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.
