Stromal–immune cell interactions

On 3–8 June 2022, the First International Aegean Conference on Mesenchymal Cells in Health & Disease took place in Chania, Crete, and brought together clinicians and scientists who work on mesenchymal or stromal cell biology across different fields including immunity, inflammation and cancer.

Here, Carmeliet and colleagues discuss the role of endothelial cells in inflammation and viral infection and propose novel therapeutic strategies for COVID-19.

Recent single-cell studies have revealed a previously unappreciated heterogeneity among endothelial cells that line the lymphatic sinuses of the lymph nodes. In this Review, the authors describe these various lymphatic endothelial cell types and how they support the trafficking of cells and antigens through lymph nodes.

Koliaraki, Prados, Armaka & Kollias review the roles of fibroblastic mesenchymal cells in tissue homeostasis and immunopathologic diseases, including chronic inflammatory disease, tissue fibrosis and cancer.

Structural cells implement a broad range of immune-regulatory functions beyond their roles as barriers and connective tissues, and they utilize an epigenetically encoded potential for immune gene activation in their rapid response to viral infection.

Takayanagi and colleagues show that thymic medullary fibroblasts can contribute to central tolerance mechanisms by expressing cell-type-specific antigens distinct from those expressed by medullary thymic epithelial cells.

Turley and Krishnamurty review new insights into lymph node stromal cells, a heterogeneous cell population that serves distinct functions during development, in maintaining lymphocyte homeostasis, and in coordinating immune responses.

In this Review, the authors encourage us to extend our concept of memory by considering the diverse cell types within a barrier tissue. They propose that any long-term resident or essential tissue cell type can store memory of previous immune events and cooperate in memory recall.

Organoid technology has emerged as a powerful tool to maintain epithelial cells in a near-native state that can be used to better understand the interactions between epithelial cells and the immune system in tissue development, homeostasis, infection and cancer.

Ludewig and colleagues use fate-mapping reporter cells, single-cell RNA-seq analysis and high-resolution microscopy to identify and track the spatial reorganization of follicular reticular cells within germinal centers during the course of an immune response.

Peyer’s patches (PPs) are sites of antibody production in the gut mucosa. Carroll and colleagues show the mechanosensory channel protein Piezo1 is required for the homeostatic maintenance of PPs. Specific loss of Piezo1 in FRCs disrupt PP structure and function, resulting in reduction of fecal IgA production and gut immunity.

Single-cell and genetic tools are used to characterize the diversity of fibroblasts across healthy and perturbed tissues in mice and humans.

Fibroblastic reticular cells (FRCs) provide structural support and soluble factors necessary for proper lymph node organization and function. Turley and colleagues use scRNA-seq to identify a unique Gremlin1-expressing FRC subset that is found in T cell zones. Grem1⁺ FRCs support the survival of resident cDCs and are necessary to promote T cell immunity.

Monocyte-derived sphingosine 1-phosphate gradients in the lymph nodes regulate the response of T cells under inflammatory conditions.

Kollias and colleagues examine the development of fibroblastic reticular cells (FRCs) during lymphoid organogenesis in gut Peyer’s patches (PPs). They show that PP FRCs develop from two separate mesenchymal cell lineages, which converge and form mosaic microenvironments that support immune cell activation and maintain intestinal homeostasis.

Fibroblasts are not just crucial structural cells; they exist as multiple functionally diverse populations, defined by their location and context, and regulate tissue immunity. Here, the authors review the immunological properties of fibroblasts, comprising both pro-inflammatory and immunosuppressive activities, in different tissues and disease states.

Visceral adipose tissue contains populations of regulatory T cells that exhibit sexual dimorphism, determined by the surrounding niche, and differ between male and female mice in terms of cell number, phenotype, transcriptional landscape and chromatin accessibility.

NOTCH3 signalling is shown to be the underlying driver of the differentiation and expansion of a subset of synovial fibroblasts implicated in the pathogenesis of rheumatoid arthritis.

Single-cell RNA-sequencing analysis of intestinal mesenchyme identified a population of fibroblasts that produce prostaglandin E₂, which, when disrupted, prevented initiation of intestinal tumours.

Recent studies using single-cell genomic technologies and in vivo fate mapping have shown that thymic epithelial cells are far more heterogeneous than previously thought, comprising multiple subpopulations with distinct molecular and functional characteristics.

Grosschedl and colleagues identify a role for the transcription factor EBF1 in bone marrow stromal cells that is required to maintain the niche to support hematopoietic stem cells and hematopoiesis.

PIC-seq characterizes cellular crosstalk by sorting and sequencing physically interacting cells.

Ageing of the haematopoietic system is accompanied by declining erythropoiesis and lymphopoiesis. Here the authors uncover upregulated IL-6 and TGFβ signalling in aged bone marrow stroma; inhibition of these signals reverses age-related haematopoietic defects, re-balancing haematopoietic stem cell lineage output.

Thymus is a unique environment hosting the development of many T cell subsets with distinct functions. Here the authors show that medullary thymic epithelial cells (mTEC) are functionally diverse, with LTβR signaling serving differential regulation of mTEC for specific control of multiple lineages of invariant natural killer T cells.

In this Review, Batsivari et al. discuss how cells in the bone marrow respond to inflammation, infection, leukaemia and chemotherapy.

Fibroblast-like synoviocytes in rheumatoid arthritis have an aggressive phenotype caused, in part, by epigenetic imprinting, which contributes to various pathological processes. Understanding the mechanisms underlying the cell abnormalities and phenotypes, including their spatial and temporal differences, could lead to new therapies.

Fibroblastic reticular cells (FRCs) are dynamic regulators of lymphoid tissue structure. Turley and colleagues show FRCs also support activated T cells by producing IL-6, which confers an advantage to CD8+ T cell memory responses.

The transcriptional landscape of cell populations of the mouse bone marrow microenvironment, mapped at single-cell resolution, reveals cellular heterogeneity in this niche as well as substantial transcriptional remodelling under stress conditions.

Distinct subsets of fibroblasts, which differ in their expression of thymus cell antigen 1 (THY1), are responsible for inflammation and tissue damage in mouse models of arthritis.

The authors find that stromal methyltransferase nicotinamide N-methyltransferase (NNMT) regulates the transition of normal fibroblasts to cancer-associated fibroblasts through histone methylation and promotes ovarian cancer growth and metastasis.

Saçma, Pospiech and co-workers show that sinusoidal niches are uniquely preserved on ageing, that they are the predominant niche for label-retaining (LR)-HSCs in aged mice and display higher reconstitution capacity compared with non-LR HSCs.

Janiszewska et al. show that minor subpopulations expressing IL11 and FIGF in breast cancer cells promote metastasis through altering local and systemic tumour microenvironments including neutrophils.

In addition to cancer cell-intrinsic effects, tumour growth can be regulated by cellular and molecular cues from the local tissue environment. This Review discusses how differences in cellular components and composition between tissue sites may influence the antitumour immune response, with potential implications for the design of therapeutic strategies.

The haematopoietic stem cell (HSC) niche in the bone marrow ensures haematopoiesis by regulating the function of HSCs and progenitor cells. An improved understanding of this regulation in homeostasis, ageing and cancer should aid the development of therapies to rejuvenate aged HSCs or niches and treat malignancies.

Tuft cells captured the attention of immunologists with recent discoveries linking them to type 2 immunity in the small intestine. As described here, these rare secretory epithelial cells act as chemosensory sentinels that detect and relay responses through immune and neuronal cells.