Lymph node stromal cells: subsets and functions in health and disease

Abstract

Lymph nodes (LNs) aid the interaction between lymphocytes and antigenpresenting cells, resulting in adequate and prolonged adaptive immune responses. LN stromal cells (LNSCs) are crucially involved in steering adaptive immune responses at different levels. Most knowledge on LNSCs has been obtained from mouse studies, and few studies indicate similarities with their human counterparts. Recent advances in single-cell technologies have revealed significant LNSC heterogeneity among different subsets with potential selective functions in immunity. This review provides an overview of current knowledge of LNSCs based on human and murine studies describing the role of these cells in health and disease. LNSCs as orchestrators of the immune systemLNs are specialized secondary lymphoid organs (SLOs) that are essential for the initiation of adaptive immunity. Most cells within LNs are lymphocytes that continuously enter the LN from the bloodstream. The afferent lymph transports antigens and antigen-presenting cells (APCs; see Glossary) to the LN, which creates an environment in which antigen-specific lymphocytes and APCs can optimally interact, resulting in adequate and prolonged immune responses [1]. The architecture of the LN is pivotal for its role in inducing humoral immune responses, and this is created and supported by LNSCs (Box 1) [2]. LNSCs create a 3D network that generates a backbone for immune cells to migrate on, and thus, during the time lymphocytes reside in the LN, they extensively interact with stromal cells. In addition to providing structural support, LNSCs also provide survival signals, nutrients, soluble factors, and antigens that are collectively required for immunosurveillance as well as for the generation and control of adaptive immune responses [3,4]. Therefore, understanding the immunobiology of LNSCs is key to comprehending specific aspects of the immune system more fully. The aim of this review is to provide an overview of the current state of knowledge about murine and human LNSC subsets and functions. We discuss recent findings regarding human and mouse LNSCs under homeostatic conditions, and describe their immunomodulatory capacities during autoimmunity, infection, and cancer. We anticipate that some of these findings may fuel further investigations into the field of LN biology and immune defense across species. HighlightsSingle-cell RNA sequencing has uncovered conspicuous heterogeneity in lymph node stromal cells (LNSCs) populations in mice and humans.Human and mouse LNSC subsets show similarities in their transcriptomic profiles and trajectory analyses.Each LNSC subset has its own specific function in regulating immune responses.Human LNSCs have the machinery to regulate peripheral tolerance, making them attractive targets for modulating tolerance induction and maintenance.LNSCs in mice and humans can suppress T cell proliferation during strong inflammatory stimuli. Different mechanisms are utilized to perform this function.LNSCs from patients with particular autoimmune diseases exhibit alte...

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“…The major rationale for classifying lymph nodes and spleen as peripheral immune organs is that these organs provide a niche for immune cell maturation, differentiation, and activation ( 104 ). If we hold the same criteria and examine recent progresses in the aorta field, we will have no difficulties to conclude that aorta is an immune organ in pathologies.…”

Lower Metabolic Potential and Impaired Metabolic Flexibility in Human Lymph Node Stromal Cells from Patients with Rheumatoid Arthritis

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Characterization of CD41+ cells in the lymph node

“…Like any other organs, LN consists of heterogeneous SC which support its specialized function. Our understanding of LN SC has greatly increased recently with transgenic mice and newer methods of characterization of LN SC (3,32). These studies have subsets of SC are responsible for specific function to ensure the overall (A) Flow cytometry analysis of the TDL from naïve C57BL/6 mouse showed that the majority of CD41 + cells were negative for Lyve1.…”