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

Abstract

The immune system combats invading pathogens with a broad cellular and molecular arsenal. Integral to this defence are secondary lymphoid organs (SLOs). It has been increasingly recognized in recent years that the non-haematopoietic stromal cells that make up much of the structure of the SLOs have many important roles in immune responses. The spleen and lymph nodes have a complex microarchitecture. Lymph nodes have B cell follicles and T cell zones in the cortex and networks of specialized blood and lymphatic vessels that wind through the organ. The spleen consists of B cell follicles and T cell zones in the white pulp surrounding central arterioles, around which is a marginal zone separating the lymphoid compartments from the red pulp. Heterogeneous populations of non-haematopoietic stromal cells are present and occupy distinct locations in SLOs. These include fibroblastic reticular cells (FRCs), follicular dendritic cells (FDCs), marginal reticular cells (MRCs), red pulp fibroblasts, lymph node medullary fibroblasts, vascular endothelial cells (including high endothelial venules in lymph nodes) and lymphatic endothelial cells. SLO stromal cells (in particular FRCs and FDCs) produce chemokines that are crucial for the migration of B and T cells into and within SLOs. Subsets of SLO stromal cells interact with antigen-presenting cells, in particular DCs. Interactions between DCs and stromal cells, and the chemokines produced by both cell types, help to induce and shape immune responses. Stromal cell subsets in SLOs are also involved in the homeostasis of lymphocytes through the production of CC-chemokine ligand 19 and interleukin-7 (by FRCs) or B cell activating factor (by FDCs). Certain SLO stromal cells also contribute to tolerance induction rather than the induction of active immune responses by expressing autoimmune regulator (AIRE). Regulation of SLO stromal cell function during inflammation can control immune responses through changes in chemokine production and cellular input or output from the tissues. Numerous pathogens target SLO stromal cells through direct infection of these cells or indirect changes to stromal cell function. This has important consequences for SLO function and immunity.