SFB 1054 Seminar - Michael Reth
Title: How B cells sense antigen and the nanoscale organisation of the B cell membrane
Humoral immunity is established by the antigen-driven selection of a small number of B lymphocytes with a cognate B cell antigen receptor (BCR). How the BCR is activated upon interaction with its cognate antigen is not fully understood. The cross linking model (CLM) of BCR activation suggested that it is the dimerization of randomly distributed BCR monomers that results in B cell activation. However, this theory fails to explain how monovalent antigens, that per se can never cross-link two BCR monomers, can activate B cell signaling. With the Dissociation Activation Model (DAM) we have proposed an alternative model of B cell activation. According to this model it is the opening of a pre-organized receptor oligomer that activates the B cell. The opening of the BCR oligomer involves relative movements of receptor monomers at a 10-20 nanometre (nm) range and thus these movements cannot be detected by classical light microscopy with a diffraction limit of 250 nm. We therefore have developed a Fab-based Proximity Ligation Assay (Fab-PLA) that can monitor alterations of the BCR conformation in a 10-20 nm range. With this technique we have now studied how the BCR react to the exposure to different monovalent antigens. Our results show that monovalent antigens are well able to open the oligomeric BCR thus providing further evidence in support of the DAM hypothesis. Interestingly, the sensing of monovalent antigens requires the presence and activity of the SRC family kinase Lyn. We also found that different classes of the BCR such as the IgM-BCR and IgD-BCR have distinct requirements for B cell activation. These findings are interesting in connection to our super-resolution studies showing that on resting B cells the IgM-BCR and IgD-BCR are localized inside separated membrane clusters or protein islands with a class-specific compositions. We currently are using several super-resolution methods to study the nanoscale environment of the IgM-BCR and IgD-BCR as well as that of other receptors in more detail. For example we found that CD19 and the chemokine receptor CXCR4 are colocalized in the IgD-specific membrane compartment and that these receptors are not only physically but also functionally connected.
Yang, J. and Reth, M. (2010). The dissociation activation model of B cell antigen receptor triggering. FEBS Letters 584(24): 4872-4877. Klasener K, Maity PC, Hobeika E, Yang J, Reth M. (2014). B cell activation involves nanoscale receptor reorganizations and inside-out signaling by Syk. Elife 3: e02069. Maity PC, Blount A, Jumaa H, Ronneberger O, Lillemeier BF, Reth M. (2015). B cell antigen receptors of the IgM and IgD classes are clustered in different protein islands that are altered during B cell activation. Sci Signal 15(8) (394):ra93. Becker, M., Hobeika, E., Jumaa, H., Reth, M. and Maity, P. C. (2017). "CXCR4 signaling and function require the expression of the IgD-class B-cell antigen receptor." PNAS U S A. This study was supported by the Excellence Initiative of the German Federal and State Governments (EXC 294), by the Deutsche Forschungsgemeinschaft through SFB746 and TRR130 and by an ERC Advanced Grant on nano-Islands.
Host: Thomas Brocker (B03)