Grant: Operating Grant

B-lymphocytes protect us from infection by making antibody proteins that eliminate pathogens. To differentiate into an antibody-producing cell, a B cell must first become activated. This involves binding of the B cell receptor (BCR) on the surface of the B cell to parts of the pathogen (antigens) that are captured by other cells and displayed on their surface. When a B cell contacts an antigen-presenting cell (APC) bearing the antigen it recognizes, it changes its shape and spreads across the surface of the APC so that its BCRs can detect additional antigens. This is followed by contraction of the B cell and formation of BCR clusters that initiate intracellular signaling pathways that lead to B cell activation. These changes in cell shape and BCR clustering require reorganization of the B cell's cytoskeleton, the structural elements that control cell shape as well as the ability of proteins such as the BCR to move within the cell membrane. We have elucidated a pathway by which antigen binding by the BCR causes cytoskeletal changes. The key step is activation of cofilin, a protein that severs actin filaments, a major structural element of the cytoskeleton. This allows BCRs to move more freely and form clusters, and promotes the formation of new cytoskeletal structures that cause the cell to spread. We have recently shown that B cells that have been exposed to danger signals that are indicative of microbial infection exhibit enhanced spreading when they contact APCs. We will now test whether B cells that have received danger signals can detect very small amounts of antigen such that they are activated more rapidly during an infection. This may suggest new ways to enhance B cell responses to infection. We will also test whether some types of B-cell lymphomas have altered cytoskeletal regulation that allows them to receive continual survival and growth signals from the BCR in the absence of antigen. This could lead to new approaches for treating such cancers.