Actin-mediated feedback loops in B-cell receptor signaling

Abstract

Upon recognizing cognate antigen, B cells mobilize multiple cellular apparatuses to propagate an optimal response. Antigen binding is transduced into cytoplasmic signaling events through B-cell antigen receptor (BCR)-based signalosomes at the B-cell surface. BCR signalosomes are dynamic and transient and are subsequently endocytosed for antigen processing. The function of BCR signalosomes is one of the determining factors for the fate of B cells: clonal expansion, anergy, or apoptosis. Accumulating evidence underscores the importance of the actin cytoskeleton in B-cell activation. We have begun to appreciate the role of actin dynamics in regulating BCR-mediated tonic signaling and the formation of BCR signalosomes. Our recent studies reveal an additional function of the actin cytoskeleton in the downregulation of BCR signaling, consequently contributing to the generation and maintenance of B-cell self-tolerance. In this review, we discuss how actin remodels its organization and dynamics in close coordination with BCR signaling and how actin remodeling in turn amplifies the activation and subsequent downregulation process of BCR signaling, providing vital feedback for optimal BCR activation.

Keywords: B cells; B-cell antigen receptor; actin cytoskeleton; endocytosis; signal transduction.

Fig. 1. Coordination of actin remodeling with dynamic reorganization of BCRs at the B-cell surface

(A) Upon antigen binding to the BCR, the cortical actin network undergoes rapid and transient depolymerization and detachment from the plasma membrane. This releases BCRs and BCR nano-clusters from mobility barriers and enables them to interact with each other. (B) Following actin disassembly, actin is reassembled at the activation surface. De novo actin polymerization is activated at BCR clusters and the membrane at the outer edge of the contact surface. (C) Actin reassembly enables B cells to spread and expand the contact area with antigen presenting surface. The extension of filopodia and lamellipodia enables the cell to gather more antigen for BCRs to bind, and their contraction brings BCR-antigen inwards to form larger microclusters. BCRs in microclusters are signaling active. (D) Actin-mediated B-cell contraction facilitates the merger of BCR microclusters into a central cluster. The BCR central cluster is surrounded by de novo actin polymerization sites and F-actin, and exhibits reduced signaling activity. Shown are images generated by Song’s laboratory using interference reflection microscopy (IRM) and total internal reflection fluorescence microscopy (TIRFM). Scale bar, 2.5 μm.