This is a renewal application to continue our studies to define the molecular mechanism operative in linking antigen receptor-generated signals into downstream B lymphocyte activation responses. B lymphocytes are the primary effector cells in the antibody-mediated immune response. A specific B cell immune response is initiated by antigen interacting with the B cell via a cell surface form of immunoglobulin (sIg). This interaction initiates a complex cascade of biochemical events occurring at the plasma membrane and within the cytoplasm of the B cell. Translation of these membrane-associated and cytoplasmic signals occurs within the nucleus where changes in gene expression regulate the activation state of the B cell and define the nature of its response to sIg signaling. While much has been learned regarding individual membrane, to cytoplasmic, and nuclear events associated with sIg-mediated B cell activation, we understand little regarding the integration of these individual events. The studies outlined in this proposal represent a continuation of a commitment by my lab to define the molecular mechanisms operative in linking sIg-generated signals to long-term phenotypic changes in the B cell that affect the activation of these cells and their involvement in an immune response to antigen. Our work in the past has allowed us to progress to the point where we can now begin to define a complete and coherent signaling pathway linking specific plasma membrane, cytoplasmic, and nuclear events with activation-associated phenotypic changes in the B cell. We have identified a transcription factor-encoding gene whose expression in B cells following sIg stimulation is important in the translation of second messenger pathways into defined cellular responses. The molecular mechanisms involved in linking induction, regulation of transcriptional activity, and target gene induction following sIg signaling in primary B cells will be studied. These studies are important because they afford us the opportunity to establish a definitive relationship between short-term biochemical and transcriptional events with long-term changes at the cellular level that have definable effects on the immune response of the organism.
