Research ArticleLYMPHATICS

Lymph node stromal CCL2 limits antibody responses

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Science Immunology  20 Mar 2020:
Vol. 5, Issue 45, eaaw0693
DOI: 10.1126/sciimmunol.aaw0693

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Sending messages to plasma cells

Lymph node stromal cells serve as a platform that facilitates functional interactions between distinct immune cell types. Here, Dasoveanu et al. have examined the role of fibroblastic reticular cells (FRCs), a type of lymph node stromal cells, in regulating the survival of antibody-producing plasma cells. They report FRCs to be a critical source of chemokine ligand 2 (CCL2), and that CCL2 produced by FRCs tempers the expansion of plasma cells. Plasma cells do not express the CCL2 receptor CCR2; rather, CCR2-expressing monocytes respond to CCL2 by generating molecules that relay signals from the FRCs to the plasma cells. The study adds to the growing appreciation of the roles of lymph node stromal cells in fine-tuning adaptive immune responses.

Abstract

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.

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