Molecular Mechanisms of B Cell Antigen Gathering and Endocytosis

Abstract

Generation of high-affinity, protective antibodies requires B cell receptor (BCR) signaling, as well as antigen internalization and presentation to helper T cells. B cell antigen internalization is initiated by antigen capture, either from solution or from immune synapses formed on the surface of antigen-presenting cells, and proceeds via clathrin-dependent endocytosis and intracellular routing to late endosomes. Although the components of this pathway are still being discovered, it has become clear that antigen internalization is actively regulated by BCR signaling at multiple steps and, vice versa, that localization of the BCR along the endocytic pathway modulates signaling. Accordingly, defects in BCR internalization or trafficking contribute to enhanced B cell activation in models of autoimmune diseases and in B cell lymphomas. In this review, we discuss how BCR signaling complexes regulate each of the steps of this endocytic process and why defects along this pathway manifest as hyperactive B cell responses in vivo.

Cytoskeletal control of B cell responses to antigens

“…4a, c) Once the antigen is extracted, it is endocytosed by a mechanism that requires clathrin coated pits (CCPs) 80 . This is similar to the endocytosis of soluble antigen, which also requires CCPs 124 . The endocytosis of antigen depends on SRC-family kinases 125 , BTK 126 , activation of the ARP2/3 complex through WAS, WASL, and WIPF1 7,35,60 and linkage of CCPs to actin by DBNL 127 .…”

“…However, the endocytic mechanism may not be identical to that involving canonical CCPs as it requires RAC1 and RAC2, but not the typical regulator of actin polymerization in CCPs, CDC42 50 . Endocytosis and BCR trafficking to degradative compartments lead to eventual termination of BCR signalling 124 . Thus, a reduction in BCR internalization caused by defects in actin polymerization is likely to contribute to B cell hyperactivity.…”

A Systems Approach Reveals MAVS Signaling in Myeloid Cells as Critical for Resistance to Ebola Virus in Murine Models of Infection

“…These mice were crossed with mice expressing either the CD19-Cre or LysM-Cre transgene, specifically expressed in B cells and monocytes/macrophages, respectively, to selectively delete MAVS expression in these cell types (termed CD19Cre+MAVS fl/fl and LysMCre+MAVS fl/fl ). Deletion of MAVS from B cells was used to control for any generalized effects on antigen presentation (Hoogeboom and Tolar, 2016). The status of MAVS was determined by intracellular staining for MAVS and flow cytometry (Figure 6C and 6D).…”

Functional Differences between IgM and IgD Signaling in Chronic Lymphocytic Leukemia

“…2F, S1D) after IgD stimulation. HS1 activation and cytoskeletal remodeling are important early events after antigen engagement by the BCR (21, 38, 39), which favor early signalosome assembly and occur prior to antigen internalization and signal transduction (40). Our data suggest that IgDs are primarily involved in these early stages of BCR pathway activation in CLL.…”