Cellular and molecular analysis of B lymphocyte development and selection

B 淋巴细胞发育和选择的细胞和分子分析

基本信息

批准号：
10084797
负责人：
JOAO PEREIRA
金额：
$ 48.35万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084797
关键词：
Address Attention Autoimmune Diseases B-Cell Development B-Lymphocytes Bacterial Infections Behavior Binding Blood-Borne Pathogens Bone Marrow CXCL12 gene Cell Compartmentation Cell Lineage Cell Maintenance Cell Shape Cells DNA Double Strand Break Defect Development Dose Down-Regulation Emergency Situation Ensure Goals Grant Hematopoiesis Hematopoietic Hematopoietic Cell Production Hematopoietic stem cells Home Homeostasis Homing Hour IL7 gene Immune System Diseases Immunologic Deficiency Syndromes Infection Inflammation Inflammatory Instruction Left Ligands Listeria monocytogenes Lymphatic Endothelial Cells Lymphocyte Lymphoid Lymphoid Cell Lymphopenia Lymphopoiesis Malignant Neoplasms Mature B-Lymphocyte Mediating Mesenchymal Stem Cells Molecular Molecular Analysis Myelogenous Myeloid Cells Myelopoiesis Natural Immunity Output Pathway interactions Peripheral Play Positioning Attribute Process Production Receptor Signaling Research Reticular Cell Role Signal Transduction Stromal Cells Systemic infection T memory cell TNFRSF1A gene Testing Tumor Necrosis Factor-Beta Virus Diseases attenuation cell growth chemokine cytokine experimental study in vivo leptin receptor lymphotoxin beta receptor novel novel therapeutic intervention prevent receptor response secondary lymphoid organ stem cell delivery stem cell survival stem cells systemic inflammatory response tertiary lymphoid organ trafficking

项目摘要

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.

骨髓（BM）以确保造血细胞的速率产生髓样细胞和淋巴样细胞稳态。如何调节造血细胞的产生以控制周围造血的大小细胞室尚不清楚。在全身感染和/或注射过程中，淋巴样的产生为在增加骨髓性的同时停止了，这一过程称为紧急骨髓性。如何系统性炎症信号改变了BM微环境以实现戏剧性和快速的造血转移在很大程度上未知。我们建议通过研究B细胞开发在稳态和系统性炎症期间。在过去的6年中，研究确定了瘦素受体表达间充质祖细胞（LEPR+ MPC）作为产生SCF，IL-7的主要细胞，并且趋化因子CXCL12，对于造血干细胞维持和造血前体至关重要投入到淋巴谱系中。这种类型的利基组织表明造血细胞和LEPR+ MPC在体内出现，但到目前为止尚无造血信号已经鉴定出细胞到LEPR+ MPC。在这笔赠款中，我们提供了证据表明LEPR+ MPCS Express 淋巴毒素β受体（LTBR）和LTBR信号传导下调IL-7的产生。成熟的B细胞通过BM自然循环LTBR配体LTA1B2。此外，虽然正常B单元祖细胞表达LIT LTA1B2，Leukemia preb细胞显着上调LTA1B2并减少IL-7 由LEPR+ MPC在体内产生。在AIM 1中，我们将测试LEPR+ MPC中LTBR信号传导的假设调节B细胞室的质量和大小。我们的初步发现也表明LEPR+ MPC以LTBR依赖性方式显着降低全身注射过程中的IL-7表达。重要的是，当LEPR+ MPC无法关闭IL-7生产时，B淋巴细胞继续进行，并且髓样细胞产生大大降低。值得注意的是，对高剂量的李斯特菌的生存单核细胞增基因感染严重取决于LTBR信号传导。通过AIM 2中描述的实验我们将检验以下假设：LEPR+ MPC中的LTBR信号传导是控制的主要分子途径紧急骨髓虫。最后，随着全身注入过程中CXCL12的产生迅速减少，大多数造血细胞从BM迅速动员到周围，但值得注意的是成熟 B炎症后凌晨，BM数量两倍的B细胞。在AIM 3中，我们将检验假设成熟的B细胞通过BM归因和相互作用在先天免疫中起新颖而无关的作用用LEPR+ MPCs在这些细胞中传递“启发性” LTBR信号传导。我们还建议研究成熟的B细胞使用的机制在家中暂时保留在BM中炎。拟议的目标将为广泛的概念和机械框架提供了解骨髓基质细胞如何影响细胞谱系决策。