The bone marrow (BM) produces myeloid and lymphoid cells at a rate that ensures hematopoietic cell homeostasis. How hematopoietic cell production is regulated to control the size of the peripheral hematopoietic cell compartment is not understood. During systemic infection and/or inflammation, lymphoid production is halted while myelopoiesis is increased, a process that is known as emergency myelopoiesis. How systemic inflammatory signals alter the BM microenvironment to enable dramatic and quick hematopoietic shifts is also largely unknown. We propose to address these fundamental questions by studying B cell development under homeostasis and during systemic inflammation. Studies over the past 6 years identified Leptin receptor- expressing mesenchymal progenitor cells (Lepr+ MPCs) as the major cells producing SCF, IL-7, and the chemokine CXCL12, that are critical for hematopoietic stem cell maintenance and hematopoietic precursor commitment into the lymphoid lineage. This type of niche organization suggests that cross-talk between hematopoietic cells and Lepr+ MPCs occurs in vivo, but so far no specific signals delivered by hematopoietic cells to Lepr+ MPCs have been identified. In this grant we provide evidence showing that Lepr+ MPCs express Lymphotoxin beta receptor (LTbR) and that LTbR signaling downregulates IL-7 production. Mature B cells that naturally recirculate through BM express the LTbR ligand LTa1b2. Furthermore, while normal B cell progenitors express little LTa1b2, pre-leukemic preB cells significantly up-regulate LTa1b2 and reduce IL-7 produced by Lepr+ MPCs in vivo.
In aim 1 we will test the hypothesis that LTbR signaling in Lepr+ MPCs regulates the quality and size of the B cell compartment. Our preliminary findings also revealed that Lepr+ MPCs significantly reduce IL-7 expression during systemic inflammation in a LTbR-dependent manner. Importantly, when Lepr+ MPCs cannot shut-down IL-7 production, B lymphocytes continue to be made, and myeloid cell production is significantly reduced. Remarkably, survival against a high dose of Listeria monocytogenes infection is critically dependent on LTbR signaling. Through experiments described in Aim 2 we will test the hypothesis that LTbR signaling in Lepr+ MPCs is the major molecular pathway controlling emergency myelopoiesis. Finally, as CXCL12 production is quickly reduced during systemic inflammation, most hematopoietic cells are rapidly mobilized from BM into the periphery, with the notable exception of mature B cells that double in number in BM in the early hours after inflammation.
In Aim 3, we will test the hypothesis that mature B cells play a novel and unsuspected role in innate immunity through BM homing and interaction with Lepr+ MPCs for delivery of ?instructive? LTbR signaling in these cells. We also propose to study the mechanism(s) used by mature B cells to home and be temporarily retained in BM during systemic inflammation. The proposed aims will provide a broad conceptual and mechanistic framework for understanding how bone marrow stromal cells influence cell lineage decisions.
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, malignancies, and autoimmune diseases.
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