Prof. Dr. Jürgen Konrad Wienands

Georg-August-Universität Göttingen
Universitätsmedizin Göttingen
Institut für Zelluläre & Molekulare Immunologie
Humboldtallee 34
37073 Göttingen

Tel. +49 (0) 551 39 5812    
jwienan@gwdg.de

Dr. Niklas Engels

Georg-August-Universität Göttingen
Universitätsmedizin Göttingen
Institut für Zelluläre & Molekulare Immunologie
Humboldtallee 34
37073 Göttingen    

Tel. +49 (0) 551 39 13858    
nengels@gwdg.de

Project summary:

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. 

Fig. 1 Schematic illustration of the different project parts. The individual project parts support and complement each other by sharing technological advancements like quantitative (phospho-) proteomics and nuclease-mediated gene disruption (TALEN).
Publications P 08:

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.

Kuhn, J., Wong, L.E., Pirkuliyeva, S., Schulz, K., Schwiegk, C., Funfgeld, K.G., Keppler, S., Batista, F.D., Urlaub, H., Habeck, M., Becker S, Griesinger, C.* and Wienands J*. (2016). The adaptor protein CIN85 assembles intracellular signaling clusters for B cell activation. Sci Signal 9, ra66.

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.

Engels, N.*, Konig, L.M., Schulze, W., Radtke, D., Vanshylla, K., Lutz, J., Winkler, T.H., Nitschke, L., and Wienands, J. (2014). The immunoglobulin tail tyrosine motif upgrades memory-type BCRs by incorporating a Grb2-Btk signalling module. Nat Commun 5, 5456. 

Engelke, M., Pirkuliyeva, S., Kuhn, J., Wong, L., Boyken, J., Herrmann, N., Becker, S., Griesinger, C., and Wienands, J. (2014). Macromolecular assembly of the adaptor SLP-65 at intracellular vesicles in resting B cells. Sci Signal 7, ra79.