Germinal centers (GCs) play a crucial role in humoral immunity by generating an evolving B cell pool that serves as the origin of protective memory B and plasma cells. B cell diversification, clonal expansion, and selection in the GC result in an overall increase in the affinity of serum antibodies for antigen during infection (i.e., affinity maturation). However, effective affinity maturation requires the enrichment of rare B cells that have acquired affinity-enhanced mutations for antigen; we now understand that selection of these B cells is controlled by competition for a limited pool of specialized T follicular helper cells (TFH). Under this T cell centric model, B cell affinity for Ag is sensed indirectly. However, we still do not understand all the factors that contribute to selection. A long-standing question has been whether BCR signaling plays a direct role in the selection of high affinity B cells and affinity maturation. This has proven difficult to study because the intricacies of GC selection dynamics can only be studied in-vivo, and genetic models compromising components of the BCR signaling pathways disrupt signaling necessary for GC formation and maintenance. The proposed project addresses these critical barriers through the development of a tool capable of tracking active BCR signaling in-vivo and novel mouse models that can be used with pharmacological BCR inhibition. Using these tools, I aim first, to identify and characterize GC B cells undergoing active BCR signal transduction in-vivo.
My second aim i s to determine how BCR signaling affects GC B cell selection to test my overall hypothesis that antigen and T cell derived signals synergize to drive positive selection and affinity maturation. The outcome of this project will be a molecular understanding of the role GC BCR signaling plays in the generation of protective antibody responses. These findings will answer questions central to GC biology and inform future vaccine design.
Vaccines remain one of the most impactful public health measures, and the success of a vaccine often depends on its ability to elicit a diverse and high affinity antibody response in germinal centers. The proposed study seeks to understand the B cell biology behind the genesis of protective antibody responses in germinal centers. This has crucial implications for studying the control and prevention of infection and our fundamental understanding of humoral immunity.
