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Transitional B cells commit to marginal zone B cell fate by Taok3-mediated surface expression of ADAM10

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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Figure 1: Taok3/ mice lack MZB cells and have reduced humoral responses to T-independent antigens.
Figure 2: The MZB cell defect in Taok3/ mice is B cell–intrinsic and subject to Taok3 gene dosage.
Figure 3: Taok3/ transitional B cells are defective in Notch activation.
Figure 4: Taok3 controls the surface expression of ADAM10.
Figure 5: ADAM10 expression on transitional B cells marks commitment to the MZB cell fate.

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References

  1. Martin, F., Oliver, A.M. & Kearney, J.F. Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 14, 617–629 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Tanigaki, K. et al. Notch-RBP-J signaling is involved in cell fate determination of marginal zone B cells. Nat. Immunol. 3, 443–450 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Kuroda, K. et al. Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway. Immunity 18, 301–312 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Tan, J.B. et al. Lunatic and manic fringe cooperatively enhance marginal zone B cell precursor competition for delta-like 1 in splenic endothelial niches. Immunity 30, 254–263 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Fasnacht, N. et al. Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses. J. Exp. Med. 211, 2265–2279 (2014).

    PubMed  PubMed Central  Google Scholar 

  6. Saito, T. et al. Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity 18, 675–685 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Witt, C.M., Won, W.J., Hurez, V. & Klug, C.A. Notch2 haploinsufficiency results in diminished B1 B cells and a severe reduction in marginal zone B cells. J. Immunol. 171, 2783–2788 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Moran, S.T. et al. Synergism between NF-κB1/p50 and Notch2 during the development of marginal zone B lymphocytes. J. Immunol. 179, 195–200 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Wu, L., Maillard, I., Nakamura, M., Pear, W.S. & Griffin, J.D. The transcriptional coactivator Maml1 is required for Notch2-mediated marginal zone B-cell development. Blood 110, 3618–3623 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gibb, D.R. et al. ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo. J. Exp. Med. 207, 623–635 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hampel, F. et al. CD19-independent instruction of murine marginal zone B-cell development by constitutive Notch2 signaling. Blood 118, 6321–6331 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Simonetti, G. et al. IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression and activity. J. Exp. Med. 210, 2887–2902 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hozumi, K. et al. Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo. Nat. Immunol. 5, 638–644 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Martin, F. & Kearney, J.F. Positive selection from newly formed to marginal zone B cells depends on the rate of clonal production, CD19, and btk. Immunity 12, 39–49 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Wen, L. et al. Evidence of marginal-zone B cell-positive selection in spleen. Immunity 23, 297–308 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Carey, J.B., Moffatt-Blue, C.S., Watson, L.C., Gavin, A.L. & Feeney, A.J. Repertoire-based selection into the marginal zone compartment during B cell development. J. Exp. Med. 205, 2043–2052 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cariappa, A. et al. The follicular versus marginal zone B lymphocyte cell fate decision is regulated by Aiolos, Btk, and CD21. Immunity 14, 603–615 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Pillai, S. & Cariappa, A. The follicular versus marginal zone B lymphocyte cell fate decision. Nat. Rev. Immunol. 9, 767–777 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Boyce, K.J. & Andrianopoulos, A. Ste20-related kinases: effectors of signaling and morphogenesis in fungi. Trends Microbiol. 19, 400–410 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Chuang, H.C., Wang, X. & Tan, T.H. MAP4K Family Kinases in Immunity and Inflammation. Adv. Immunol. 129, 277–314 (2016).

    Article  CAS  PubMed  Google Scholar 

  21. Guinamard, R., Okigaki, M., Schlessinger, J. & Ravetch, J.V. Absence of marginal zone B cells in Pyk-2-deficient mice defines their role in the humoral response. Nat. Immunol. 1, 31–36 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Balázs, M., Martin, F., Zhou, T. & Kearney, J. Blood dendritic cells interact with splenic marginal zone B cells to initiate T-independent immune responses. Immunity 17, 341–352 (2002).

    Article  PubMed  Google Scholar 

  23. Kin, N.W., Crawford, D.M., Liu, J., Behrens, T.W. & Kearney, J.F. DNA microarray gene expression profile of marginal zone versus follicular B cells and idiotype positive marginal zone B cells before and after immunization with Streptococcus pneumoniae. J. Immunol. 180, 6663–6674 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Arnon, T.I., Horton, R.M., Grigorova, I.L. & Cyster, J.G. Visualization of splenic marginal zone B-cell shuttling and follicular B-cell egress. Nature 493, 684–688 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Cinamon, G. et al. Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nat. Immunol. 5, 713–720 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Lu, T.T. & Cyster, J.G. Integrin-mediated long-term B cell retention in the splenic marginal zone. Science 297, 409–412 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Hobeika, E. et al. Testing gene function early in the B cell lineage in mb1-cre mice. Proc. Natl. Acad. Sci. USA 103, 13789–13794 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Descatoire, M. et al. Identification of a human splenic marginal zone B cell precursor with NOTCH2-dependent differentiation properties. J. Exp. Med. 211, 987–1000 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Roundy, K.M., Jacobson, A.C., Weis, J.J. & Weis, J.H. The in vitro derivation of phenotypically mature and diverse B cells from immature spleen and bone marrow precursors. Eur. J. Immunol. 40, 1139–1149 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Weskamp, G. et al. ADAM10 is a principal 'sheddase' of the low-affinity immunoglobulin E receptor CD23. Nat. Immunol. 7, 1293–1298 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. De Strooper, B., Vassar, R. & Golde, T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat. Rev. Neurol. 6, 99–107 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gupta, N. et al. Quantitative proteomic analysis of B cell lipid rafts reveals that ezrin regulates antigen receptor-mediated lipid raft dynamics. Nat. Immunol. 7, 625–633 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Karlsson, M.C. et al. Macrophages control the retention and trafficking of B lymphocytes in the splenic marginal zone. J. Exp. Med. 198, 333–340 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Moriyama, Y. et al. Delta-like 1 is essential for the maintenance of marginal zone B cells in normal mice but not in autoimmune mice. Int. Immunol. 20, 763–773 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Chen, X., Martin, F., Forbush, K.A., Perlmutter, R.M. & Kearney, J.F. Evidence for selection of a population of multi-reactive B cells into the splenic marginal zone. Int. Immunol. 9, 27–41 (1997).

    Article  PubMed  Google Scholar 

  36. Pillai, S., Cariappa, A. & Moran, S.T. Marginal zone B cells. Annu. Rev. Immunol. 23, 161–196 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Casola, S. et al. B cell receptor signal strength determines B cell fate. Nat. Immunol. 5, 317–327 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Deng, W., Cho, S., Su, P.C., Berger, B.W. & Li, R. Membrane-enabled dimerization of the intrinsically disordered cytoplasmic domain of ADAM10. Proc. Natl. Acad. Sci. USA 111, 15987–15992 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Xu, P., Liu, J., Sakaki-Yumoto, M. & Derynck, R. TACE activation by MAPK-mediated regulation of cell surface dimerization and TIMP3 association. Sci. Signal. 5, ra34 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Kapfhamer, D. et al. JNK pathway activation is controlled by Tao/TAOK3 to modulate ethanol sensitivity. PLoS One 7, e50594 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Srivastava, B., Quinn, W.J. III., Hazard, K., Erikson, J. & Allman, D. Characterization of marginal zone B cell precursors. J. Exp. Med. 202, 1225–1234 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dammers, P.M., de Boer, N.K., Deenen, G.J., Nieuwenhuis, P. & Kroese, F.G. The origin of marginal zone B cells in the rat. Eur. J. Immunol. 29, 1522–1531 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Tortola, L. et al. IL-21 induces death of marginal zone B cells during chronic inflammation. Blood 116, 5200–5207 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Tolia, A., Chávez-Gutiérrez, L. & De Strooper, B. Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the gamma-secretase complex. J. Biol. Chem. 281, 27633–27642 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Kuhn, P.H. et al. ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J. 29, 3020–3032 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Holmes, R. & Zuniga-Pflucker, J.C. The OP9–DL1 system: generation of T-lymphocytes from embryonic or hematopoietic stem cells in vitro. Cold Spring Harb. Protoc. 2009, pdb.prot5156 (2009).

Download references

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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Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Bart N Lambrecht.

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The authors declare no competing financial interests.

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.

Supplementary Figure 6 Immunoblot analysis showing expression of pro-ADAM10 and mature ADAM10 in lysates of CD93+ TB cells purified from the spleens of Taok3+/+ and Taok3−/– mice.

Supplementary Figure 7 Flow cytometry showing expression of CD1d and CD21/35 by ADAM10+ and ADAM10 T1B cells.

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Supplementary Figures 1–7 (PDF 671 kb)

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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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