The B cell antigen receptor (BCR)

The B cell antigen receptor (BCR) is a multiprotein complex expressed on the surface of B cells transmitting critical signals for B cell development, proliferation, and activation. Using mass spectrometry, the laboratory of Prof. Schamel identified novel interaction partners of resting and stimulated BCR, such as Kidins220. The expertise of my group in animal models and in vivo study of the immune system motivated us to collaborate and study the role of Kidins220 in animal models. We performed fetal liver transfer experiments and generated a conditional B cell–specific Kidins220 knockout (B-KO) mouse strain. We clearly showed that Kidins220 couples the BCR to several signaling pathways, such as PLCg2, Ca²⁺, and extracellular signal-regulated kinase (Erk). Consequently, BCR-mediated B cell activation in vitro and T-independent immune responses in vivo were reduced upon Kidins220 deletion. Furthermore, B cell development was impaired at stages where pre-BCR or BCR signaling is required. Importantly, BCR signaling regulates the generation of a naïve antibody repertoire in which autoreactive specificities have been removed during B cell development. Indeed, decreased BCR signaling impairs the counterselection of B cells expressing autoreactive BCRs by failing to induce tolerance mechanisms at immature B cell stages in mice and humans. In those immature B cells, only IgM-BCRs are expressed on their cell surface, whereas mature B cells co-express both IgM- and IgD-BCRs. It has recently recognized, that these receptors form oligomeric structures on the surface of resting B cells (also named nanoclusters). Recent reports suggest that BCR nanoclustering is important for shaping BCR signaling. Based on the expertise of my group in plasma membrane nano-organization and signaling transmission, we are now investigating if the absence of this protein influences BCR nanoclustering and functioning.