Actin assembly and disassembly factors regulate BCR organization and signaling

The immune synapse is a contact-dependent cellular communication platform that is important for activating, amplifying and executing immune responses. A B cell immune synapse is formed when B cells encounter antigens (Ags) on the surface of an Ag-presenting cell (APC). The binding of the B cell receptor (BCR) to these Ags triggers dynamic, multi-scale reorganization of the BCR and associated signal transduction machinery. Initially, BCRs are gathered into microclusters that are dispersed throughout the B cell-APC contact site. Microclusters are then moved centripetally and coalesce into the central supramolecular activation cluster (cSMAC) of an immune synapse. Although the formation of BCR-Ag microclusters recruits key signaling enzymes and increases BCR signaling efficiency, the mechanisms controlling BCR organization during immune synapse formation are not fully understood. Importantly, how the spatial patterning of the BCR promotes the translation of extracellular information (recognition of membrane-associated Ags) into functional outcomes (B cell activation) is not clear. I showed that the coalescence of BCR microclusters is dependent on the actin-related protein 2/3 (Arp2/3) complex, which nucleates branched actin networks. Moreover, I showed that this dynamic spatial reorganization of BCR microclusters is critical for amplifying proximal BCR signaling reactions and enhancing the ability of membrane-associated Ags to induce transcriptional responses and proliferation. My finding that Arp2/3 complex activity is important for B cell responses to spatially restricted membrane-bound Ag, but not for soluble Ags, highlights a critical role for Arp2/3 complex-dependent actin remodeling in B cell responses to APC-bound Ags. I also demonstrated that the disassembly of actin networks mediated by the actin severing protein, cofilin, and its regulators is important for cytoskeletal remodeling during immune synapse formation. In addition, I showed that actin dynamics mediated by cofilin activity is important for amplifying BCR signaling in response to membrane- bound Ags. Thus, by controlling the dynamic spatial reorganization of BCR-Ag microclusters, the actin cytoskeleton amplifies APC-induced BCR signaling and B cell activation responses. Supplementary material available at: http://hdl.handle.net/2429/77283.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat