Lim Vivian Y, Zehentmeier Sandra, Fistonich Chris, Pereira João P
Yale University School of Medicine, New Haven, CT, United States.
Yale University School of Medicine, New Haven, CT, United States.
Adv Immunol. 2017;134:47-88. doi: 10.1016/bs.ai.2017.02.001. Epub 2017 Mar 18.
B lymphocytes develop from hematopoietic stem cells (HSCs) in specialized bone marrow niches composed of rare mesenchymal lineage stem/progenitor cells (MSPCs) and sinusoidal endothelial cells. These niches are defined by function and location: MSPCs are mostly perisinusoidal cells that together with a small subset of sinusoidal endothelial cells express stem cell factor, interleukin-7 (IL-7), IL-15, and the highest amounts of CXCL12 in bone marrow. Though rare, MSPCs are morphologically heterogeneous, highly reticular, and form a vast cellular network in the bone marrow parenchyma capable of interacting with large numbers of hematopoietic cells. HSCs, downstream multipotent progenitor cells, and common lymphoid progenitor cells utilize CXCR4 to fine-tune access to critical short-range growth factors provided by MSPCs for their long-term maintenance and/or multilineage differentiation. In later stages, developing B lymphocytes use CXCR4 to navigate the bone marrow parenchyma, and predominantly cannabinoid receptor-2 for positioning within bone marrow sinusoids, prior to being released into peripheral blood circulation. In the final stages of differentiation, transitional B cells migrate to the spleen where they preferentially undergo further rounds of differentiation until selection into the mature B cell pool occurs. This bottleneck purges up to 97% of all developing B cells in a peripheral selection process that is heavily controlled not only by the intensity of BCR signaling and access to BAFF but also by the proper functioning of the B cell motility machinery.
B淋巴细胞由造血干细胞(HSCs)在由罕见的间充质谱系干/祖细胞(MSPCs)和窦状内皮细胞组成的特殊骨髓微环境中发育而来。这些微环境由功能和位置定义:MSPCs大多是窦周细胞,它们与一小部分窦状内皮细胞一起表达干细胞因子、白细胞介素-7(IL-7)、IL-15以及骨髓中含量最高的CXCL12。尽管罕见,但MSPCs在形态上具有异质性,高度网状化,并在骨髓实质中形成一个庞大的细胞网络,能够与大量造血细胞相互作用。造血干细胞、下游多能祖细胞和普通淋巴祖细胞利用CXCR4来微调对MSPCs提供的关键短程生长因子的获取,以维持其长期生存和/或多谱系分化。在后期阶段,发育中的B淋巴细胞利用CXCR4在骨髓实质中导航,在释放到外周血液循环之前,主要利用大麻素受体-2在骨髓窦内定位。在分化的最后阶段,过渡性B细胞迁移到脾脏,在那里它们优先经历进一步轮次的分化,直到被选择进入成熟B细胞库。这个瓶颈在一个外周选择过程中清除了高达97%的所有发育中的B细胞,这个过程不仅受到BCR信号强度和获得BAFF的严格控制,还受到B细胞运动机制正常运作的严格控制。