Grant: Project Grant

Activated B cells make antibodies that protect against infection. However, people with autoimmune diseases make antibodies that attack parts of their own body. Hence the ability to modulate B cell activation has significant implications for health and disease. Each B cell has B cell receptor (BCR) proteins on its surface that determine what molecule it responds to (i.e. the antigen). Binding of antigen to the BCR triggers intracellular signals that cause B cell activation and antibody production. However even in the absence of antigen, the BCR continually generates a low-level of antigen-independent "tonic" signaling. The strength of this tonic BCR signaling determines whether a B cell is in a resting, partially activated (primed), or activated state prior to encountering antigen. We showed that bacterial components drive B cells into a primed state in which they are more sensitive to antigen and need less to become activated. Understanding how B cells become primed in this way may help us design better vaccines. Conversely, B cells from autoimmune patients are hyperactive and may require little or no antigen to become activated and make damaging antibodies. Reverting these cells to a resting state could prevent autoimmunity. Our project builds on new ideas about how BCR signaling is controlled by the movement and organization of the BCR within the cell membrane. To signal, BCRs must form clusters with each other, interact with other membrane proteins that organize signaling machinery, and move away from negative regulators. New advances in microscopy have allowed us to visualize the movement and clustering of the BCR in the membrane, as well as its interactions with positive and negative regulators. Our goal is to elucidate how BCR mobility, organization, and interactions are controlled, and how this determines the strength of tonic BCR signaling. This may suggest new ways to modulate B cell activation in order to improve vaccines and prevent autoimmunity.