Integration of Signaling Cascades in B Cell Development

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DESCRIPTION (provided by applicant): Optimal humoral responses depend on the activation of the appropriate antigen-specific B cells followed by their progression toward a fully differentiated phenotype, either a memory cell or a plasma cell. T cells play a key role in guiding this developmental program by providing both contact-dependent as well as soluble signals. Although the pivotal roles of the CD4O/CD4OL interaction as well as of IL-4 in this process are well recognized, the molecular mechanisms utilized by B cells to integrate these distinct classes of signals are poorly characterized. Utilizing the regulation of CD23 as a model system, we have identified IRF-4 as a novel component of both CD4O and IL-4 signal transduction pathways. We have furthermore found that IRF-4 function can be modulated in a stage-specific manner by interaction with developmentally restricted sets of Kruppel zinc finger proteins. We now propose that IRF-4 plays a crucial role in the integration of B cell activation pathways and that selective modulation of IRF-4 function by Kruppel zinc finger proteins is critical for regulating the developmental fate of activated B cells. To test these hypotheses we will: 1) Dissect the molecular mechanisms controlling IRF-4 function. 2) Characterize the role of IRF-4 in the regulation of additional CD4O/IL-4 target genes. 3) Investigate the role of the IRF-4/Kruppel interaction during terminal B cells differentiation. Completion of these studies will yield a better understanding of the molecular mechanisms utilized by lymphocytes to integrate distinct activation pathways. Moreover, knowledge of these pathways may allow for selective targeting of pathophysiological states characterized by inappropriate lymphocyte activation.