Compartmentalized multicellular crosstalk in lymph nodes coordinates the generation of potent cellular and humoral immune responses

Abstract

Distributed throughout the body, lymph nodes (LNs) constitute an important crossroad where resident and migratory immune cells interact to initiate antigen-specific immune responses supported by a dynamic 3-dimensional network of stromal cells, that is, endothelial cells and fibroblastic reticular cells (FRCs). LNs are organized into four major subanatomically separated compartments: the subcapsular sinus (SSC), the paracortex, the cortex, and the medulla. Each compartment is underpinned by particular FRC subsets that physically support LN architecture and delineate functional immune niches by appropriately providing environmental cues, nutrients, and survival factors to the immune cell subsets they interact with. In this review, we discuss how FRCs drive the structural and functional organization of each compartment to give rise to prosperous interactions and coordinate immune cell activities. We also discuss how reciprocal communication makes FRCs and immune cells perfect compatible partners for the generation of potent cellular and humoral immune responses.

Keywords: adaptive immunity; fibroblastic reticular cells; germinal center; immune crosstalk; lymph nodes.

Figure 1

*Coordinated crosstalk between FRCs and immune cells govern the establishment of adaptive immune response in LN. Schematic representation of interactions occurring between FRCs and immune cells, upon antigen challenge. The names of the 4 major LN compartments are shown in different colors in each part of the figure: Paracortex/T cell zone in orange, Cortex/B cell zone in blue, SSC in grey, and medulla in purple. The different LN cell types are detailed in the bottom left panel of the figure. Direct cell/cell interactions are represented by large arrows, while the main interactions occurring through soluble molecules are represented by curved arrows. Different arrows colors refer to the color of the cell type providing the signal. Chemokines are represented by colored circles. The sequential events that drive B cell differentiation from the GC toward a plasma cell phenotype in the medulla are numbered from 1 to 6. In the T cell zone, immune response initiation results in simultaneous interactions between DCs, T cells, and TRCs. Immune cells induce TRC stretching and differentiation that support LN expansion. Conversely, TRCs influence DCs and T cells positioning and behavior and promote their encounter by producing CCL19 and CCL21 and survival signals such as IL‐6 and IL‐7. Reciprocally, immune cells produce IL1b, LTB, and TNF‐α and promote TRCs survival. In parallel to T cell zone activities, B cells activation occurs close to SSC and B cells zone boundaries. Pre‐TfH cells and newly activated B cells migrate at the T:B border to complete their activation before reaching the primary follicle. The coalescence and proliferation of both T_FH cells and B cells induce the remodeling of the primary follicle into a secondary follicle with a GC. They also secrete LTB that induces FDC maturation. Mature FDCs organize GC into a dark and a light zone by generating CXCL12 and CXCL13 gradients. In the dark zone, B cells clonally expand and undergo class switching recombination and somatic hypermutation, before migrating to n the light zone, attracted by CXCL13 from FDCs. In the light zone, FDCs and T_FH cells alternatively select B cells with the highest BCR affinity. Selected B cells received IL‐6 and BAFF from FDCs and are rescued from apoptosis. Conversely, they maintain FDC in a mature state by providing them LTB. At the end of the light zone cycle, T_FH cells decide B cell fate by modulating IL‐4 and IL‐21 production and CD40L expression and orient them toward a return to a centroblast phenotype for dark zone recycling or induce their differentiation into antibody‐secreting cells. Plasmablasts transit toward the T/B border and differentiate into plasma cells. The newly differentiated plasma cells reach the medulla, in which MedRCs and myeloid cells create a privileged IL‐6/APRIL‐ rich environment for their homeostasis.