Grant: Project Grant

Activated B cells make antibodies that protect against infection. Impaired B cell activation can cause immunodeficiency diseases with chronic infections. Conversely, in some autoimmune diseases, abnormal B cells make antibodies that attack one's own cells and tissues. Each B cell in the body has B cell receptor (BCR) proteins on its surface that determine what molecule (antigen) it responds to. Binding of antigen to the BCR triggers intracellular signals that cause B cell activation. Other cell types in the body can capture antigens and display them on their surface. These antigen-presenting cells (APCs) effectively activate B cells. Our work focuses on how the spatial organization of the BCR at the B cell-APC contact site impacts the magnitude of BCR signaling and whether a B cell becomes activated. When B cells contact an APC with a relevant antigen on its surface, the B cell forms an immune synapse (IS). At the IS, BCRs are organized into a spatial pattern that increase their signaling output. Antigen-bound BCRs initially form microclusters, which then coalesce into one large cluster. The movement and coalescence of BCR microclusters depend on the cell's actin cytoskeleton that lies just beneath the cell surface. The actin cytoskeleton is composed of actin protein units that can be rapidly disassembled and then reassembled in different ways. The movement of BCR microclusters towards the center of the B cell-APC contact site requires rapid actin remodeling. Using sophisticated microscopy, we have visualized actin reorganization at the IS and shown how this drives BCR microcluster movement, enhances BCR signaling, and promotes B cell activation. We now aim to identify specific proteins that control actin remodeling and determine how they regulate B cell activation. Because actin-regulatory proteins are mutated in multiple immunodeficiency and autoimmune diseases, elucidating their mechanisms of action may suggest new approaches for treating these diseases.