Integration of Signaling Cascades in B Cell Development

描述(申请人提供)：最佳的体液反应取决于 激活适当的抗原特异性B细胞，然后再激活其 向完全分化的表型发展，要么是记忆细胞，要么是 浆细胞。T细胞在指导这一发育计划中发挥着关键作用，它通过 既提供接触相关信号，也提供可溶信号。尽管 CD4O/CD4OL相互作用和IL-4在这一过程中的关键作用 是公认的，B细胞用来整合的分子机制 这些不同类别的信号没有得到很好的描述。利用 作为调控CD23的一个模型系统，我们已经确定IRF-4是一个新的 CD4O和IL-4信号转导通路的组成部分。我们有 进一步发现，IRF-4功能可以在阶段特异性地调节 与发育受限的Kruppel锌组相互作用的方式 手指蛋白。我们现在提出，IRF-4在 B细胞活化途径整合及其选择性调控 Kruppel锌指蛋白的IRF-4功能对调节 激活的B细胞的发育命运。为了检验这些假设，我们将：1) 剖析控制IRF-4功能的分子机制。2)描述 IRF-4在CD4O/IL-4靶基因调控中的作用3) 研究IRF-4/Kruppel相互作用在终末B细胞中的作用 差异化。完成这些研究将使我们更好地了解 淋巴细胞整合不同基因的分子机制 激活途径。此外，对这些途径的了解可能会允许 以不适当的病理生理状态为特征的选择性靶向 淋巴细胞活化。

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.