Activation of the Small GTPase Rac2 via the B Cell Receptor Regulates B Cell Adhesion and Immunological-Synapse Formation

Abstract

The integrin leukocyte function-associated antigen-1 (LFA-1) is important in the promotion of B cell adhesion, thereby facilitating immunological synapse (IS) formation and B cell activation. Despite this significance, the associated signaling mechanisms regulating LFA-1 activation remain elusive. Here, we show that both isoforms of the small GTPase Rac expressed by primary B cells, Rac1 and Rac2, were activated rapidly downstream of Src-family kinases, guanine-nucleotide exchange factors Vav1 and Vav2, and phosphoinositide-3 kinase (PI3K) after BCR engagement. We identify Rac2, but not Rac1, as critical for B cell adhesion to intercellular adhesion molecule-1 (ICAM-1) and IS formation. Furthermore, B cells expressing constitutively active Rac2 are highly adhesive. We observe that Rac2-deficient B cells exhibit lower amounts of Rap1-GTP and severe actin polymerization defects, identifying a potential mechanism underlying their behavior. We postulate that this critical role for Rac2 in mediating B cell adhesion and IS formation might apply in all lymphocytes.

B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

“…These results from T cells studies and the results of B cell studies presented in this study show that for lymphocyte cells, the mechanosensing abilities may not solely function through conventional ICAM-1 and LFA-1 interactions, where LFA-1 serves as a well-established mechanosensor. However, note that the potential contribution of ICAM-1 and LFA-1 interactions to maintaining and regulating the mechanosensing ability of lymphocyte cells cannot be neglected, as there are many early studies showing that ICAM-1 and LFA-1 interactions can fine-tune the adhesion and activation of both B and T lymphocyte cells (54)(55)(56)(57)(58)(59)(60). From this point of view, it will be very interesting to investigate the exact role of ICAM-1 and LFA-1 interactions in regulating the mechanosensing ability of B cells.…”

Rac-mediated Stimulation of Phospholipase Cγ2 Amplifies B Cell Receptor-induced Calcium Signaling

“…Syk (44), Btk (45), and BLNK (46,47), are known to physically interact with and activate the Rac activator Vav. BCR cross-linking caused activation of both Rac1 and Rac2 within minutes (48). Rac cooperated with PLC␥ 2 in BCR-mediated activation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, SRF, and NFAT (49,50).…”

Transfusion of IgG-Opsonized Foreign Red Blood Cells Mediates Reduction of Antigen-Specific B Cell Priming in a Murine Model

“…Common to both responses is BCR-induced signaling. However, in the case of particulate Ags, BCR-induced signaling is followed by B cell spreading onto the particulate Ag surface (37)(38)(39)(40)(41). BCR-mediated Ag internalization is thought to promote Ag processing and assembly of MHC-peptide complexes (38,39).…”

“…Ag processing and presentation to T cells should then occur. In the case of soluble Ags, accessory cells, such as dendritic cells (44,45) or macrophages (46), can array Ags on their cell surface, facilitating B cell priming; this may not be necessary with particulate Ags (40,41).…”