Regulation of integrin activation through the B-cell receptor

Abstract

Journal of Cell Science 2280 activation (Lanzavecchia, 1985;Rock et al., 1984). Subsequently activated B cells can develop into plasma cells that are competent for large-scale production of soluble antibodies, or memory cells that provide long-lasting immunological memory.In this Commentary we highlight recent investigations of the mechanism underlying inside-out integrin activation in response to antigen stimulation through the BCR. Intriguingly, we observe a number of important differences in the mechanism that underlies inside-out activation according to the particular integrin activated and the cellular context of integrin expression. We discuss recent evidence that identifies key signalling molecules that govern the activity and distribution of LFA-1 and VLA-4 following engagement of the BCR. Finally, we propose a mechanism whereby these regulatory molecules mediate the cytoskeleton rearrangements that are required for the integrin activation and subsequent IS formation that occur during the antigen-recognition process. Antigen-induced BCR signallingThe BCR can be described as a receptor tyrosine kinase, and its stimulation by a specific antigen results in the proliferation and differentiation of B cells. The BCR comprises a membrane immunoglobulin (Ig) in complex with the heterodimeric Igα-Igβ sheath (Fig. 1B), which allows its stable expression in the membrane (Reth, 1989;Venkitaraman et al., 1991). The constituents of the BCR act in concert to couple the recognition of extracellular antigens with the initiation of intracellular signalling through the immunoreceptor tyrosine-based activation motifs (ITAMs) of the Igα-Igβ sheath (Hombach et al., 1990;Reth, 1989). These activated ITAMs subsequently act as recruitment sites for the assembly of a complex array of intracellular adaptors and signalling molecules in a structure known as the signalosome (DeFranco, 2001;Fruman et al., 2000). The precise composition of a signalosome is dictated by the nature and context of the antigenic stimulant, and determines the outcome of signalling through the BCR (Depoil et al., 2008;Weber et al., 2008). In the specific case of inside-out activation of integrins it would be expected that this outcome involves the direct targeting of the cytoplasmic domains of the integrin itself, in addition to the extensive reorganisation of the cytoskeleton that is necessary for the recognition of antigens that are presented on a spatially constrained surface.The mechanism of inside-out activation of integrins has been investigated extensively in T cells (reviewed in Kinashi, 2005). The Journal of Cell Science 121 (14) Fig. 1. Molecular mechanisms required for the activation of integrin-mediated B-cell adhesion in response to membrane-bound antigens. (A) Prior to antigen stimulation, the 'resting' B cell contains BCRs and inactive integrins that are distributed throughout the membrane. Following BCR engagement with antigen on the surface of an antigen-presenting cell (APC) that expresses integrin ligands, crosslinking of BCRs initiates int...

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.…”

Integrins in immunity

“…Clustered antigen in the cSMAC can then be presented to T cells. There are similarities as well as differences as to how B cells make use of LFA-1 and integrin α4β1 in the process of antigen gathering and associated signalling (reviewed by Arana et al, 2008).…”

Bam32/DAPP1 Promotes B Cell Adhesion and Formation of Polarized Conjugates with T Cells

“…In the case of membrane-bound Ag, elegant studies have identified signaling via Vav-Rac as critical for BCR-mediated Ag gathering via a cell spreading and contraction response (14,15). The signaling requirements for Ag capture from cell surfaces likely reflect integration between BCR and integrins through inside-out signaling mechanisms that facilitate adhesion of B cells to the Ag-bearing surface (16). In addition to facilitating Ag internalization, BCR-induced kinase cascades may be involved in intracellular targeting of BCR-Ag complexes to mature MHC-II loading compartments (17).…”