The quest for understanding lymphocyte migration has challenged multiple laboratories for several decades now. The recent development of multi-photon microscopes is beginning to shed some light on the dynamics of lymphocyte movement in secondary lymphoid organs. In contrast, there is still an almost complete lack of information on B-lineage cell migration and positioning during differentiation in bone marrow (BM). B-cell precursors interact with specialized BM stromal cells expressing critical signals, such as IL-7. IL7 is essential for maintaining B-lineage specification and differentiation. Yet, the mechanism, and the dynamics, of early B cell precursor interaction with IL-7+ cells remain uncharacterized.
In specific aim 1, we define a strategy for visualizing B cell precursor interactions with IL-7+ stromal cells by intravital multiphoton microscopy. Moreover, we will test the hypothesis that defects in B cell precursor migration and adhesion to IL-7+ cells cripple B cell development and cause of B-lymphopenia. We have previously described movement of developing B cells in BM parenchyma and sinusoids. The mechanism(s) controlling B cell precursor motility in BM remain uncharacterized.
In specific aim 2 we propose to characterize the mechanism of B cell precursor migration in BM. In late stages of B cell development, immature B-lymphocytes acquire egress capability and exit BM through the sinusoidal network. A significant body of work has demonstrated that the signaling lipid sphingosine-1-phosphate (S1P), and S1P receptors are critical for lymphocyte egress from primary and secondary lymphoid organs. However, we were, recently, surprised to find a minimal role for S1P and its G?i protein coupled receptor S1P1 in immature B cell egress from BM. In an attempt to further define S1P-independent egress mechanism(s), we propose in specific aim 3 to assess if alternative G?i protein coupled receptor(s) are involved in this process. Finally, we will devise a strategy for visualizing immature B cell egress from BM into sinusoids. Combined these studies will begin to detail a model of the microanatomy of B cell development.
Defects in B cell development are major causes of immunological diseases. By investigating where and how B cells migrate and position within bone marrow we may develop new therapeutic strategies against devastating immunodeficiencies.
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