Abstract
B-cell receptor (BCR)-mediated antigen internalization and presentation are essential for humoral memory immune responses. Antigen encountered by B-cells is often tightly associated with the surface of pathogens and/or antigen-presenting cells. Internalization of such antigens requires myosin-mediated traction forces and extracellular release of lysosomal enzymes, but the mechanism triggering lysosomal exocytosis is unknown. Here, we show that BCR-mediated recognition of antigen tethered to beads, to planar lipid-bilayers or expressed on cell surfaces causes localized plasma membrane (PM) permeabilization, a process that requires BCR signaling and non-muscle myosin II activity. B-cell permeabilization triggers PM repair responses involving lysosomal exocytosis, and B-cells permeabilized by surface-associated antigen internalize more antigen than cells that remain intact. Higher affinity antigens cause more B-cell permeabilization and lysosomal exocytosis and are more efficiently presented to T-cells. Thus, PM permeabilization by surface-associated antigen triggers a lysosome-mediated B-cell resealing response, providing the extracellular hydrolases that facilitate antigen internalization and presentation.
Highlights
B-cells are responsible for generating antibody responses that neutralize pathogens and attract other immune cells
Our results indicate that B-cell plasma membrane (PM) permeabilization by binding to surface-associated antigen is a reversible event, and that lysosomal exocytosis is required for PM resealing as previously shown for other cell types (Andrews et al 2014). 269 B-cell permeabilization and lysosomal exocytosis facilitate internalization and presentation of surface-associated antigen We investigated the relationship between PM permeabilization by surface-associated antigen and antigen internalization using fluorescent M covalently bound to beads or tethered to PLB
We show that interaction of the B-cell receptor (BCR) with surface-associated antigen can permeabilize the B-cell PM, triggering lysosomal exocytosis as part of the PM repair response (Rodríguez et al 1997; Reddy et al 2001)
Summary
B-cells are responsible for generating antibody responses that neutralize pathogens and attract other immune cells. Mechanical forces, generated by non-muscle myosin II (NMII) activation at sites of antigen-BCR interaction, can directly pull antigen from presenting surfaces for endocytosis. In this study we found that interaction of the BCR with surface-associated antigen can permeabilize the mouse primary B-cell PM, triggering a resealing mechanism that involves exocytosis of lysosomes. We investigated this process by determining if antigen induced PM permeabilization depends on the BCR-antigen binding affinity, BCR signaling and 85 NMII motor activity, and if it influences the ability of B-cells to internalize and present surface associated antigens to T-cells. We investigated this process by determining if antigen induced PM permeabilization depends on the BCR-antigen binding affinity, BCR signaling and 85 NMII motor activity, and if it influences the ability of B-cells to internalize and present surface associated antigens to T-cells. 87
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