B cell activation is a highly regulated process involving multiple different signals. The net effect of these interacting signal pathways is to determine the B cell response to recognition of antigen. A detailed understanding of how signal transducing molecules on B cells work is essential to understanding, and potentially controlling, B cell proliferation and antibody secretion. Thus, specifically targeted therapies for B cell hyperproliferative diseases, such as B cell malignancies, require an understanding of how B cell signaling pathways function and interact. The majority of B lymphocyte activation events involve specific binding of B cell membrane Ig to antigen, and interaction with T helper cells via both polymorphic and non-polymorphic transmembrane molecules. Nonspecific B cell activation signals can be provided by T cell-secreted lymphokines and nonpolymorphic T cell membrane molecules, such as CD40 ligand (CD40L) on activated T cells. However, it is our hypothesis that specific interactions with antigen prepare B cells to respond optimally to subsequent T cell-mediated signals, and specific interactions between T cell receptors and B cell MHC class II molecules preserve the specificity of T cell-B cell interactions. Our laboratory and others have demonstrated that class II MHC molecules preserve the specificity of T cell-B interactions. Our laboratory and others have demonstrated that class II MHC molecules deliver regulatory signals to B lymphocytes, and that these signals synergize with signals delivered by the binding of antigen to membrane ig. In addition, class II-mediated signals counteract antigen-mediated anergy signals, which may be a mechanism by which T cells stimulate B cell hyperproliferation in malignancy and autoimmune disease. More recently, we have obtained data indicating that signals delivered via class II cooperate with signals delivered to B cells by the binding of T cell CD40L B cell CD40. We thus believe that signals delivered by antigen and cognate interaction with T cells (i.e., signals delivered by binding of mig and MHC class II molecules) increase the effectiveness of CD40-mediated signals following T cell activation, and decrease the probability of inappropriate B cell activation through """"""""bystander"""""""" effects. Thr proposed experiments will test determine the molecular basis of this interaction between signal receptors. Three major experimental approaches will be used to test our hypotheses. First, we will use recombinant DNA technology to produce alterations in the genes encoding MHC class II and CD40 molecules. Using B cell lines as models, we will introduce these altered genes and study the signaling function of the proteins they produce, to define a detailed relationship between structure and function for these signaling molecules. Second, we will use state-of=- the-art biochemical signaling assays to identify the intracellular events which result from signaling via class II MHC and CD40 molecules. Finally, we will perform in vitro and in vivo experiments examining the molecular mechanisms by which these signals cooperate in the regulation of B cell activation. The combination of these three approaches will yield a better understanding of how to manipulate athe process of B cell activation, through better understanding of the mechanism of, and interactions between the component parts of the process.
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