Lymph node stromal CCL2 limits antibody responses
Lymph node stromal CCL2 limits antibody responses
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DOI：
10.1126/sciimmunol.aaw0693
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发表时间：
2020-03-01
影响因子：
24.8
通讯作者：
Lu, Theresa T.
中科院分区：
文献类型：
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作者：
Dasoveanu, Dragos C.;Park, Hyeung Ju;Lu, Theresa T.
淋巴结中的非造血基质细胞，如成纤维网状细胞（FRC），可以支持浆母细胞和浆细胞的存活[一起，抗体形成细胞（AFC）]。然而，在AFC积累的基质室的调节功能尚未得到赞赏。在这里，我们表明，趋化因子配体2（CCL2）表达的基质细胞限制AFC的生存。FRC在AFC所在的T细胞区和髓质的血管丰富区域表达高水平的CCL 2。FRC CCL 2在AFC蓄积过程中上调，我们使用淋巴结移植显示BP3（+）FRC和淋巴管内皮细胞中的CCL 2缺陷可增加AFC存活率，而不影响B或生发中心细胞数量。单核细胞是CCL2受体CCR2的关键表达者，因为AFC应答中的单核细胞耗竭和转移晚期分别增加和减少AFC蓄积。单核细胞以NADPH氧化酶2（NOX2）依赖性方式表达活性氧（ROS），而NOX2缺陷单核细胞无法减少AFC数量。基质CCL2调节单核细胞的积累和ROS的产生，并且部分地通过调节血管通透性的操作来调节。总之，我们的研究结果表明，淋巴结间质区室，通过影响单核细胞的积累和功能表型，在AFC生存的调节作用。我们的研究结果进一步表明炎症诱导的血管活性在调节淋巴结微环境中的作用。对血管丰富环境中基质介导的AFC调节的理解可能被用于控制抗体介导的自身免疫。
Nonhematopoietic stromal cells in lymph nodes such as fibroblastic reticular cells (FRCs) can support the survival of plasmablasts and plasma cells [together, antibody-forming cells (AFCs)]. However, a regulatory function for the stromal compartment in AFC accumulation has not been appreciated. Here, we show that chemokine ligand 2 (CCL2)-expressing stromal cells limit AFC survival. FRCs express high levels of CCL2 in vessel-rich areas of the T cell zone and the medulla, where AFCs are located. FRC CCL2 is up-regulated during AFC accumulation, and we use lymph node transplantation to show that CCL2 deficiency in BP3(+) FRCs and lymphatic endothelial cells increases AFC survival without affecting B or germinal center cell numbers. Monocytes are key expressers of the CCL2 receptor CCR2, as monocyte depletion and transfer late in AFC responses increases and decreases AFC accumulation, respectively. Monocytes express reactive oxygen species (ROS) in an NADPH oxidase 2 (NOX2)-dependent manner, and NOX2-deficient monocytes fail to reduce AFC numbers. Stromal CCL2 modulates both monocyte accumulation and ROS production, and is regulated, in part, by manipulations that modulate vascular permeability. Together, our results reveal that the lymph node stromal compartment, by influencing monocyte accumulation and functional phenotype, has a regulatory role in AFC survival. Our results further suggest a role for inflammation-induced vascular activity in tuning the lymph node microenvironment. The understanding of stromal-mediated AFC regulation in vessel-rich environments could potentially be harnessed to control antibody-mediated autoimmunity.