Identification of a new subset of lymph node stromal cells involved in regulating plasma cell homeostasis

Abstract

Antibody-secreting plasma cells (PCs) arise rapidly during adaptive immunity to control infections. The early PCs are retained within the reactive lymphoid organ where their localization and homeostasis rely on extrinsic factors, presumably produced by local niche cells. While myeloid cells have been proposed to form those niches, the contribution by colocalizing stromal cells has remained unclear. Here, we characterized a subset of fibroblastic reticular cells (FRCs) that forms a dense meshwork throughout medullary cords of lymph nodes (LNs) where PCs reside. This medullary FRC type is shown to be anatomically, phenotypically, and functionally distinct from T zone FRCs, both in mice and humans. By using static and dynamic imaging approaches, we provide evidence that medullary FRCs are the main cell type in contact with PCs guiding them in their migration. Medullary FRCs also represent a major local source of the PC survival factors IL-6, BAFF, and CXCL12, besides also producing APRIL. In vitro, medullary FRCs alone or in combination with macrophages promote PC survival while other LN cell types do not have this property. Thus, we propose that this FRC subset, together with medullary macrophages, forms PC survival niches within the LN medulla, and thereby helps in promoting the rapid development of humoral immunity, which is critical in limiting early pathogen spread.

Impact of B cell/lymphoid stromal cell crosstalk in B-cell physiology and malignancy

“…survival, and allow the diffusion of small molecules throughout the LN [1]. The second one, called medullary FRC (MedRCs), forms the major structural component of the plasma cell niche within LN medullary cords [3]. Of note, the landmark gene expression study of mouse LN stromal and endothelial cells performed by the Immgen consortium has defined the transcriptomic profile of podoplanin pos CD31 neg cells, but TRCs, MedRCs, MRCs, CRCs, and FDCs all fall into this subset [4].…”

“…Second, MedRCs generate different extracellular matrix structure than TRCs and specifically produce high amounts of CXCL12, BAFF, APRIL, and IL-6. They were shown to guide the migration of CXCR4 pos plasma cell within the medulla and to contribute, together with medullary macrophages, to plasma cell survival in situ [3]. At the earliest stage of GC response, both Tfh and a specific FRC subset producing APRIL have recently been involved in the output of plasmablasts at the GC-T zone interface before terminal maturation into plasma cells [36].…”

Neutrophils mediate the capture of peritoneal contaminants by fat-associated lymphoid clusters of the omentum

“…1D,I and Supplementary Fig. 1E) (Huang et al, 2018;Malhotra et al, 2012;Perez-Shibayama et al, 2018). We thus assigned this cluster the name Ccl19 + Pdgfra + FALC FRCs.…”

Role of lymph node stroma and microenvironment in T cell tolerance

“…107,108 Laminins are a family of extracellular matrix components expressed on basement membranes. 107,108 Laminins are a family of extracellular matrix components expressed on basement membranes.…”

“…Although these have not been specifically studied in the context of suppression and tolerance, they likely contribute to immunologic regulation since they are essential to maintain LN structure and homeostasis. 107,108 Laminins are a family of extracellular matrix components expressed on basement membranes. 109 As trimeric glycoproteins, laminins are composed of α, β, and γ chains which make up to 16 isoforms 110 and laminin α4β1γ1 (411) and α5β1γ1 (511) are primary components in LN extracellular matrix.…”