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).

Author information

Author notes

    • Hamida Hammad
    • , Matthias Vanderkerken
    •  & Philippe Pouliot

    These authors contributed equally to this work.

Affiliations

  1. VIB Inflammation Research Center, Ghent University, Ghent, Belgium.

    • Hamida Hammad
    • , Matthias Vanderkerken
    • , Philippe Pouliot
    • , Kim Deswarte
    • , Wendy Toussaint
    • , Karl Vergote
    • , Lana Vandersarren
    • , Sophie Janssens
    • , Ioanna Ramou
    • , Savvas N Savvides
    • , Jody J Haigh
    •  & Bart N Lambrecht
  2. Department of Respiratory Medicine, Ghent University, Ghent, Belgium.

    • Hamida Hammad
    • , Matthias Vanderkerken
    • , Philippe Pouliot
    • , Kim Deswarte
    • , Wendy Toussaint
    • , Karl Vergote
    • , Lana Vandersarren
    • , Sophie Janssens
    •  & Bart N Lambrecht
  3. The Laboratory for Protein Biochemistry and Biomolecular Engineering (L-Probe), Ghent University, Ghent, Belgium.

    • Ioanna Ramou
    •  & Savvas N Savvides
  4. Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

    • Rudi Hendriks
    •  & Bart N Lambrecht
  5. Institute for Molecular Health Sciences, ETH, Zürich, Switzerland.

    • Manfred Kopf
  6. VIB Center for Brain and Disease, VIB, Leuven, Belgium.

    • Katleen Craessaerts
    •  & Bart de Strooper
  7. Center for Human Genetics, KULeuven, Leuven, Belgium.

    • Katleen Craessaerts
    •  & Bart de Strooper
  8. Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • John F Kearney
  9. Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, Virginia, USA.

    • Daniel H Conrad

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Bart N Lambrecht.

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DOI

https://doi.org/10.1038/ni.3657

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