Stromal cell contributions to the homeostasis and functionality of the immune system

Abstract

A defining characteristic of the immune system is the constant movement of many of its constituent cells through the secondary lymphoid tissues, mainly the spleen and lymph nodes, where crucial interactions that underlie homeostatic regulation, peripheral tolerance and the effective development of adaptive immune responses take place. What has only recently been recognized is the role that non-haematopoietic stromal elements have in many aspects of immune cell migration, activation and survival. In this Review, we summarize our current understanding of lymphoid compartment stromal cells, examine their possible heterogeneity, discuss how these cells contribute to immune homeostasis and the efficient initiation of adaptive immune responses, and highlight how targeting of these elements by some pathogens can influence the host immune response.

Figure 1. Organized architecture of the spleen

Schematic representation of the organization of the spleen (left panel). The white pulp consists of T cell zones (also known as the periarteriolar lymphoid sheath (PALS)) containing networks of fibroblastic reticular cells (FRC) surrounding a central arteriole, together with B cell follicles containing a central network of follicular dendritic cells (FDC). Marginal zones (MZ) surrounding the white pulp contain marginal reticular cells (MRC), particularly at the edges of the B cell follicles. Blood and leukocytes entering the spleen pass through branches of the central arteriole, which end in the marginal sinuses and red pulp. In the cords of the red pulp, a dense network of reticular fibroblasts and fibres construct an open blood network, which is marked by its lack of a typical endothelial cell lining. Large numbers of macrophages phagocytose dying or damaged red blood cells in the red pulp (not shown). Immune cells enter the white pulp at regions where the T cell zones abut the MZ, known as the MZ bridging channels. An image of a section of mouse spleen generated using multicolour immunofluoresence microscopy illustrates the organization of the white pulp, red pulp, and MZ (centre panel). The distribution of CD3⁺ T cells (white), B220⁺ B cells (blue), CD169⁺ MZ macrophages (cyan), CD11c⁺ dendritic cells (DCs) (green), and ER-TR7⁺ stromal cells (red) is shown. The distinct organization of stromal cells in different regions of the spleen is shown by single-colour immunofluoresence staining (right panel). Networks of stromal cells and reticular fibres form in the white pulp, including the fibroblastic reticular cells (FRCs) in T cell zones, follicular dendritic cells (FDCs) in B cell follicles (ER-TR7⁻) and marginal reticular cells (MRCs) in the MZ. A dense network of stromal cells and reticular fibres is present in the red pulp. Scale bars represent 130 μM.

Figure 2. Organized architecture of lymph nodes

Schematic representation of the organization of a lymph node (left panel). Afferent lymphatics enter lymph nodes and deliver lymph to the subcapsular sinus (SCS), which forms a channel around the periphery of the lymph node. Lymphatic sinuses run from the SCS through the cortex to the medulla, and exit the lymph node via efferent lymphatic vessels on the opposite, hilar, side of the organ. B cell follicles containing follicular dendritic cell (FDC) networks are arranged in the lymph node cortex and are separated from the SCS by a layer of marginal reticular cells (MRC). The T cells zones in the paracortex, which contain many fibroblastic reticular cells (FRC), are separated by the cortical ridge, an area rich in T cells, dendritic cells (DCs), blood vessels, and FRC. Blood vessels enter and exit the lymph node on the hilar side, and snake through the lymph node like the branches of a tree. Specialized high endothelial venules (HEVs) in the paracortex and cortical ridge allow entry of leukocytes from the blood. An image of a mouse popliteal lymph node generated using multi-colour immunofluoresence microscopy illustrates the distribution of CD3⁺ T cells (white), B220⁺ B cells (blue), CD11c⁺ DCs (green), LYVE1⁺ (Lymphatic Vessel Endothelial Receptor 1) lymphatics (cyan), PNAd⁺ (peripheral node addressin) HEVs (yellow), and ER-TR7⁺ stromal cells (red) (centre panel). The organization of stromal cells in the lymph node is shown by single-colour immunofluoresence staining for ER-TR7 (right panel). Scale bars represent 200 μM.