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Stromal cells have for a long time been viewed as structural cells that support distinct compartments within lymphoid tissues and little more. Instead, an active cross-talk between endothelial and fibroblastic stromal cells drives the maturation of lymphoid niches, a relationship that is recapitulated during lymph node organogenesis, steady-state conditions, and following inflammation. In this review, we go over recent advances in genetic models and high-resolution transcriptomic analyses that have propelled the finer resolution of the stromal cell infrastructure of lymph nodes, revealing that the distinct subsets are strategically positioned to deliver a catered mixture of niche factors to interacting immune cell populations. Moreover, we discuss how changes in the activation state of poised stromal cell–underpinned niches rather than on-demand differentiation of new stromal cell subsets govern the efficient interaction of Ag, APC, and cognate B and T lymphocytes during adaptive immune responses.

Inflammation in the CNS must be tightly regulated to respond efficiently to infection with neurotropic pathogens. Access of immune cells to the CNS and their positioning within the tissue are controlled by stromal cells that construct the barriers of the CNS. Although the role of the endothelium in regulating the passage of leukocytes and small molecules into the CNS has been studied extensively, the contribution of fibroblastic stromal cells as portals of entry into the CNS was only recently uncovered. We review the critical immune-stimulating role of meningeal fibroblasts in promoting recruitment and retention of lymphocytes during CNS inflammation. Activated meningeal fibroblastic stromal cells have the capacity to rapidly elaborate an immune-competent niche that sustains protective immune cells entering the CNS from the draining cervical lymph node. Such stromal cell niches can ultimately foster the establishment of tertiary lymphoid tissues during chronic neuroinflammatory conditions.

Secondary lymphoid organs (SLO) such as the spleen, lymph nodes and Peyer’s patches are strategically positioned to survey bodily surfaces and to support the generation of cellular and humoral immunity. The movement and interaction of antigens, antigen presenting cells, B and T lymphocytes within SLOs is coordinated by specialized fibroblastic reticular cells (FRCs) that form dedicated microenvironments and provide essential niche molecules such as the chemokine CXCL13. High-resolution transcriptomic analysis of Cxcl13-expressing cells in mouse models has previously enabled the molecular characterization of heterogenous B cell-interacting reticular cells (BRC) in lymph nodes. However, it remains unknown to what extent the molecular identity of niche-forming BRCs is conserved across SLOs. Here, we employed single cell RNA-sequencing of Cxcl13-expressing cells from murine lymph node, spleen and Peyer’s patch to compare the molecular identity of BRCs across SLOs. While structural and developmental genes dominated organ-specific gene signatures, we found conserved gene signatures reflecting crucial immunomodulatory functions. The highest conservation was observed in follicular dendritic cells, a BRC subset specialized in the capture and presentation of antigen. Moreover, immunomodulatory gene signatures were preserved in BRCs from human lymph nodes and palatine tonsils highlighting the important role of BRC-defined microenvironments in steering efficient immune responses in SLOs across species.