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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI098996-01
Application #
8531469
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Miller, Lara R
Project Start
2012-09-01
Project End
2013-12-31
Budget Start
2012-09-01
Budget End
2013-12-31
Support Year
1
Fiscal Year
2012
Total Cost
$415,209
Indirect Cost
$165,209
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Nadrah, Kristina; Beck, Thomas C; Pereira, João P (2015) Immature B Cell Egress from Bone Marrow Is SOCS3 Independent. PLoS One 10:e0136061
Nevius, Erin; Pinho, Flavia; Dhodapkar, Meera et al. (2015) Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis. J Exp Med 212:1931-46
Beck, Thomas C; Gomes, Ana Cordeiro; Cyster, Jason G et al. (2014) CXCR4 and a cell-extrinsic mechanism control immature B lymphocyte egress from bone marrow. J Exp Med 211:2567-81