiss National Science Foundation (SNF 310030-163443/1). J.F.K. was supported by NIAID AI14782 and AI100005. B.N.L. was supported by an ERC consolidator grant 261231, the University of Ghent Multidisciplinary Research Platform (MRP-GROUP-ID) and a Ghent University grant (GOA 01G02817).
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H.H. designed, performed and analyzed experiments and wrote the manuscript. M.V. performed and analyzed experiments and wrote the manuscript. P.P., K.D., W.T., K.V., L.V., S.J., I.R., S.N.S., R.H., and K.C. performed and analyzed experiments. J.J.H. constructed mice. M.K., B.d.S., J.F.K., and D.H.C. provided crucial tools and analyzed experiments. B.N.L. conceived the study, designed and analyzed experiments and wrote the manuscript.
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Integrated supplementary information
Supplementary Figure 1 Generation of Taok3−/– mice and level of Taok3 expression in mice.
(a) Genetrap construct and targeting strategy used to generate Taok3-/- mice. (b) The absence of Taok3 expression in thymus and kidney of mice was analyzed by qRT-PCR and (c) Western-blot. (d-e) Mendelian inheritance rates in Homozygous Taok3-/- and heterozygous Taok3+/-. (f) Cellularity of lymphoid organs in Taok3+/+ and Taok3-/- mice.
Supplementary Figure 2 Titers of different antibody isotypes following injection of TNP-Ficoll or TNP-KLH in Taok3+/+ and Taok3−/– mice.
Antibody responses were measured 7 days after injection for TNP-Ficoll and at day 42 for TNP-KLH. See Materials and Methods.
Supplementary Figure 3 Effect of Taok3 on noncanonical NF-κB signaling.
(a) Western blot showing NFκB2/p100 to p52 processing in lysates of CD93+ TB cells exposed for 16 hours to 2 μg/ml recombinant BAFF. Equal loading of the gel lanes was evaluated by the detection of actin. (b) Survival of CD93+ TB cells exposed or not to 2 μg/ml recombinant BAFF for 72 hours.
Supplementary Figure 4 Notch2 expression in spleen lysates of Taok3+/+ and Taok3−/– mice.
Western blot showing Notch2 expression in spleen lysates of Taok3+/+ and Taok3-/- mice. Equal loading of the gel lanes was evaluated by the detection of tubulin.
Supplementary Figure 5 Effect of Taok3 on amyloid precursor protein cleavage.
(Left panel) Expression of full length amyloid precursor protein (APP) and α-stub (what’s left behind after ADAM10 cleavage) in the membrane of Taok3+/+ and Taok3-/- MEFs. Left lanes are untransfected MEFs showing endogenous production of APP and generation of the α-stub in Taok3+/+ MEFs. Right lanes are MEFs transfected with full length APP. (right panel) MEFs showing less APP cleavage and less generation of the soluble sAPPα fragment in the supernatant of MEFs obtained from Taok3+/+ mice. Left lanes are sAPPα generation from untransfected MEFs, right lanes are sAPPα generation in the supernatant of MEFs transfected with full length APP.
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Hammad, H., Vanderkerken, M., Pouliot, P. et al. Transitional B cells commit to marginal zone B cell fate by Taok3-mediated surface expression of ADAM10. Nat Immunol 18, 313–320 (2017). https://doi.org/10.1038/ni.3657
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DOI: https://doi.org/10.1038/ni.3657
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