Role of the BCR in B lymphocyte survival and development

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DESCRIPTION (provided by applicant): The division between normal cellular homeostasis and malignant transformation is maintained by regulation of the balance between cell death and survival, proliferation and differentiation. Cell surface receptors, whose signals affect the balance between these cell fates, often do so in a manner that depends upon the differentiation and activation state of the cell and the strength of the signal generated. The B cell antigen receptor (BCR) can generate signals that lead to a variety of outcomes depending upon the developmental stage of the B cell and the degree and persistence of receptor aggregation. Genetic and biochemical studies have shown that various forms of the BCR are expressed at defined stages of B cell development. Although expression of these receptors is required for development of B cells, we currently have little understanding of how signals are generated at these developmental checkpoints. We hypothesize that these different receptor structures exist to chaperone the BCR-associated signaling molecules Iga and IgB to the plasma membrane. At the plasma membrane, Iga and IgB generate signals in a ligand-independent manner. This hypothesis maintains that the BCR and BCR-like structures on developing B cells are capable of ligand-dependent (in the case of the mature BCR) as well as ligand-independent functions (all stages of BCR expression). The existence, regulation, and biological relevance of these ligand-independent "tonic" signals represent the broad goals of the proposed studies. Specifically, in Aim 1 we propose to establish the existence of ligand-independent signals through the BCR within the context of normal physiological control and to define to what extent it differs biochemically from aggregation-dependent signaling. In Aim 2 we will determine the biological relevance of ligand-independent tonic signaling and to what extent targeting Iga/IgB complexes to the plasma membrane defines the minimal requirement for positive selection at defined, checkpoints in B cell development. Finally, in studies planned for Aim 3, we expect to define the structural requirements for BCR tonic signaling in the context of positive selection during B cell development and survival in the periphery. Based upon preliminary data that strongly support the central hypothesis of these studies, accomplishing these specific aims will provide a new understanding of the role of the B cell antigen receptor in regulating development and survival of developing and mature B cells.