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  • Review Article
  • Published:

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

Key Points

  • 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.

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.

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Figure 1: Organized architecture of the spleen.
Figure 2: Organized architecture of the lymph nodes.
Figure 3: Lymphocyte migration on stromal networks in secondary lymphoid organs.

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Acknowledgements

The authors thank I. Ifrim for invaluable assistance with immunohistochemistry to generate the images in the figures, A. O. Anderson, J. Egen and W. Kastenmüller for helpful comments on the manuscript and R. Ahmed for support. The authors were supported by the Intramural Research Program of the US National Institutes of Health, National Institute of Allergy and Infectious Diseases and grant AI30048 (to S.N.M.).

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Supplementary information

Supplementary information S1 (figure)

Stromal cell populations in the spleen. (PDF 362 kb)

Supplementary information S2 (table)

Stromal cell subsets in secondary lymphoid organs (PDF 110 kb)

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Glossary

Primary and secondary lymphoid tissues

The primary lymphoid organs are the bone marrow and thymus, which are involved in the development of mature B and T cells, respectively. The secondary lymphoid organs, including the spleen, lymph nodes and mucosa-associated lymphoid tissues, assist in the induction of immune responses by capturing and presenting antigens and facilitating interactions between cells of the innate and adaptive immune systems.

Multi-photon laser scanning microscopy

A fluorescence imaging technique that makes use of the fact that fluorescent molecules can absorb two photons nearly simultaneously during excitation before they emit light. This technique uses infrared lasers that reduce heat damage and light scattering and facilitate imaging deeper into tissues, allowing the study of cellular interactions in real time.

Peyer's patches

Groups of lymphoid nodules present in the small intestine (usually the ileum). They occur massed together on the intestinal wall, opposite the line of attachment of the mesentery. Peyer's patches consist of a dome area, B cell follicles and interfollicular T cell zones. High endothelial venules are present mainly in the interfollicular areas.

High endothelial venule

(HEV). A specialized venule that occurs in secondary lymphoid organs, except the spleen. HEVs allow continuous transmigration of lymphocytes as a consequence of the constitutive expression of adhesion molecules and chemokines at their luminal surface.

Follicular T helper cell

A CD4+ T helper cell that is essential for B cell antibody class switching, which localizes to B cell follicles during immune responses.

plt/plt mice

A mouse mutation that leads to loss of expression of the chemokines CC-chemokine ligand 19 (CCL19) and CCL21 in lymphoid organs, resulting in altered lymphoid architecture and migration of T cells and mature dendritic cells expressing CC-chemokine receptor 7.

Autoimmune regulator

(AIRE). A transcription factor expressed mainly in the thymus by medullary thymic epithelial cells. It is involved in the transcription of diverse tissue-specific antigens that, once processed and presented, promote the negative selection of self-reactive T cells.

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Mueller, S., Germain, R. Stromal cell contributions to the homeostasis and functionality of the immune system. Nat Rev Immunol 9, 618–629 (2009). https://doi.org/10.1038/nri2588

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