Prof. Dr. Jürgen Konrad Wienands
Institut für Zelluläre & Molekulare Immunologie
Dr. Niklas Engels
Institut für Zelluläre & Molekulare Immunologie
B cell antigen receptor activation signals for naïve and IgG-switched memory B cells
The B cell antigen receptor (BCR) can be expressed on naïve and antigen-experienced B cells in different classes that are determined by the isotype of membrane-bound immunoglobulins (mIg). It was assumed that all mIg isotypes signal via the canonical Igα/β heterodimer that activates the primary BCR transducer complex. The latter was thought to comprise the protein tyrosine kinase Syk and its substrate SLP65. Recently, our group showed that this signal microanatomy is incomplete as it lacks two essential building blocks. First, we identified the Cbl-interacting protein of 85 kDa (CIN85) as a missing link of the primary BCR transducer complex that, moreover, defines a novel marker for X-linked primary immune deficiencies in humans. How exactly CIN85 receives and processes BCR signals is unclear and will be addressed in this project proposal. Second, we demonstrated that BCR classes of antigen-experienced cells comprising mIgG or mIgE contain conserved signaling motifs, termed immunoglobulin tail tyrosine (ITT), that are absent in mIgM- or mIgD-BCRs on naïve B cells. Antigen-mediated phosphorylation of the ITT amplifies signals emanating from the canonical ITAM-containing BCR signaling subunits Igα and Igβ. Gene targeting showed that this BCR-intrinsic signaling boost is a critical determinant of memory B cell responses in the mouse. Elucidation of the ITT signaling network is a second goal of our research project. Both of our aims will be supported by novel proteomic approaches that we have developed and that allow for an unbiased and comprehensive elucidation of the B cell 'signalotome' under different stimulation conditions. The proteome analyses will be complemented by genetic studies including TALEN-mediated mutagenesis to delineate the signaling function of individual BCR effector proteins. The expected results will provide a mechanistic understanding of the signals that govern primary and secondary antibody responses and how these processes are dysregulated in a novel type of human antibody deficiency.
Schmitt, M.E.R., Lutz, J., Haase, P., Bösl, M.R., Wienands, J., Engels, N. and Voehringer, D. (2020). The
B-cell antigen receptor of IgE-switched plasma cells regulates memory IgE responses. J. Allergy Clin. Immunol. 146, 642-651.e5.
Wong, L.E., Bhatt, A., Erdmann, P.S., Hou, Z., Maier, J, Pirkuliyeva, S., Engelke, M., Becker, S., Plitzko, J.,* Wienands, J.,* and Griesinger. C.* (2020). Tripartite phase separation of two signal effectors with vesicles priming B cell responsiveness. Nat. Commun. 11, 848. *corresponding authors.
Gomes de Castro, M.A., Wildhagen, H., Sograte-Idrissi, S., Hitzing, C., Binder, M., Trepel, M., Engels, N. and Opazo, F. (2019). Differential organization of tonic and chronic B cell antigen receptors in the plasma membrane. Nat. Commun. 10, 820.
Setz, C.S., Khadour, A., Renna, V., Iype, J., Gentner, E., He, X., Datta, M., Young, M., Nitschke, L., Wienands, J., Maity, P.C., Reth, M. and Jumaa, H. (2019). PTEN controls B-cell responsiveness and germinal center reaction by regulating the expression of IgD BCR. EMBO J. 38, e100249.
Engels, N. and Wienands, J. (2018) Memory control by the B cell antigen receptor. Immunol. Rev. 283, 150-160.
Keller, B., Shoukier, M., Schulz, K., Bhatt, A., Heine, I., Strohmeier, V., Speckmann, C., Engels, N., Warnatz, K. and Wienands, J. (2018). Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency. J. Exp. Med. 215, 1327-1336.
Vanshylla, K., Bartsch, C., Hitzing, C., Krumpelmann, L., Wienands, J. and Engels, N. (2018). Grb2 and GRAP connect the B cell antigen receptor to Erk MAP kinase activation in human B cells. Sci. Rep. 8, 4244.
Vanshylla, K., Opazo, F., Gronke, K., Wienands, J. and Engels, N. (2018). The extracellular membrane-proximal domain of membrane-bound IgE restricts B cell activation by limiting B cell antigen receptor surface expression. Eur. J. Immunol. 48, 441-453.
Weis, V., Königsberger, S., Amler, S., Wienands, J. and Kiefer, F. (2017). Unperturbed immune function
despite mutation of C-terminal tyrosines in Syk previously implicated in signaling and activity regulation. Mol. Cell. Biol. 37, doi:10.1128/MCB.00216-17.
Kühn, J., Wong, L., Pirkuliyeva, S., Schulz, K. Schwiegk, C., Gencalp-Fünfgeld, K., Keppler, S., Batista, F.D., Urlaub, H., Habeck, M., Becker, S., Griesinger, C.* and Wienands, J.* (2016). CIN85 triggers formation of intracellular signaling clusters for B cell activation. Sci. Signal. 9, ra66. *corresponding authors.
Manno, B., Oellerich, T., Schnyder, T., Corso, J., Lösing, M., Neumann, K., Urlaub, H., Batista, F.D., Engelke, M.* and Wienands, J.* (2016). The Dok-3/Grb2 adaptor module promotes inducible association of the lipid phosphatase SHIP with the BCR in a co-receptor independent manner. Eur J Immunoldoi: 10.1002/eji.201646431.
Wienands, J., and Engels, N. (2016). Control of memory B cell responses by extrinsic and intrinsic mechanisms. Immunol Lett 178, 27-30.
Corso, J., Pan, K.T., Walter, R., Doebele, C., Mohr, S., Bohnenberger, H., Strobel, P., Lenz, C., Slabicki, M., Hullein, J., Comoglio, F., Rieger, M.A., Zenz, T., Wienands, J., Engelke, M., Serve, H., Urlaub, H., and Oellerich, T. (2016). Elucidation of tonic and activated B-cell receptor signaling in Burkitt's lymphoma provides insights into regulation of cell survival. Proc Natl Acad Sci U S A 113, 5688-5693.
Wienands, J., and Engels, N. (2016). The memory function of the B cell antigen receptor. Curr Top Microbiol Immunol 393, 107-121.
Lutz, J., Dittmann, K., Bosl, M.R., Winkler, T.H., Wienands, J.*, and Engels, N. (2015). Reactivation of IgG-switched memory B cells by BCR-intrinsic signal amplification promotes IgG antibody production. Nat Commun 6, 8575.