Molecular basis of the requirements for IRF4 and IRF8 in pre-B cell development

描述(由申请人提供)：B淋巴细胞由祖细胞通过依赖于复杂调控分子阵列的协调活动的过程而发展。这种高度调控的发育过程的破坏往往会导致B细胞发育异常，导致自身免疫、白血病和淋巴瘤等疾病。因此，更好地理解控制B细胞发育的分子机制可以为B细胞性疾病的发病机制提供新的见解。缺乏免疫系统特异性转录因子IRF4和IRF8(IRF4，8)的小鼠在前B细胞发育方面存在严重缺陷。我们的长期目标是了解IRF4，8如何协调B细胞的发育。这一应用的目的是阐明IRF4，8控制前B细胞发育的分子机制。我们将测试这一假设，即IRF4，8是Pre-BCR启动的信号通路的核效应器，该信号通路限制Pre-B细胞的增殖并促进Pre-B细胞的分化。我们根据以前的研究和初步的发现提出了这一假说，认为IRF4，8的表达受Pre-BCR信号的调控，在缺乏IRF4，8的情况下，Pre-B细胞在退出细胞周期和重排轻链方面存在缺陷。该建议包括以下具体目标： 目的：1.阐明IRF4、8负性调节前B细胞增殖的分子机制。我们将检验这样的假设，即IRF4，8作为替代轻链Vpre-B和lambda5表达的负调节因子，以及IRF4，8在关闭前B细胞对IL-7的反应中是必不可少的。 目的#2.确定IRF4、8控制前B细胞分化的分子机制。由于IRF4、8-/-Pre-B细胞的轻链重排和转录严重受损，我们将检验IRF4、8控制V(D)J重组酶轻链基因座可及性的假设。 目的#3.建立IRF4、8作为BCR前信号通路的核效应因子。在没有IRF4，8的情况下，前B细胞的发育似乎是正常的，但前B细胞的发育受阻。我们假设IRF4，8的表达是在Pre-B阶段通过BLNK/BTK介导的信号被Pre-BCR诱导的。

DESCRIPTION (provided by applicant): B lymphocyte develops from progenitor cell through a process that is dependent on the coordinated activity of a complex array of regulatory molecules. The disruption of this highly regulated developmental process often leads to abnormal B cell development, resulting in diseases such as autoimmunity, leukemia and lymphoma. Therefore, improved understanding of the molecular mechanisms that control B cell development could provide novel insights into pathogenesis of B cell-derived diseases. Mice lacking immune system specific transcription factors IRF4 and IRF8 (IRF4,8) have a profound defect in pre-B cell development. Our long-term goal is to understand how B cell development is orchestrated by IRF4,8. The objective for this application is to elucidate the molecular mechanisms by which IRF4,8 control pre-B cell development. We will test the hypothesis that IRF4,8 are the nuclear effectors of a pre-BCR initiated signaling pathway that limits pre-B cell expansion and promotes pre-B cell differentiation. We have formulated this hypothesis based on our previous study and preliminary findings, which suggest that IRF4,8 expression are regulated by pre-BCR signaling and in the absence of IRF4,8, pre-B cells show defects in exiting from cell cycle and in rearranging light chain. The proposal includes the following specific aims: Aim #1. To elucidate the molecular mechanisms by which IRF4,8 negatively regulate pre-B cell expansion. We will test the hypothesis that IRF4,8 function as negative regulators of the expression of surrogate light chain Vpre-B and lambda5, and that IRF4,8 are essential in shutting down pre-B cell response to IL-7. Aim #2. To determine the molecular mechanisms by which IRF4,8 control pre-B cell differentiation. Because light chain rearrangement and transcription are severely impaired in IRF4,8-/- pre-B cells, we will test the hypothesis that IRF4,8 control the accessibility of light chain loci to V(D)J recombinase. Aim #3. To establish IRF4,8 as the nuclear effectors of pre-BCR signaling pathway. In the absence of IRF4,8, pro-B cell development appears to be normal but pre-B cell development is blocked. We hypothesize that expression of IRF4,8 is induced at the pre-B stage by pre-BCR though Blnk/Btk-mediated signaling.