Integrin Clustering at the Immune Synapse Vinculin Arrests Motile B Cells by Stabilizing

Lymphocytes use integrin-based platforms to move and adhere firmly to the surface of other cells. The molecular mechanisms governing lymphocyte adhesion dynamics are however poorly understood. In this study, we show that in mouse B lymphocytes, the actin binding protein vinculin localizes to the ring-shaped integrin-rich domain of the immune synapse (IS); the assembly of this platform, triggered by cognate immune interactions, is needed for chemokine-mediated B cell motility arrest and leads to firm, long-lasting B cell adhesion to the APC. Vinculin is recruited early in IS formation, in parallel to a local phosphatidylinositol (4,5)-bisphosphate wave, and requires spleen tyrosine kinase activity. Lack of vinculin at the IS impairs firm adhesion, promoting, in turn, cell migration with Ag clustered at the uropod. Vinculin localization to the B cell contact area depends on actomyosin. These results identify vinculin as a major controller of integrin-mediated adhesion dynamics in B cells. T he regulated interplay between cell adhesion and cell motility is critical for B lymphocyte function. B cells must explore entire follicles in secondary lymphoid organs, where Ags are collected and presented by various APCs (1). To do this, B cells migrate continuously by random walking in response to the chemokine CXCL13 (2–4). This chemokine is produced mainly at the network of follicular dendritic cells; they expose it on their surface in the context of integrin ligands, which might assist in B cell motility (4, 5). Specific BCR recognition of Ag above a signaling threshold leads B cells to adhere firmly to the APC; a large LFA-1 integrin cluster is assembled, and the IS is formed (6, 7). The synapse platform has an important role in several aspects of the B cell activation process (6, 8, 9). The control of integrin activation , clustering, and localization thus underlies the precise modulation of B cell behavior. Chemokine receptor and BCR signaling activate LFA-1 by modulating integrin affinity (conformational change) and avidity (spatial distribution and clustering) for its ligand ICAM-1 (10, 11). IS formation also drives LFA-1/ICAM-1 segregation into a peripheral ring (peripheral supramolecular activation cluster [pSMAC]) that surrounds the central BCR/Ag cluster (central SMAC [cSMAC]) at the site of B cell–APC contact (6). IS assembly involves actin cytoskeleton remodeling and the formation of an F-actin—rich ring at the pSMAC, where LFA-1 anchors through the scaffold protein talin (12, 13). The strength of cognate interactions through the BCR determines synapse formation or the establishment …